A fall in effective perfusion pressure stimulates release of ADH [3]. Hypovolemic hyponatremia can occur in states of volume depletion or in edematous individuals with congestive heart failure (CHF) or advanced liver disease because each of these conditions is associated with a reduced effective arterial blood volume. As discussed previously, the resulting increase in the U_Osm (e.g., to 600 mOsm per kg) would limit renal water excretion on a 900 mOsm per day diet to 1.5 L, assuming all of the ingested solute were excreted (900 mOsm per kg 600). Solute excretion tends to be reduced in these settings, which are characterized by enhanced tubular salt reabsorption. In addition, most stimuli that activate angiotensin II release also stimulate thirst and lead to increased water ingestion, despite concurrent hypoosmolality.

The ability to excrete a dilute urine is impaired by diuretics, whether they act in the thick ascending limb of Henle (loop diuretics) or in the distal tubule (thiazide-type diuretics) (Fig. 72.2). Each class reduces salt transport out of the diluting segment, thus raising the minimum achievable U_Osm. Raising the minimum U_Osm, however, does not usually lead to hyponatremia because a large volume of urine can still be excreted by most patients.

Almost all cases of diuretic-induced hyponatremia in otherwise healthy individuals have been caused by thiazide-type, rather than loop, diuretics [4]. This observation is attributable, in part, to different sites of the action within the renal tubule (Fig. 72.2). Loop diuretics, which act in the outer medulla, reduce the solute concentration in the renal medullary interstitium. Although ADH permits water reabsorption from the collecting tubule, medullary osmolality drives the process. A fall in the interstitial osmolality from 1,200 to 300 mOsm per kg, for instance, would limit the maximum U_Osm that can be generated from 1,200 to 300 mOsm per kg. By comparison, thiazide diuretics, which act in the cortex, impair diluting capacity but have a lesser effect on concentrating ability. Thus, the U_Osm may be 600 mOsm per kg in the thiazide-treated individual; if the urinary osmoles are primarily NaCl and KCl, urinary electrolyte losses can exceed those contained in an equal volume of plasma. In these patients, therefore, the plasma Na⁺ may actually fall in the absence of ongoing water intake. For reasons that are not well understood, however, most individuals with thiazide-induced hyponatremia gain weight, indicating that the hyponatremia is at least in part a result of increased water intake [4]. This disorder occurs more frequently in women, typically occurs early in therapy (within 1 to 4 weeks), and is more likely to be observed in elderly individuals [5]. As discussed previously, accompanying hypokalemia also may contribute to the fall in P_Osm.

The normal glomerular filtration rate (GFR) is approximately 180 L per day. As renal function decreases, the ability to excrete water also decreases. The limitation in water excretion occurs for two reasons: tubular dysfunction leads to an inability to dilute the urine maximally, even in the absence of ADH, and the drop in GFR, particularly when severe, reduces daily solute excretion.

Hypothyroidism and hypocortisolism can impair water excretion. Both may reduce cardiac output or
stroke volume, leading to increased ADH release. The resulting fall in GFR adversely affects free water excretion by diminishing delivery of filtrate to the diluting segments. Decreased delivery may be particularly important in patients with myxedema in whom hyponatremia may develop despite appropriate suppression of ADH release [6].

Another factor contributing to the hyponatremia of hypocortisolism is that corticotropin-releasing factor promotes the corelease of adrenocorticotropic hormone (ACTH) and ADH, although the reason for the concomitant release of these hormones is not known [7]. It is important to note that adrenocortical dysfunction (as in Addison’s disease) leads to reduced cortisol and aldosterone levels, the latter predisposing to hyperkalemia. The presence of a low cortisol level alone, due to either pituitary or hypothalamic disease, or the abrupt withdrawal from prolonged exogenous corticosteroid administration may cause hyponatremia but should not alter potassium homeostasis, because aldosterone release is normal.

The syndrome of inappropriate ADH secretion (SIADH) is characterized by the following: plasma hypoosmolality; U_Osm more than 100 to 150 mOsm per kg (because ADH should be absent in the hypoosmolar state); urinary Na⁺ concentration of more than 20 mEq per L, reflecting normal renal perfusion; normal adrenal, renal, and thyroid function; and normal potassium and acid–base balance. The U_Osm does not need to exceed the P_Osm to make this diagnosis. SIADH may be caused by enhanced hypothalamic ADH secretion, ectopic hormone production (usually by cancer), or administration of medications with ADH activity (Table 72.2).

In approximately one third of patients, the SIADH is associated with resetting of the hypothalamic osmostat. This disorder has been described in patients with hypovolemia, psychosis, and chronic malnutrition and in normal pregnancy (in which the plasma Na⁺ concentration decreases by the second trimester from 140 to 135 mEq per L). ADH release is not suppressed until the P_Osm falls well below normal in this disorder. As a result, the P_Osm may vary between 240 and 250 mOsm per kg (plasma Na⁺ approximately 120 to 125 mEq per L), compared with the normal value of approximately 285 to 292 mOsm per kg. In contrast to the classic form of the SIADH, in which nonsuppressible ADH release is seen, ADH secretion ceases when the P_Osm falls below this new, reset level. Because suppression of ADH prevents a further fall in the plasma Na⁺ concentration, the severity of hyponatremia is limited in this condition.

