Fig. 2: A diagnostic algorithm for NDI.

Nephrogenic diabetes insipidus (NDI) should be suspected in patients with unexplained polyuria, polydipsia, failure to thrive and/or hypernatraemic dehydration. The initial biochemical work-up consists of measuring urine and serum osmolality, and serum sodium. In patients with urine osmolality <200 mOsm/kg H₂O and normal or high serum sodium, the diagnosis of DI is probable and early genetic testing is recommended. Early genetic testing should also be performed in patients at risk of NDI (for example, male offspring of a mother carrying an AVPR2 mutation). When early genetic testing is not available, other diagnostic tests can be recommended. Extended biochemical evaluation is performed to exclude polyuric disorders other than NDI. Plasma copeptin measurements are validated in adults, but not in children. The desmopressin (DDAVP) test can distinguish patients with central DI (CDI) (normal urine concentration capacity after the administration of DDAVP) and NDI (no response to DDAVP). Partial response to DDAVP is defined as an ability to increase urine osmolality above the baseline, but not reaching the reference values (600 mOsm/kg H₂O in children <1 year; 600–800 mOsm/kg H₂O in children aged 1–2 years; 800 mOsm/kg H₂O in children aged >2 years). In patients with suspected primary polydipsia, a water deprivation test can be considered, although its diagnostic accuracy is limited. Of note, a water deprivation test is contraindicated in patients with a history of hypernatraemic dehydration and inappropriately diluted urine. In adults, copeptin levels after stimulation with hypertonic saline or arginine can help to distinguish primary polyuria and DI. *An assessment of copeptin levels is only useful to exclude CDI (arginine vasopressin (AVP) deficiency) if they are ≥21.4 pmol/l (indicative of NDI) and sodium levels are above 147 mmol/l because there is a large overlap between unstimulated copeptin levels in patients with AVP deficiency and primary polydipsia.