Beyond Biomarkers: Blending Copeptin and Clinical Cues to Distinguish Central Diabetes Insipidus from Primary Polydipsia in Children

<b>Background</b>: Polyuria-polydipsia syndrome (PPS) in children poses a major diagnostic challenge, as central diabetes insipidus (CDI) and primary polydipsia (PP) require distinct treatments. Although copeptin is a robust diagnostic biomarker, using only fixed thresholds may not adequately support decision making in borderline cases. To address this gap, we evaluated a multimodal diagnostic approach that integrates copeptin dynamics with clinical profiling. <b>Methods</b>: In a prospective diagnostic study (2019-2025), 24 children with PPS (CDI = 11, PP = 13) underwent hypertonic saline testing with serial sodium, osmolality, and copeptin sampling. Predictors included stimulated copeptin, peak sodium, peak osmolality, test duration, and tolerability. A Ridge regression model was applied and internally validated with stratified cross-validation. <b>Results</b>: Stimulated copeptin was the strongest discriminator, while sodium/osmolality dynamics and tolerability provided complementary value. The multimodal model achieved cross-validated AUC of 0.937 with 83.3% accuracy, and the procedure was safe and feasible in children. These findings support moving beyond biomarker cut-offs toward integrative diagnostic approaches that better reflect real-world clinical practice. <b>Conclusions</b>: Combining copeptin with clinical profiling in a penalized regression framework yields a robust and interpretable tool for distinguishing CDI from PP. More broadly, such integrative models may enhance diagnostic precision in rare pediatric disorders and provide a foundation for future multicenter validation and clinical decision-support applications.