An increasingly common cause of hyponatremia is symptomatic human immunodeficiency virus (HIV) infection [8]. Although hyponatremia in HIV-infected patients may result from volume deficiency or adrenal insufficiency, many patients have SIADH. Pneumonia due to Pneumocystis jiroveci or other organisms, central nervous system infections, and malignant disease are most often responsible in this setting.

Elevated ADH levels have been reported with the use of medications and various recreational drugs. The association of hyponatremia with the use of 3,4-methylenedioxymethamphetamine (Ecstasy) has been reported. The cause has been reported to be related to increased water drinking and the inappropriate presence of ADH [2]. Similar effects may be seen with the commonly prescribed selective serotonin reuptake inhibitors (SSRIs) used for the treatment of depression [9].

Cerebral salt wasting is a rare disorder characterized by a low P_Osm, a U_Osm above 100 to 150 mOsm per kg, and a urine Na⁺ concentration greater than 20 mEq per L [10]. Unlike SIADH, however, evidence of volume depletion (including low central filling pressures) is present. In affected individuals, therefore, the high urinary Na⁺ represents inappropriate salt wasting rather than a response to normal tissue perfusion (as in SIADH patients).

The cause of this putative syndrome is unclear. It has been proposed that there may be increased release of natriuretic peptide from hormone-producing neurons in the brain that are activated by central nervous system dysfunction [11]. Both hypouricemia and renal tubular dysfunction have been reported. Mineralocorticoid replacement therapy with fludrocortisone acetate has been effective in some patients.

As discussed previously, a reduction in salt and protein intake can lead to hypoosmolality if water intake exceeds output. Severely reduced solute intake, as occurs with a tea-and-toast diet, can cause hyponatremia even with normal degrees of water intake. “Beer drinkers’ hyponatremia” occurs for a similar reason; the limited amount of solute in beer relative to its water content may be inadequate to permit excretion of the ingested water. In both conditions, the U_Osm should be maximally dilute (U_Osm < 100 mOsm per kg). The absence of polyuria and the development of hyponatremia with normal or slightly above normal fluid intake distinguish these
individuals from those with primary polydipsia (see following discussion).

Psychiatric patients, particularly those with schizophrenia, often have abnormalities in water balance. Evaluation of psychotic patients has revealed that a variety of defects in water handling can occur that affect thirst, the release of ADH, and the renal response to ADH. Depending on the abnormality that is present, the patient may present with polydipsia and polyuria or hyponatremia.

Hyponatremia has been reported in as many as 13% of marathon runners and may occasionally be fatal. Although the exact mechanism has not been elucidated, risk factors for developing low serum sodium levels include weight gain during the race, female sex, racing time, and lower body mass index [12].

These individuals may have psychiatric disorders or may intentionally drink large volumes of water for social (dietary) or health reasons. This may be manifested clinically by exaggerated weight gain during the day associated with a transient reduction in the plasma sodium concentration [13].

In some individuals, a central defect in thirst regulation plays an important role in the pathogenesis of polydipsia. For example, the osmotic threshold for thirst may be reduced below the threshold for the release of ADH [14]. These patients continue to drink until the P_Osm is less than the threshold level. This implies truly prodigious water intake, as ADH secretion is suppressed by the fall in P_Osm, resulting in rapid excretion of the excess water and continued stimulation of thirst. The osmotic regulation of thirst differs from that of healthy subjects, in whom the thirst threshold is roughly equal to or a few milliosmoles per kilogram higher than the threshold for ADH [15]. The mechanism responsible for abnormal thirst regulation in this setting is unclear [16]. Drug therapy may contribute to the increase in water intake if the medication induces the sensation of a dry mouth.

Because people with normally functioning kidneys and regulation of ADH secretion are capable of excreting more than 10 to 15 L of urine per day, hyponatremia due to polydipsia is unusual. Despite this, there are rare patients in whom severe, and potentially fatal, hyponatremia has developed even though the U_Osm was appropriately dilute. More commonly, however, polydipsic patients manifesting hyponatremia have a concurrent abnormality in ADH release or response [17]. Concurrent thiazide diuretic therapy for systemic hypertension can lead to a marked and symptomatic reduction in the plasma sodium concentration in these patients.

There is no proven specific therapy for primary polydipsia with or without hyponatremia in psychotic patients. Limiting water intake rapidly raises the plasma sodium concentration because the excess water is readily excreted in a dilute urine. The risk of inducing osmotic demyelination (see later) in this setting is unclear; it has been suggested that patients with primary polydipsia and repeated episodes of acute hyponatremia are generally resistant to neurologic injury induced by rapid correction (see following discussion).

Over time, limiting the use of drugs that cause dry mouth, restricting fluid intake, and frequent weighing (to detect water retention) may be helpful. Antagonists to ADH are not likely to be useful if the urine is already maximally dilute but may help in patients with primary polydipsia and concomitant SIADH.

