Update in Differential Diagnosis of Diabetes Insipidus

Diabetes insipidus (DI) is a form of polyuria–polydipsia syndrome, and is characterized by hypotonic polyuria and polydipsia. DI is a rare disease with a prevalence of ~1 in 25,000 individuals. Regardless of the etiology, all four forms of DI result in a water diuresis due to an inability to maximally concentrate urine. Distinguishing between the types of DI is important, as treatment strategies differ and application of the wrong treatment can be dangerous. Central DI (also known as hypothalamic or neurogenic DI) results from inadequate secretion and usually deficient synthesis of arginine vasopressin (AVP) in the hypothalamic–neurohypophyseal system in response to osmotic stimulation. Nephrogenic DI is the result of an inadequate response of the kidneys to AVP. Primary polydipsia is characterized by excessive fluid intake that leads to polyuria, despite intact AVP secretion and an appropriate antidiuretic renal response. Gestational DI results from the enzymatic breakdown of endogenous AVP by increased placental vasopressinase levels in pregnancy. The indirect water deprivation test was the gold standard for differential diagnosis of polyuria–polydipsia syndrome for many years. This test has been shown to have considerable diagnostic limitations; overall diagnostic accuracy is 70%, and accuracy is only 41% in patients with primary polydipsia .To overcome these limitations of the indirect water deprivation test, direct measurement of AVP levels has been proposed to improve the differential diagnosis of DI. Several technical limitations of the AVP assay result in a high preanalytical instability of AVP in samples. Copeptin, the C-terminal segment of the AVP pro- hormone, is an easy-to-measure AVP surrogate that is very stable ex vivo, a basal copeptin level of > 21.4 pmol/l without prior thirsting unequivocally identifies nephrogenic DI, rendering a further water deprivation test unnecessary in these patients. An osmotically stimulated copeptin level of > 4.9 pmol/l after infusion of 3% saline (aiming at a sodium level > 150 mmol/l) had an overall diagnostic accuracy of 96.5% (93.2% sensitivity and 100% specificity) in distinguishing between patients with primary polydipsia and those with central DI, compared with only 76% for the indirect water deprivation test. However, this test needs sodium overstimulation, and therefore, close monitoring. Several caveats must be considered and an easier way to stimulate copeptin without inducing high sodium levels would be ideal. Arginine infusion is known to stimulate anterior pituitary hormones such as growth hormone and so is widely used as a simple and well-tolerated tool to diagnose growth hormone deficiency. A copeptin cutoff of 3·8 pM/L at 60 min after arginine infusion had an accuracy of 93% to diagnose diabetes insipidus in a dataset of patients with diabetes insipidus and primary polydipsia. The test was safe and had an acceptable tolerability profile. Arginine-stimulated copeptin measurements show a similar diagnostic accuracy to the hypertonic saline approach, but are more practical in clinical routine and associated with fewer adverse effects and risks. It is expected that the convenient arginine stimulation test will become the standard diagnostic test for diabetes insipidus.