Comparative Diagnostic Performance of Copeptin After Hypertonic Saline Infusion Versus Water Deprivation Test in Pediatric Patients with Polyuria-Polydipsia Syndrome

Abstract

Differentiating central diabetes insipidus (CDI), nephrogenic diabetes insipidus (NDI), and primary polydipsia (PP) in pediatric patients with polyuria-polydipsia syndrome (PPS) remains a clinical challenge. The water deprivation test (WDT) is the traditional gold standard; however, it is time-consuming, burdensome, and prone to equivocal results. Stimulated copeptin, a surrogate marker of vasopressin, has emerged as a promising diagnostic alternative. We conducted a prospective, observational, cross-sectional study involving 27 pediatric patients (ages 2-17) presenting with PPS. Each patient underwent a WDT with desmopressin and hypertonic saline infusion (3% NaCl) for stimulated copeptin testing. Diagnostic accuracy was assessed using clinical diagnoses as a reference. The WDT showed high accuracy with an area under the curve (AUC) of 0.97, and there was an increased optimal threshold of ≥14% urine osmolality after desmopressin acetate (1-deamino-8-D-arginine vasopressin, DDAVP) administration (sensitivity 88.9%, specificity 100%). Stimulated copeptin at a threshold of <6.5 pmol/L demonstrated 100% sensitivity and specificity (AUC = 1.00) for CDI versus PP. Basal copeptin ≥21.4 pmol/L accurately identified all NDI cases. The agreement between the WDT and copeptin was low (κ = 0.06, McNemar p = 0.021), suggesting that copeptin has greater specificity, particularly for borderline or partial CDI. These results support the use of stimulated copeptin as a first-line diagnostic tool in pediatric PPS, offering improved objectivity, tolerability, and diagnostic clarity compared with the WDT. Basal copeptin also demonstrated excellent performance in rapid noninvasive NDI identification.

Keywords: arginin–vasopresin; central diabetes insipidus; copeptin; nephrogenic diabetes insipidus; primary polydipsia; water deprivation test.

Figure 1

ROC curve for the water deprivation test (WDT) based on percentage increase in urine osmolality after desmopressin administration.

Figure 2

ROC curve for stimulated copeptin in differentiating central diabetes insipidus (CDI) from primary polydipsia (PP), with diagnostic thresholds <4.9 pmol/L and <6.5 pmol/L highlighted.

Figure 3

Basal copeptin levels by diagnostic group. Boxplot showing basal (unstimulated) copeptin concentrations across the main diagnostic categories: central diabetes insipidus (complete and partial), nephrogenic diabetes insipidus (NDI complete and partial), and primary polydipsia (PP). Each box represents the interquartile range (IQR), with the median marked by a horizontal line; whiskers extend to the minimum and maximum values, excluding outliers. The dashed red line at 21.4 pmol/L indicates the diagnostic threshold of NDI. All patients with basal copeptin ≥21.4 pmol/L were clinically confirmed as having NDI. Patients with CDI (complete and partial) exhibited uniformly low copeptin levels (<6.5 pmol/L), whereas PP cases showed intermediate values. This pattern supports the diagnostic utility of basal copeptin, particularly for distinguishing NDI from other polyuria–polydipsia etiologies.

Figure 4

Stimulated copeptin levels by diagnostic group. Boxplot of copeptin concentrations measured after 3% NaCl hypertonic saline infusion. Each box represents the interquartile range (IQR), with the median indicated by a horizontal line and whiskers extending to non-outlier values. Two dashed lines represent key diagnostic thresholds: blue for 4.9 pmol/L and green for 6.5 pmol/L. Patients with NDI (complete forms) showed markedly elevated stimulated copeptin levels (often >30 pmol/L), while patients with complete CDI remained below 4.9, and those with partial CDI remained below 6.5 pmol/L. Those with PP showed normal or elevated values. The figure highlights the physiological separation of diagnostic subtypes based on copeptin response.

Figure 5

Diagnostic agreement between WDT and copeptin classification. Heatmap-style confusion matrix comparing diagnostic classification between the water deprivation test (WDT) and stimulated copeptin test (<6.5 pmol/L). Rows represent WDT-derived classification, and columns represent the copeptin-derived diagnosis (using <6.5 pmol/L threshold). The WDT classified more patients as having central diabetes insipidus (CDI) than the copeptin test, with statistically significant discordance (McNemar’s p = 0.021).

Figure 6

Power curve for post hoc analysis of diagnostic sensitivity. Power curve showing the relationship between sample size and statistical power to detect a diagnostic difference between an observed sensitivity of 100% and a null hypothesis sensitivity of 60% using α = 0.05. The vertical green line marks the actual sample size used in this study (n = 27), which achieved a power of 0.999. The red dashed line indicates the conventional 80% power threshold.