ETIOLOGY OF HYPONATREMIA

The serum Na+ concentration is determined by the body's content of sodium, potassium, and TBW. Thus:

This formula has been simplified from the observations made by Edelman in the 1950s. This simplification introduces some errors in the prediction of changes in serum sodium based on the previous formula and has been subject of some reinterpretation by Nguyen and Kurtz.[263] Whereas their revision of the formula is more accurate, as pointed out by Sterns, there are so many inaccuracies in the measurements of sodium, potassium, and water losses as well as intake that there is no substitute for frequent measurements of serum sodium concentration in rapidly changing clinical settings.[264]

As the previous relationship depicts, hyponatremia can therefore occur by an increase in TBW, a decrease in body solutes (either Na+ or K+), or any combination of these. In most cases, more than one of these mechanisms is operant. Therefore, an alternative approach is presented here. In approaching the hyponatremic patient, the physician's first task is to ensure that hyponatremia in fact reflects a hypo-osmotic state and is not a consequence of the causes of pseudohyponatremia or translocational hyponatremia, discussed earlier. Thereafter, an assessment of ECF volume provides a useful working classification of hyponatremia as it can be associated with decreased, normal, or high total body sodium [265] [266]: (1) hyponatremia with ECF volume depletion, (2) hyponatremia with excess ECF volume, and (3) hyponatremia with normal ECF volume.

Hyponatremia with Extracellular Fluid Volume Depletion

Patients with hyponatremia who have ECF volume depletion have sustained a deficit in total body Na+ that exceeds the deficit in water. The decrease in ECF volume is manifested by physical findings such as flat neck veins, decreased skin turgor, dry mucous membranes, orthostatic hypotension, and tachycardia.

If sufficiently severe, volume depletion is a potent stimulus to AVP release. When the osmoreceptor and volume receptor receive opposing stimuli, the former remains fully active but the set-point of the system is lowered. Thus, in the presence of hypovolemia, AVP is secreted and water is retained despite hypo-osmolality. Whereas the hyponatremia in this setting clearly involves a depletion of body solutes, a concomitant failure to excrete water is critical to the process.

As shown in Figure 13-17 , an examination of the urinary Na+ concentration is helpful in assessing whether the fluid losses are renal or extrarenal in origin. A urinary Na+ concentration of less than 20 mEq/L reflects a normal renal response to volume depletion and points to an extrarenal source of fluid loss. This is most commonly seen in patients with gastrointestinal disease with vomiting or diarrhea. Other causes include loss of fluid into the third space, such as the abdominal cavity in pancreatitis or the bowel lumen with ileus. Burns and muscle trauma can also be associated with large fluid and electrolyte losses. Because many of these pathologic states are associated with thirst, an increase in either orally or parenterally taken free water leads to hyponatremia. Hypovolemic hyponatremia in patients

whose urinary Na+ concentration is greater than 20 mEq/L points to the kidney as the source of the fluid losses.

Diuretic-induced hyponatremia, a commonly observed clinical entity, accounts for a significant proportion of symptomatic hyponatremia in hospitalized patients. It occurs almost exclusively with thiazide rather than loop diuretics, most likely because the former have no effect on urine concentrating ability but the latter do. The hyponatremia is usually evident within 14 days but can occur up to 2 years later in most patients.[267] Underweight women appear to be particularly prone to this complication,[268] and advanced age has been found to be a risk factor in some, [267] [269] but not all,[268] studies. A careful study on diluting ability in the elderly revealed that thiazide diuretics exaggerate the already slower recovery from hyponatremia induced by water ingestion in this population.[270] Diuretics can cause hyponatremia by a variety of mechanisms[271]: (1) volume depletion, which results in impaired water excretion by both enhanced AVP release and decreased fluid delivery to the diluting segment; (2) a direct effect of diuretics on the diluting segment; and (3) K+ depletion causing a decrease in the water permeability of the collecting duct as well as an increase in water intake. K+ depletion leads to hyponatremia independent of the Na+ depletion that frequently accompanies diuretic use.[272] The concomitant administration of K+-sparing diuretics does not prevent the development of hyponatremia. Although the diagnosis of diuretic-induced hyponatremia is frequently obvious, surreptitious diuretic abuse is being increasingly recognized and should be considered in patients in whom other electrolyte abnormalities and high urinary Cl- excretion suggest this possibility.

