ETIOLOGY OF HYPERNATREMIA
Hypernatremia is defined as an increase in the plasma Na+ concentration to >145 mM. Considerably less common than hyponatremia, hypernatremia is nonetheless associated with mortality rates of as high as 40–60%, mostly due to the severity of the associated underlying disease processes. Hypernatremia is usually the result of a combined water and electrolyte deficit, with losses of H2O in excess of Na+. Less frequently, the ingestion or iatrogenic administration of excess Na+ can be causative, for example after IV administration of excessive hypertonic Na+-Cl– or Na+-HCO3– (Fig. 49-6).
The diagnostic approach to hypernatremia. ECF, extracellular fluid.
Elderly individuals with reduced thirst and/or diminished access to fluids are at the highest risk of developing hypernatremia. Patients with hypernatremia may rarely have a central defect in hypothalamic osmoreceptor function, with a mixture of both decreased thirst and reduced AVP secretion. Causes of this adipsic DI include primary or metastatic tumor, occlusion or ligation of the anterior communicating artery, trauma, hydrocephalus, and inflammation.
Hypernatremia can develop following the loss of water via both renal and nonrenal routes. Insensible losses of water may increase in the setting of fever, exercise, heat exposure, severe burns, or mechanical ventilation. Diarrhea is, in turn, the most common gastrointestinal cause of hypernatremia. Notably, osmotic diarrhea and viral gastroenteritides typically generate stools with Na+ and K+ <100 mM, thus leading to water loss and hypernatremia; in contrast, secretory diarrhea typically results in isotonic stool and thus hypovolemia with or without hypovolemic hyponatremia.
Common causes of renal water loss include osmotic diuresis secondary to hyperglycemia, excess urea, postobstructive diuresis, or mannitol; these disorders share an increase in urinary solute excretion and urinary osmolality (see “Diagnostic Approach,” below). Hypernatremia due to a water diuresis occurs in central or nephrogenic DI (NDI).
NDI is characterized by renal resistance to AVP, which can be partial or complete (see “Diagnostic Approach,” below). Genetic causes include loss-of-function mutations in the X-linked V2 receptor; mutations in the AVP-responsive aquaporin-2 water channel can cause autosomal recessive and autosomal dominant NDI, whereas recessive deficiency of the aquaporin-1 water channel causes a more modest concentrating defect (Fig. 49-2). Hypercalcemia can also cause polyuria and NDI; calcium signals directly through the calcium-sensing receptor to downregulate Na+, K+, and Cl– transport by the TALH and water transport in principal cells, thus reducing renal concentrating ability in hypercalcemia. Another common acquired cause of NDI is hypokalemia, which inhibits the renal response to AVP and downregulates aquaporin-2 expression. Several drugs can cause acquired NDI, in particular lithium, ifosfamide, and several antiviral agents. Lithium causes NDI by multiple mechanisms, including direct inhibition of ...