Hyponatremia in SIADH results primarily from ADH-induced retention of ingested water. Appropriate therapy in this disorder depends on the severity of the hyponatremia and on the fact that, although water excretion is impaired, sodium handling is intact because there is no abnormality in volume-regulating mechanisms such as the renin–angiotensin–aldosterone system. Water restriction is the mainstay of therapy in asymptomatic hyponatremia of chronic SIADH. The associated negative water balance raises the plasma sodium concentration toward normal.

Severe, symptomatic, or resistant hyponatremia often requires the administration of salt. If the plasma sodium concentration is to be elevated, the osmolality of the fluid given must exceed that of the urine. This can be illustrated by a simple example (Table 72.3). Suppose a patient with SIADH and hyponatremia has a U_Osm that cannot be reduced below 616 mOsm per kg. If 1,000 mL of isotonic saline is given (containing 154 mEq each of Na and Cl or 308 mOsm), all of the salt is excreted (because sodium handling is intact), but in only 500 mL of water (308 mOsm in 500 mL of water equals 616 mOsm per kg). The retention of half of the administered water leads to a further reduction in the plasma sodium concentration. As a result, correction of the hyponatremia in these cases requires the administration of hypertonic 3% saline intravenously or salt tablets orally, preferably in combination with a drug that lowers the U_Osm and increases water excretion by impairing the renal responsiveness to ADH. A loop diuretic is most often used for this purpose.

Demeclocycline and lithium act on the collecting tubule cell to diminish its responsiveness to ADH, thereby increasing water excretion. These drugs tend to be too toxic or ineffective in most patients. Specific antagonists to the ADH-V₂ (antidiuretic) receptor in the cortical collecting tubule have shown promise and two have now been approved for clinical use. Two of these have been approved by the Food and Drug Administration (FDA) at the time of this writing.

Conivaptan, an antagonist to both the V₁ (vascular) and V₂ (ADH) receptors, was the first. It must be given intravenously in the hospital and has the propensity to cause phlebitis. Recent data suggest that a single 20 mg bolus intravenously over 30 minutes results in a sustained water diuresis and may avoid vascular injury. It is not suitable for chronic use. Tolvaptan is an oral ADH antagonist which is specific for the V₂ receptor. It must also be initiated in the hospital but can be administered in the outpatient setting after that. Tolvaptan has been shown to decrease body weight in chronic heart failure patients in a single controlled study [36].

The choice of initial therapy in symptomatic patients is usually 3% saline and this is the preferred treatment with severe neuropathology (such as seizures). In less symptomatic individuals, a vaptan may be effective. However, as there are no controlled prospective studies comparing hypertonic saline with the vaptans, it is difficult to recommend the latter in the SIADH as first-line agents, particularly when cost is considered. When they are administered, it is important to relax fluid restriction during the initial titration with these agents to avoid an excessive rise in the serum sodium concentration.

Hyponatremia due to a reset osmostat may occur in association with any of the causes of SIADH and accounts for between 25% and 30% of cases overall. Downward resetting of the osmostat can also occur in hypovolemic states in which the baroreceptor stimulus to ADH release is superimposed on osmoreceptor function; quadriplegia, in which effective volume depletion may result from venous pooling in the legs; psychosis; tuberculosis; and chronic malnutrition. The plasma sodium concentration also falls by approximately 5 mEq per L in normal pregnancy. How this occurs is incompletely understood, but human chorionic gonadotropin may play an important role [37].

The presence of a reset osmostat should be suspected in any patient with apparent SIADH who has mild hyponatremia (usually between 125 and 135 mEq per L) that is stable over many days despite variations in sodium and water intake. The diagnosis can be confirmed clinically by observing the response to a water load (10 to 15 mL per kg given orally or intravenously during 30 minutes). Healthy subjects and those with a reset osmostat should excrete more than 80% within 4 hours, whereas excretion is impaired in classic SIADH.

Identification of a reset osmostat is important because the therapeutic recommendations for SIADH discussed here do not apply in this setting. These patients generally have mild, asymptomatic hyponatremia due to downward resetting of the threshold for both ADH release and thirst. Because osmoregulatory function is normal around the new baseline, attempting to raise the plasma sodium concentration increases ADH levels and makes the patient very thirsty, a response that is similar to that seen with water restriction in healthy subjects. Thus, efforts to raise the plasma sodium concentration are both unnecessary and likely to be ineffective. Treatment should be primarily directed at the underlying disease.

Raising the plasma sodium concentration in patients with edema may be more difficult than in those conditions described earlier. Most of these individuals have advanced CHF or liver disease. Consequently, sodium administration is generally contraindicated.

Restricting water intake is the mainstay of therapy in hyponatremic patients with heart failure, although this is often not tolerable because of the intense stimulation of thirst. The combination of an angiotensin-converting enzyme (ACE) inhibitor (or angiotensin receptor blocker [ARB]) and a loop diuretic may induce an elevation in the plasma sodium concentration [38,39]. Tolvaptan may be useful in some patients (see above) but must be initiated in the hospital. Conivaptan is not indicated for treatment of hyponatremia in this setting.