Salt-losing nephropathy occurs in some patients with advanced renal insufficiency. In the majority of these patients, the Na+-wasting tendency is not one that manifests itself at normal rates of sodium intake; however, some patients with interstitial nephropathy, medullary cystic disease, polycystic kidney disease, or partial urinary obstruction with sufficient Na+ wasting exhibit hypovolemic hyponatremia.[273] Patients with proximal renal tubular acidosis exhibit renal sodium and potassium wasting despite modest renal insufficiency because bicarbonaturia obligates these cation losses.

It has long been recognized that adrenal insufficiency is associated with impaired renal water excretion and hyponatremia. This diagnosis should be considered in the volume-contracted hyponatremic patient whose urinary Na+ concentration is not low, particularly when the serum K+, BUN, and creatinine levels are elevated. Separate mechanisms for mineralocorticoid and glucocorticoid deficiency have been defined.[274]

Observations in glucocorticoid-replete adrenalectomized experimental animals provide evidence to support a role of mineralocorticoid deficiency in the abnormal water excretion, as both AVP release and intrarenal factors appear to be causal mechanisms. Thus, conscious adrenalectomized dogs given physiologic doses of glucocorticoids develop hyponatremia. Either saline or physiologic doses of mineralocorticoids corrected the defect in association with both ECF volume repletion and improvement in renal hemodynamics. Immunoassayable AVP levels were elevated in a similarly treated group of mineralocorticoid-deficient dogs despite hypo-osmolality.[275] The decreased ECF volume thus provides the nonosmotic stimulus of AVP release. More direct evidence for the role of AVP was provided in studies employing an AVP antagonist. When glucocorticoid-replete, adrenally insufficient rats were given an AVP antagonist, the minimal urine osmolality was significantly lowered.[276] Urine dilution was not corrected, in contrast to mineralocorticoid-replete rats, supporting a role for an AVP-independent mechanism. This is in concert with studies of adrenalectomized

homozygous Brattleboro rats, which also have a defect in water excretion that can be partially corrected by mineralocorticoids or by normalization of volume. In summary, therefore, the mechanism of the defect in water excretion associated with mineralocorticoid deficiency is mediated by AVP and by AVP-independent intrarenal factors, both of which are activated by decrements of ECF volume, rather than by deficiency of the hormone per se.

The presence in the urine of an osmotically active nonreabsorbable or poorly reabsorbable solute causes renal excretion of Na+ and culminates in volume depletion. Glycosuria secondary to uncontrolled diabetes mellitus, mannitol infusion, or urea diuresis after relief of obstruction is a common setting for this disorder. In patients with diabetes, the Na+ wasting caused by the glycosuria can be aggravated by ketonuria because hydroxybutyrate and acetoacetate also cause urinary electrolyte losses. In fact, ketonuria can contribute to the renal Na+ wasting and hyponatremia seen in starvation and alcoholic ketoacidosis. Na+ and water excretion are also increased when a nonreabsorbable anion appears in the urine. This is observed principally with the metabolic alkalosis and bicarbonaturia that accompany severe vomiting or nasogastric suction. In these patients, the excretion of HCO3

- requires, for the maintenance of electroneutrality, the excretion of cations, including Na+ and K+. Whereas the renal losses in these clinical settings may be hypotonic, the volume contraction-stimulated thirst and water intake can result in the development of hyponatremia.

Cerebral salt wasting is a rare syndrome described primarily in patients with subarachnoid hemorrhage; it leads to renal salt wasting and volume contraction.[277] Although hyponatremia is increasingly reported in these patients, true cerebral wasting is probably less common than reported.[278] In fact, one critical review found no conclusive evidence for volume contraction or renal salt wasting in any of the patients.[279] The mechanism of this natriuresis is unknown but the increased release of natriuretic peptides has been suggested.[280]