A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis

Abstract

Hyponatremia, the most frequent electrolyte disorder, is caused predominantly by the syndrome of inappropriate antidiuresis (SIAD). A comprehensive characterization of SIAD subtypes, defined by type of osmotic dysregulation, is lacking, but may aid in predicting therapeutic success. Here, we analyzed serial measurements of serum osmolality and serum sodium, plasma arginine vasopressin (AVP), and plasma copeptin concentrations from 50 patients with hyponatremia who underwent hypertonic saline infusion. A close correlation between copeptin concentrations and serum osmolality existed in 68 healthy controls, with a mean osmotic threshold±SD of 282±4 mOsM/kg H2O. Furthermore, saline-induced changes in copeptin concentrations correlated with changes in AVP concentrations in controls and patients. With use of copeptin concentration as a surrogate measure of AVP concentration, patients with SIAD could be grouped according to osmoregulatory defect: Ten percent of patients had grossly elevated copeptin concentrations independent of serum osmolality (type A); 14% had copeptin concentrations that increased linearly with rising serum osmolality but had abnormally low osmotic thresholds (type B); 44% had normal copeptin concentrations independent of osmolality (type C), and 12% had suppressed copeptin concentrations independent of osmolality (type D). A novel SIAD subtype discovered in 20% of patients was characterized by a linear decrease in copeptin concentrations with increasing serum osmolality (type E or "barostat reset"). In conclusion, a partial or complete loss of AVP osmoregulation occurs in patients with SIAD. Although the mechanisms underlying osmoregulatory defects in individual patients are presumably diverse, we hypothesize that treatment responses and patient outcomes will vary according to SIAD subtype.

Figure 1.

Physiological plasma copeptin response to hypertonic saline-induced osmotic stimulation. The gray area illustrates the area of normality describing the relationship between plasma copeptin and serum osmolality based on 384 data pairs of 68 healthy controls that were osmotically stimulated using a hypertonic saline infusion. The regression curves were constructed with 95% CIs for the relation between serum osmolality and plasma copeptin levels with a cubic regression yielding the best fit. The detection limit (DL) of copeptin determination was 0.4 pmol/L. In contrast, the data points in the hypo-osmotic range illustrate the relationship between baseline plasma copeptin and serum osmolality levels in 50 patients with clinical features of SIAD (n=50).

Figure 2.

Individual patient response to saline-induced osmotic stimulation of all 50 patients with SIADH. Graphic characterization of the different subtypes of SIAD (A–E) illustrates all plasma copeptin data points of all individuals (n=50) during hypertonic saline infusion. Please note that the y axis varies according to variation in absolute plasma copeptin release. (F) Relative plasma copeptin response to osmotic stimulation, in percentages, when defining the mean copeptin concentration of each patient as 100%.

Figure 3.

Working hypothesis on osmotic and nonosmotic dysregulation underlying the SIADH subtype E. In healthy persons, minor decreases in BP or blood volume induce small increases in copeptin release. In patients with SIAD type E, the altered baroreceptor signaling mimics volume depletion despite normovolemia, thus shifting the copeptin response to the right (gray shaded arrows). Modified from ref. with permission.