Copeptin is secreted from the posterior pituitary as a precursor protein pre‐provasopressin together with AVP and neurophysin II [4]. Copeptin is a peptide consisting of 39‐amino acids, with a molecular weight of approximately 5 kDa [4,5]. Copeptin is very stable ex vivo, and easy to measure with sandwich immunoassay [5]. The main stimuli of the copeptin secretion are the same as those of AVP—the osmotic and other nonosmotic stimuli [6]. Although its physiological function is uncertain, the role of copeptin as a surrogate of AVP has been highlighted, as it is secreted in an equimolar amount to AVP. The use of copeptin is best illustrated in the differential diagnosis of polyuria-polydipsia syndrome (central and nephrogenic diabetes insipidus, and primary polydipsia), which has been suggested by Timper et al. [1]. Combined measurement of random and hypertonic saline-stimulated copeptin provides high diagnostic accuracy of 96% in the differential diagnosis of central diabetes insipidus from primary polydipsia, suggesting the diagnostic value of copeptin in hyperosmolar conditions [1]. On the other hand, the use of copeptin in the hypoosmolar disorder has been not been established until now.

In this regard, Go et al. [7] conducted analyses from a total of 100 participants in a prospective cohort to investigate the role of copeptin as a biomarker for the diagnosis and prognosis in hypoosmolar disorders. All participants were defined as having symptomatic hyponatremia (corrected serum sodium of ≤125 mmol/L) and were treated with hypertonic saline, where mean serum sodium and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. In the analyses to evaluate the copeptin levels as a marker for responses to hypertonic saline treatment in hyponatremic patients, low (below-median) copeptin levels at the baseline were associated with a significantly higher target correction rate in 6 hours (adjusted odds ratio [OR], 2.97; 95% confidence interval [CI], 1.16–7.64; p = 0.02) and 24 hours (adjusted OR, 6.21; 95% CI, 1.67–23.09; p = 0.006) after treatment start. Meanwhile, low copeptin levels at 24-hour after treatment was associated with a significantly higher overcorrection rate in 48-hour after treatment (adjusted OR, 18.00; 95% CI, 1.59–203.45; p = 0.02). The authors presented a plausible explanation for these findings that low baseline copeptin may indicate less chance of previous hyperosmolar or hypovolemic stimuli, thereby enhancing the response to a hypertonic saline infusion (Table 1). The authors also suggested that a low copeptin level at 24 hours after treatment may indicate that a greater excretion of free water can occur to augment the effect on serum sodium level by the same amount of hypertonic saline (Table 1).

In the current study, Go et al. [7] also investigated the usefulness of copeptin for differentiating etiologies of hyponatremia. The participants were classified into five categories, based on the patient’s history, physical examination, and laboratory test results: (1) decreased extracellular fluid (ECF) volume due to renal Na loss (e.g., diuretics, especially thiazides); (2) decreased ECF volume due to nonrenal sodium loss (e.g., gastrointestinal Na loss or third spacing: vomiting, diarrhea, or malnutrition); (3) increased ECF volume (e.g., heart failure, liver cirrhosis, and nephrotic syndrome); (4) normal ECF volume with adrenal insufficiency; and (5) normal ECF volume fulfilling the essential criteria for SIAD. Although the ratio of copeptin-to-urine sodium improved the differential diagnosis of hyponatremic patients with insufficient effective circulatory volume from the others, the authors were not able to present any cutoff values of copeptin levels to discriminate the etiologies of hyponatremia, due to widely overlapping copeptin levels among the different etiologies of hyponatremia and large variability within a single category. This finding is in agreement with a previous report [8] and seems clear that hyponatremia is not solely dependent on inappropriate AVP secretion, but also other factors, such as medications, volume status, or stress [9].

The cost-effectiveness of copeptin measurement in hyponatremic patients is a remaining question, which should be considered for routine practice. As it is still important to repeatedly measure serum sodium level in the treatment of hyponatremic patients, copeptin should be measured in addition to serum sodium measurement. Further, although osmotic demyelination syndrome is obviously a dreaded complication of overcorrection in the treatment of hyponatremia, its frequency is rare [10]. Hence, it should be validated whether the cost of routine copeptin measurement could be balanced by the prevention of osmotic demyelination syndrome.

In summary, Go et al. [7] suggested a novel role of copeptin as a biomarker for the prediction of treatment response in hyponatremia. The authors demonstrated that low copeptin levels at the baseline are associated with a significantly higher target correction rate in 6 and 24 hours after hypertonic saline treatment start, and that low copeptin levels at 24-hour after hypertonic saline treatment is associated with a significantly higher overcorrection rate in the next 24 hours. The cost-effectiveness of copeptin measurement in hyponatremic patients is a remaining question requiring further consideration.