The syndrome of inappropriate antidiuresis: a copeptin-based classification and identification of a novel subtype

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Hyponatremia is the most frequent electrolyte disorder with the syndrome of inappropriate antidiuresis (SIAD) as its most common cause. However, comprehensive characterization of SIAD subtypes is still lacking, but may predict therapeutic success. Using hypertonic saline infusion, the osmoregulation in SIAD was studied in 50 patients with hyponatremia (serum sodium < 130 mmol/L) by serial measurements of serum osmolality, sodium, plasma arginine vasopressin (AVP), and copeptin concentrations. Sixty-eight healthy subjects served as controls showing a close correlation between plasma copeptin and osmolality with an osmotic threshold of 282 ± 4 mOsm/kg H2O. In SIAD, different types of altered AVP osmoregulation were identified: 10% of patients with grosly elevated copeptin concentrations independent of serum osmolality (type A); 14% with linear osmotic response to rising serum osmolality, but abnormally low osmotic threshold (type B); 44% of patients with a plateau-like copeptin secretion (type C); 12% with suppressed copeptin levels (type D). A novel SIAD subtype was discovered in 20% of patients, characterized by a plasma copeptin decrease with increasing osmolality during hypertonic saline infusion (type E or 'barostat reset'). The main alteration in SIAD is a partial or complete loss of AVP osmoregulation over the entire osmotic range. The novel subtype of 'barostat reset' is presumably caused by impaired non-osmotic inhibitory pathways in combination with an altered osmoregulation. Ectopic AVP secretion or AVP-independent antidiuresis has to be assumed in a subset of patients. We hypothesize that the different SIAD subtypes will affect treatment response and patient outcome.