Arginin-stimulated Copeptin in Polyuria-polydipsia Syndrome in Children

The exploration of polyuro-polydipsia syndrome (PPS) with hypotonic polyuria should distinguished, primary polydipsia (PP) due to excessive water intake, central diabetes insipidus (CDI) related to insufficient secretion of antidiuretic hormone (AVP), and nephrogenic diabetes insipidus (NDI) related to AVP insensitivity. The determination of plasma AVP is not relevant (unstable concentration, short in vitro half-life, long technical time and large blood sample). The differential diagnosis is currently based on a water deprivation test (WDT), an indirect reflection of AVP action, requiring more than 6 hours of hospitalization with risk of dehydration and low accuracy. Copeptin represents a new biomarker, direct mirror of AVP release with remarkable characteristics (stable, rapid determination, small blood volume). Copeptin has become a diagnostic tool in adult PPS and eliminated WDT in the diagnostic process. In children, basal copeptin values help for NDI and to exclude CDI (basal copeptin threshold \> 30 and \> 3.53 pmol/l (Se 100%, Sp 87.4%), respectively). Below 3.53 pmol/l, basal copeptin performance was inadequate to discriminate PP and CDI, highlighting the relevance of the stimulated copeptin study to improve this strategy. The arginine stimulation test is widely used as a simple, short duration (2 hours) and well tolerated tool to diagnose growth hormone deficiency in pediatrics. The performance of this test for copeptin stimulation was studied in adults with PPS with a high diagnostic accuracy.

The aim of the study is identify the best discriminant threshold of the arginine stimulation test in the uncertain diagnosis (basal copeptin \<30 pmol/l) in the polyuro-polydipsic syndrome in children.

Then evaluate the discriminative capacities of the arginine stimulation test between the primary polydipsia and central insipid diabetes in the polyuro-polydipsic syndrome in children. And finally evaluate the cost-effectiveness of a new decisional algorithm for the differential diagnosis of PPS in children and evaluate the impact of infusion volume on copeptin secretion using the protidemia copeptin ratio.

Routine biochemical tests are performed to screen patients for PPS and determine basal copeptin level after solid fasting since midnight without water restriction: 1/ a basal copeptin value ≥ 30 pmol/L defines the diagnosis of NDI and results in a specific care; 2/ a basal copeptin \< 30 pmol/L defines the group of eligible patients for arginine stimulation. The arginine-stimulated copeptin test start at 8 am, at the dose of 0.5 g/kg over 30min. Copeptin is measured at T0 (before infusion), T45, T60, T90, and T120 min after infusion.

Patients with basal copeptin value over 3.53 pmol/L are considered as positive diagnosis of PP (Se 100%, Sp 87.4%) and cerebral MRI is not performed for this group of patients (PP group).

Patients with basal copeptin value \< 3.53 pmol/L are considered as an uncertain diagnosis (UD) and cerebral and pituitary MRI is performed with a least two independent interpretations. Abnormal pituitary MRI allows a diagnosis of CDI leading to etiological investigations and AVP treatment. Patients with basal copeptin ≥ 3.53 pmol/l (PP group), and UD patients with normal MRI have gradual reduction of water intake without AVP treatment. For all these latest patients, a clinical and biological reevaluation is performed one month later.

The gold standard will be the final diagnosis PP vs. CDI based on a set of indicators: medical history, physical examination, pituitary hormonal assessment, hypothalamo-pituitary MRI, follow-up at 1 month.

Eligibility Criteria:
Inclusion Criteria:

* Children aged 2 to 18 years with polyuro-polydipsia syndrome (defined as hypotonic diuresis \&gt; 50 mL/kg/day in pediatric age or 30 mL/kg/day in late puberty (Tanner 5)) presenting for differential diagnosis between PP and DIC
* Basal copeptin of less than 30 pmol/l
* Agreeing to participate in the study
* Whose two parents' consent to have their child participate in the study.

Exclusion Criteria:

* Diabetes mellitus
* Unbalanced dysthyroidism
* Corticotropic deficiency
* Ionic disorders (dysnatremia \&lt; 135 or \&gt; 145 mmol/l, dyskalemia \&lt; 3 or \&gt; 5 mmol/l, corrected dyscalcemia \&lt; 2.2 or \&gt; 2.6 mmol/L)
* Moderate to severe clinical dehydration (recent weight loss \&gt; 5% of body weight, clinical or biological signs of dehydration) requiring immediate therapeutic management
* Renal failure with GFR \&lt; 60 mL/min/1.73 m2
* Uropathy
* Tumor syndrome (except hypothalamo-pituitary tumor)
* Intracranial hypertension
* ROHHAD syndrome
* Fever or biological inflammatory syndrome with CRP \&gt; 5 mg/L
* Hepatic insufficiency
* Contraindication to MRI
* Contraindication to progressive water intake restrictions
* History of contraindication to arginine
* Positive test for Pregnancy
* Lack of authorization by both parents or legal representatives