Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis

Abstract

Copeptin is secreted in an equimolar amount to arginine vasopressin (AVP) but can easily be measured in plasma or serum with a sandwich immunoassay. The main stimuli for copeptin are similar to AVP, that is an increase in osmolality and a decrease in arterial blood volume and pressure. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation. Copeptin has, therefore, been evaluated as diagnostic biomarker in vasopressin-dependent disorders of body fluid homeostasis. Disorders of body fluid homeostasis are common and can be divided into hyper- and hypoosmolar circumstances: the classical hyperosmolar disorder is diabetes insipidus, while the most common hypoosmolar disorder is the syndrome of inappropriate antidiuresis (SIAD). Copeptin measurement has led to a "revival" of the direct test in the differential diagnosis of diabetes insipidus. Baseline copeptin levels, without prior thirsting, unequivocally identify patients with nephrogenic diabetes insipidus. In contrast, for the difficult differentiation between central diabetes insipidus and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is clearly superior to the classical water deprivation test. On the contrary, in the SIAD, copeptin measurement is of only little diagnostic value. Copeptin levels widely overlap in patients with hyponatraemia and emphasize the heterogeneity of the disease. Additionally, a variety of factors lead to unspecific copeptin elevations in the acute setting further complicating its interpretation. The broad use of copeptin as diagnostic marker in hyponatraemia and specifically to detect cancer-related disease in SIADH patients can, therefore, not be recommended.

Keywords: SIAD; copeptin; diabetes insipidus; diagnosis; hypernatremia; hyponatraemia; primary polydipsia.

Figure 1

Structure of Copeptin. Structure of pre‐provasopressin. The prohormone is packaged into neurosecretory granules of magnocellular neurons. During axonal transport of the granules from the hypothalamus to the posterior pituitary, enzymatic cleavage of the prohormone generates the final products: AVP, neurophysin and the COOH‐terminal glycoprotein copeptin [Colour figure can be viewed at http://www.wileyonlinelibrary.com]

Figure 2

Correlation of copeptin with AVP and plasma osmolality. A, The correlation of copeptin with AVP during osmotic stimulation with hypertonic saline infusion (modified from Rref.23). Linear regression (solid line) with slope b and coefficient of determination R ², the smoothing line (dashed line) and Spearman's rank correlation coefficient rS are shown. B, The correlation of plasma copeptin and AVP concentrations as a scatter plot ranging from hypoosmolality (induced by water load) to hyperosmolality (induced by hypertonic saline infusion) (modified from Ref.9). rS denotes Spearman's rank correlation coefficients

Figure 3

Stimulated copeptin levels in response to the hypertonic saline infusion and water deprivation test in patients with polyuria‐polydipsia syndrome. Shown are stimulated copeptin levels in response to the hypertonic saline infusion test (HIS) and water deprivation test (WDT) in patients with polyuria‐polydipsia syndrome that was caused by complete central diabetes insipidus (DI) or partial central diabetes insipidus as compared with primary polydipsia. The horizontal line in each box represents the median, the lower and upper boundaries of the boxes the interquartile range, the ends of the whisker lines the minimum and maximum values within 1.5 times the interquartile range, and the dots outliers (modified from Ref.46)

Figure 4

New copeptin‐based diagnostic workflow for the differential diagnosis of polyuria‐polydipsia syndrome [Colour figure can be viewed at http://www.wileyonlinelibrary.com]

Figure 5

Plasma copeptin levels in different aetiologies of hyponatraemia (modified from Ref.69). Boxplots show median and interquartile range. ^§ P = <0.0001 compared to patients with PP, *P = <0.001 compared to patients with hypervolemic hyponatraemia, **P = <0.05 compared to patients with hypovolaemic hyponatraemia, °P = 0.05 compared to patients with hypervolemic hyponatraemia

Figure 6

Plasma copeptin levels in different subtypes of SIAD (modified from Ref.73) [Colour figure can be viewed at http://www.wileyonlinelibrary.com]