Regulation of Arginine Vasopressin in the Syndrome of Inappropriate Antidiuresis

The syndrome of inappropriate antidiuresis (SIAD) is a disorder of sodium and water balance characterized by hypotonic hyponatremia and impaired water excretion in the absence of renal insufficiency, adrenal insufficiency, or any recognized stimulus for the antidiuretic hormone arginine vasopressin (AVP). Hyponatremia is primarily a result of excessive water retention caused by a combination of excessive intake and inappropriate antidiuresis. It is sometimes aggravated by a sodium deficiency caused by decreased intake and/or a secondary natriuresis triggered by and largely corrective of the increase in extracellular volume. Hence, there is neither edema nor signs of hypovolemia. Inappropriate antidiuresis is usually due to administration or endogenous production of AVP or another vasopressin receptor agonist such as desmopressin. Endogenous production can be either ectopic (from a tumor) or eutopic (from the neurohypophysis). The latter apparently is induced by a wide variety of diseases, drugs, or injuries and is divisible into 3 different types of abnormal AVP release during hypertonic saline infusion: high, erratic fluctuations unrelated to increases in plasma sodium (type A); a slow constant “leak” that is also unaffected by increases in plasma sodium (type B); and rapid progressive increases in plasma AVP that correlate closely with plasma sodium as it rises toward the normal range (type C or “reset osmostat”). In 5% to 10% of patients, there is no demonstrable abnormality in the osmoregulation of AVP (type D) and the cause of inappropriate antidiuresis is unclear. In some children it appears to be due to an activating mutation of the V2 receptor (V2R). In other patients, it may be due to abnormal control of aquaporin-2 water channels in renal collecting tubules or production of an antidiuretic principle other than AVP. These different types of osmoregulatory dysfunction underlying SIAD may result in marked differences in clinical presentation or response to therapy with fluid restriction, hypertonic saline infusion, or vasopressin antagonists.