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Etiology & Pathogenesis

Hypotonic hyponatremia has multiple etiologies1-3

Hypotonic hyponatremia has multiple etiologies1-3

Etiologies can be categorized under the 3 main volume statuses: hypovolemic hyponatremia, euvolemic hyponatremia, and hypervolemic hyponatremia. Laboratory data and a physical exam will help assess patients’ volume status. The volume status will help determine the etiology of the hyponatremia.1-3

Etiologies of the 3 main classes of hypotonic hyponatremia1-3

  • Cerebral salt-wasting
  • Diuretic therapy
  • GI losses (diarrhea, vomiting)
  • Ketonuria
  • Mineralocorticoid deficiency
  • Osmotic diuresis
  • Third-spacing (burns, pancreatitis)
  • Exercise associated
  • Glucocorticoid deficiency
  • Hypothyroidism
  • Low solute intake
  • NSIAD*
  • Primary polydipsia
  • Reset osmostat
  • SIADH**
  • Acute/chronic renal failure
  • Cirrhosis
  • Heart failure
  • Nephrotic syndrome

*NSIAD=Nephrogenic Syndrome of Inappropriate Antidiuresis

**SIADH=Syndrome of Inappropriate Antidiuretic Hormone

Pathogenesis of hyponatremia and the role of vasopressin

Hypotonic hyponatremia typically results from a disruption in the excretion of water from the kidneys, which is usually due to vasopressin release or renal failure.4


Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone (ADH), is a small peptide hormone produced in the hypothalamus. Vasopressin is primarily involved in regulating cardiovascular homeostasis and fluid balance, through activation of its 3 receptors (V1a, V1b, V2) located throughout the body.5,6 Vasopressin is regulated by osmoreceptors and baroreceptors, and is released in response to4,7:

  • Increased plasma osmolality
  • Decreased blood volume or pressure

When released, vasopressin binds to its 3 different G-protein-coupled receptors that lead to a variety of events that influence blood pressure control and body fluid balance.5

The table below describes some of the areas in the body where these different receptors are located.

Vasopressin Receptors and Locations5,6

V1a Receptor V1b Receptor V2 Receptor
  • Adrenal cortex
  • Brain
  • Vascular smooth muscle
  • Adrenal medulla
  • Anterior pituitary
  • Renal collecting duct

Blood pressure homeostasis occurs through activation of both the V1 and V2 receptors while body fluid homeostasis occurs mainly through activation of the V2 receptors5

Activation of the V1a receptor regulates blood pressure homeostasis through several different mechanisms5

Activation of the V1a receptor:

  • In vascular smooth muscle cells results in smooth muscle contraction5
  • In the adrenal cortex results in aldosterone/glucocorticoid release from the adrenal gland causing an increase in sodium reabsorption and body fluid retention5
  • In the brain increases baroreceptor sensitivity and sympathetic nerve activity5

Activation of the V1b receptor:

  • In the anterior pituitary, results in adrenocorticotropic hormone release5
  • In the adrenal medulla, results in catecholamine release5

Activation of the V2 receptor:

  • In renal collecting duct cells, results in renal water reabsorption via the aquaporin-2 pathway5
  • The aquaporin-2 pathway for water reabsorption is illustrated below5,7-10

The Aquaporin-2 (AQ2) Pathway Following V2 Receptor Activation8,10

The Aquaporin-2 (AQ2) Pathway Following V2 Receptor Activation

The image above illustrates the following series of events that occur in the AQ2 pathway following V2 receptor activation:

  • Vasopressin binds to the Gs-protein-coupled vasopressin V2 receptor on the basolateral membrane of the renal collecting duct cells
  • Vasopressin binding leads to an increase in intracellular cAMP through stimulation of adenylate cyclase
  • cAMP binds to protein kinase A (PKA) resulting in phosphorylation of the AQP2 channels by PKA
  • Phosphorylation of the AQP2 channels leads to translocation of the AQP2 channels to the luminal membrane of the renal collecting duct cell
  • Translocation of AQP2 channels to the luminal membrane of the collecting duct cell allows water to be reabsorbed from the collecting duct

Adapted from NV Knoers. N Engl J Med. 2005 and Stockhand JM. Kidney Int. 2010.

Vasopressin often plays a role in hyponatremia7,9,11,12

Vasopressin secretion is suppressed once serum osmolality drops below normal; however, there are 2 instances in which vasopressin secretion will be sustained or even increased despite serum hypo-osmolality. These 2 cases are listed below7,9:

Hemodynamic or baroreceptor stimuli
  • Osmotic signals to suppress vasopressin secretion are overridden when the arterial baroreceptors sense a decrease in effective circulatory volume4,9,13
  • Decreases in effective circulatory volume can be due to9,13:
    • Decreased cardiac output (CO)
    • Plasma volume depletion
    • Systemic arterial vasodilation
  • Diseases that cause a decrease in effective circulatory volume include7,13:
    • Cirrhosis (systemic vasodilation)
    • High-CO heart failure (systemic vasodilation)
    • Low-CO heart failure (decreased cardiac output)
  • Sustained or increased vasopressin release as a result of decreased effective circulatory volume occurs by the following mechanisms7,13,14:
    1. The decreased effective circulatory volume is sensed by the arterial baroreceptors in the carotid sinus and aortic arch resulting in afferent signals to the brain
    2. The afferent signals result in the release of vasopressin as well as stimulation of sympathetic efferent pathways
    3. Increased sympathetic stimulation may also lead to the release of vasopressin
    4. Increased sympathetic stimulation can result in activation of the renin-angiotensin system (RAS), which can cause the release of vasopressin
Dysregulation of cells that secrete vasopressin
  • Vasopressin release in this case is not caused by osmotic or hemodynamic stimuli7,9,15
  • Causes for vasopressin release include:
    • Ectopic production of vasopressin by tumors9,15
    • Stimulation vasopressin release by drugs9,15
    • A lowered threshold for vasopressin release15
    • Dysfunction of hypothalamus that results in persistent low-grade vasopressin secretion15
  • This occurs in hyponatremia caused by SIADH9

The 3 Types of Hypotonic Hyponatremia

Watch videos discussing the definitions, etiologies, and pathogenesis of hypovolemic, euvolemic, and hypervolemic hyponatremia.