Chapter 046. Sodium and Water (Part 6) Hyponatremia in the setting of ECF volume expansion is usually associated with edematous states, such as congestive heart failure, hepatic cirrhosis, and the nephrotic syndrome. These disorders all have in common a decreased effective circulating arterial volume, leading to increased thirst and increased AVP levels. Additional factors impairing the excretion of solute-free water include a reduced GFR, decreased delivery of ultrafiltrate to the diluting site (due to increased proximal fractional reabsorption of Na + and water), and diuretic therapy. The degree of hyponatremia often correlates with the severity of the underlying condition and is an important prognostic factor. Oliguric acute and chronic renal failure may be associated with hyponatremia if water intake exceeds the ability to excrete equivalent volumes. Hyponatremia in the absence of ECF volume contraction, decreased effective circulating arterial volume, or renal insufficiency is usually due to increased AVP secretion resulting in impaired water excretion. Ingestion or administration of water is also required since high levels of AVP alone are usually insufficient to produce hyponatremia. This disorder, commonly termed the syndrome of inappropriate antidiuretic hormone secretion (SIADH), is the most common cause of normovolemic hyponatremia and is due to the nonphysiologic release of AVP from the posterior pituitary or an ectopic source (Chap. 334). Renal free-water excretion is impaired while the regulation of Na + balance is unaffected. The most common causes of SIADH include neuropsychiatric and pulmonary diseases, malignant tumors, major surgery (postoperative pain), and pharmacologic agents. Severe pain and nausea are physiologic stimuli of AVP secretion; these stimuli are inappropriate in the absence of hypovolemia or hyperosmolality. The pattern of AVP secretion can be used to classify SIADH into four subtypes: (1) erratic autonomous AVP secretion (ectopic production); (2) normal regulation of AVP release around a lower osmolality set point or reset osmostat (cachexia, malnutrition); (3) normal AVP response to hypertonicity with failure to suppress completely at low osmolality (incomplete pituitary stalk section); and (4) normal AVP secretion with increased sensitivity to its actions or secretion of some other antidiuretic factor (rare). Patients with the nephrogenic syndrome of inappropriate antidiuresis have clinical and laboratory features consistent with SIADH but undetectable levels of AVP. It is hypothesized that this disorder is due to gain of function mutations in the V2 receptor. Hormonal excess or deficiency may cause hyponatremia. Adrenal insufficiency (Chap. 336) and hypothyroidism (Chap. 335) may present with hyponatremia and should not be confused with SIADH. Although decreased mineralocorticoids may contribute to the hyponatremia of adrenal insufficiency, it is the cortisol deficiency that leads to hypersecretion of AVP both indirectly (secondary to volume depletion) and directly (cosecreted with corticotropin- releasing factor). The mechanisms by which hypothyroidism leads to hyponatremia include decreased cardiac output and GFR and increased AVP secretion in response to hemodynamic stimuli. Finally, hyponatremia may occur in the absence of AVP or renal failure if the kidney is unable to excrete the dietary water load. In psychogenic or primary polydipsia, compulsive water consumption may overwhelm the normally large renal excretory capacity of 12 L/d (Chap. 334). These patients often have psychiatric illnesses and may be taking medications, such as phenothiazines, that enhance the sensation of thirst by causing a dry mouth. The maximal urine output is a function of the minimum urine osmolality achievable and the mandatory solute excretion. Metabolism of a normal diet generates about 600 mosmol/d, and the minimum urine osmolality in humans is 50 mosmol/kg. Therefore, the maximum daily urine output will be about 12 L (600 ÷ 50 = 12). A solute excretion rate of greater than ~750 mosmol/d is, by definition, an osmotic diuresis. A low-protein diet may yield as few as 250 mosmol/d, which translates into a maximal urine output of 5 L/d at a minimum urine tonicity of 50 mosmol/kg. Beer drinkers typically have a poor dietary intake of protein and electrolytes and consume large volumes (of beer), which may exceed the renal excretory capacity and result in hyponatremia. This phenomenon is referred to as beer potomania. Clinical Features The clinical manifestations of hyponatremia are related to osmotic water shift leading to increased ICF volume, specifically brain cell swelling or cerebral edema. Therefore the symptoms are primarily neurologic, and their severity is dependent on the rapidity of onset and absolute decrease in plasma Na + concentration. Patients may be asymptomatic or complain of nausea and malaise. As the plasma Na + concentration falls, the symptoms progress to include headache, lethargy, confusion, and obtundation. Stupor, seizures, and coma do not usually occur unless the plasma Na + concentration falls acutely below 120 mmol/L or decreases rapidly. As described above, adaptive mechanisms designed to protect cell volume occur in chronic hyponatremia. Loss of Na + and K + , followed by organic osmolytes, from brain cells decreases brain swelling due to secondary transcellular water shifts (from ICF to ECF). The net effect is to minimize cerebral edema and its symptoms. . Chapter 046. Sodium and Water (Part 6) Hyponatremia in the setting of ECF volume expansion is usually associated. of solute-free water include a reduced GFR, decreased delivery of ultrafiltrate to the diluting site (due to increased proximal fractional reabsorption of Na + and water) , and diuretic therapy severity of the underlying condition and is an important prognostic factor. Oliguric acute and chronic renal failure may be associated with hyponatremia if water intake exceeds the ability to