Copeptin stimulation by combined intravenous arginine and oral LevoDopa/Carbidopa in healthy short children and children with the polyuria-polydipsia syndrome.

INTRODUCTION: Stimulated copeptin may provide an alternative to water deprivation testing (WDT) in the evaluation of polyuria-polydipsia syndrome (PPS). Though best studied, arginine stimulation alone produces a modest copeptin response in children. We investigated the effectiveness of the arginine + LevoDopa/Carbidopa stimulation test (ALD-ST) for copeptin. METHODS: 47 healthy short children (controls), 10 children with primary polydipsia and 10 children with AVP deficiency received arginine hydrochloride (500 mg/Kg intravenously over 30 minutes) and Levodopa/carbidopa (10:1 ratio; 175 mg of L-Dopa/m2 BSA) orally. Serum copeptin was measured at 0 60, 90 and 120 minutes. RESULTS: In controls, ALD-ST increased copeptin from a median of 7.0 pMol/L (IQR 5.0-10.0) to a peak of 44.0 pMol/L (IQR 21.4-181.0) between 60-120 minutes (p<0.001). Copeptin peak was higher in subjects who experienced nausea or vomiting (57%) than in those who did not (131.0 pMol/L [IQR 42.5-193.8] vs 22.7 pMol/L [IQR 16.0-33.7], p<0.001). While subjects with primary polydipsia had similar baseline (8.5 pMol/L [IQR 8.0-11.0]) and stimulated (125.2 pMol/L [IQR 87.6-174.0]) copeptin levels as controls, subjects with AVP deficiency had lower baseline (2.5 pMol/L [IQR 2.0-3.1]) and peak levels (4.6 pMol/L [IQR 2.4-6.0]). A peak copeptin of ≥9.3 pMol/L best predicted absence of complete or partial AVP deficiency with a sensitivity of 100% and specificity of 80%. CONCLUSIONS: ALD-ST induced a robust peak copeptin in healthy short children and children with primary polydipsia. Nausea/vomiting, a side effect of ALD-ST, amplified the copeptin response. The ALD-ST may be a suitable initial screening test in children with PPS.

Very elevated serum copeptin concentrations occur in a subset of healthy children in the minutes after phlebotomy.

OBJECTIVES: Although AVP and its surrogate, copeptin, are mainly regulated by osmotic and volume stimuli, their secretion is also elicited by stress and growth hormone (GH) stimulating agents. The aim of this report is to describe unusual patterns of copeptin response in a subset of children undergoing GH stimulation tests (GH-ST). METHODS: We conducted a secondary analysis of a cohort of 93 healthy short children with no polydipsia, polyuria or fluid/electrolyte abnormalities, undergoing GH-ST with intravenous arginine, insulin, oral clonidine, or L-Dopa/carbidopa in various combinations. Serum copeptin concentrations were measured 1-3 min after phlebotomy (0 min) and at 60, 90, 120 min during GH-ST. RESULTS: In 85 subjects (normal response group, NRG) serum copeptin concentrations increased from a 0 min median of 9 pmol/L (IQR 6, 11.5) (all values ≤21) to a median peak between 60 and 120 min of 22 (IQR15, 38) pmol/L, which varied depending on the stimulating agent. Conversely, in the eight outliers, copeptin concentrations decreased gradually from a median of 154 (IQR 61, 439) pmol/L (all ≥40 pmol/L) to values as low as 14 % of the basal value, by 120 min. Test-associated anxiety was described in 17 subjects in the NRG (20 %) and five of the outliers (63 %). CONCLUSIONS: A distinctive pattern of very elevated serum copeptin concentrations occurred in 9 % of children undergoing GH-ST, similar to reports in previous pediatric studies. Etiology may include pain or stress of phlebotomy. This phenomenon should be recognized for proper interpretation of copeptin values in children.

Combined Arginine and Insulin Stimulation Elicits a Robust and Consistent Copeptin Response in Short Children.

INTRODUCTION: Copeptin, co-secreted with arginine vasopressin, is regulated by osmotic and volume stimuli but also responds to intravenous arginine and insulin-induced hypoglycemia. The serum copeptin response to the latter agents has been studied in adults but only to a limited extent in children. The objective of this study was to describe the copeptin response to combined arginine and insulin in children with normal posterior pituitary function. METHODS: We conducted a prospective, single-arm assessment of serum copeptin concentrations in children (age 7-16 years, n = 38) undergoing growth hormone stimulation testing with an arginine-insulin tolerance test (AITT) for short stature or growth deceleration in a tertiary referral center. After overnight fasting, arginine (500 mg/kg) was administered between 0 and 30 min intravenously (IV) followed by insulin (0.1 units/kg IV) at 60 min. Copeptin serum concentrations were measured at baseline (0 min), at the post-arginine peak (60 min), and at the post-insulin peak (90 min; 30 min post-insulin), respectively. The main outcome was the peak copeptin concentration. RESULTS: Mean ± SD copeptin concentrations increased from 9.9 ± 5.0 pmol/L at 0 min to 13.2 ± 5.8 pmol/L at 60 min (p < 0.0001 vs. 0 min) and 27.7 ± 14.2 pmol/L at 90 min (p < 0.0001 vs. 0 and 60 min). There was no significant correlation between copeptin concentrations and age, BMI, pubertal status, cortisol, growth hormone, or glucose concentrations. DISCUSSION/CONCLUSION: Arginine and insulin appear to have an additive and consistent effect resulting in significant stimulation of copeptin secretion in children. The AITT may be a useful tool to evaluate for normal posterior pituitary function in this age-group, with potential implications for the evaluation of polyuria-polydipsia syndrome.