Startseite The changing landscape in the evaluation of hypotonic polyuria in children and adolescents: the role of the new copeptin stimulation tests
Artikel Open Access

The changing landscape in the evaluation of hypotonic polyuria in children and adolescents: the role of the new copeptin stimulation tests

  • Luigi R. Garibaldi EMAIL logo , Shruti Sastry , Michael J. McPhaul und Christine A. March EMAIL logo
Veröffentlicht/Copyright: 23. Mai 2025
Artikel downloaden (PDF)
Journal of Pediatric Endocrinology and Metabolism
Aus der Zeitschrift Journal of Pediatric Endocrinology and Metabolism Band 38 Heft 7

Abstract

Hypotonic polyuria, also known as the polyuria-polydipsia syndrome (PPS), caused by primary polydipsia (PP), arginine vasopressin deficiency (AVP-D or central diabetes insipidus), or uncommonly by AVP resistance (AVP-R), is diagnostically challenging due to overlapping symptoms and the need to conclusively diagnose or exclude AVP-D caused by serious organic lesions of the central nervous system. Diagnostic tests that stimulate AVP secretion by increasing plasma osmolality include the water deprivation test (WDT) and the hypertonic saline test (HST). The WDT, considered the gold standard for evaluating PPS in children, has suboptimal diagnostic accuracy, is burdensome, and requires hospitalization. The HST has been used rarely in children due to safety concerns and need for intensive monitoring. The finding that some anterior pituitary stimulating agents also stimulate the posterior pituitary, and the availability of a robust serum/plasma assay for copeptin as a reliable surrogate of AVP, has allowed development of nonosmotic, copeptin/AVP stimulation tests. In the present review, we focus on these new copeptin stimulation tests, which include single stimuli with intravenous (IV) arginine, IV insulin, intramuscular glucagon, oral levodopa, and double stimuli (IV arginine-insulin or AITT; IV arginine and oral Levodopa/carbidopa or ALD-ST), which we have previously shown to induce very robust copeptin secretion. Specifically, the ALD-ST differentiated AVP-D from PP in 20 children with high diagnostic accuracy at a cutoff stimulated copeptin of 9.3 pmol/L. We propose the utilization of the outpatient ALD-ST in the early stages of PPS evaluation in children, given its safety, cost-effectiveness, and limited side effects.

Keywords: copeptin; vasopressin (AVP); diabetes insipidus; AVP-deficiency; polyuria-polydipsia syndrome; primary polydipsia

Introduction

Hypotonic (nonosmotic) polyuria, also known as the polyuria-polydipsia syndrome (PPS) [1], poses a diagnostic challenge in the pediatric endocrinology clinic. An accurate differential between the more common diagnoses, primary polydipsia (PP) and arginine vasopressin deficiency (AVP-D), also known as central diabetes insipidus (DI) [2], is critical, as AVP-D may be caused by potentially life-threatening inflammatory or neoplastic conditions of the central nervous system (CNS) [3]. The third cause of PPS, AVP resistance (AVP-R, nephrogenic DI), [2] is rare in children, both in the congenital form, which is diagnosed in the first few months of life, and the acquired form, more common in adults, which can be suspected in individuals on lithium therapy or with kidney disease [4]. It will be mentioned only incidentally in this review.

For many years, the water deprivation test (WDT) has been, and currently remains, the gold standard for the investigation of PPS in children [5], [6], [7] after the original description in adults, but it has substantial limitations. The advent of the copeptin assay almost two decades ago [8] opened a new chapter in the diagnostic evaluation of PPS. In the present manuscript, our aim is to summarize the progress made in the last decade regarding the use of copeptin measurements in the evaluation of hypotonic polyuria in the pediatric and adolescent age group. We will present data from studies in adults, too, since these have provided most of the research that is the basis of our understanding of AVP/copeptin's role in physiology and PPS at any age and also because a substantial proportion of the adult data can be applied to pediatrics (past infancy), given the similar pathophysiology of fluid regulation by AVP across ages and similar mean/median copeptin levels in children and adults (Table1 and [9], [10], [11]). Additionally, adult data are even more directly applicable to young adult patients who are currently followed in a number of pediatric programs (at least in the United States, and possibly other countries). As comprehensive recent reviews on copeptin [12], 13], as well as pediatric PPS and AVP-D [3], 11], 14] are available, this review will focus on diagnostic testing, including our experience with new copeptin stimulation tests, and how to incorporate them into the approach to the child with PPS.

Table 1:

Summary of pediatric papers evaluating the baseline and stimulated copeptin response.

Reference n Age, years Mean ± SD, or median (IQR N,N) or range (N-N) Overnight restriction (>6 h) of H2O or WDT(h) Baseline copeptin range pmol/L Baseline copeptin mean±SD or median (IQR), pmol/L Stimulating agent or WDT Peak time minutes Peak copeptin, pmol/L (stimulated or WDT) Percent increase from baseline Proposed cutoff for baseline copeptin (sens/spec %) Proposed cutoff for stimulated copeptin (sens/spec %) Proposed cutoff for WDT (sens/spec %)
Bonnet [37]
 Controls 238 10.3 ± 4.1 No 7.6 (4.9, 12.3)
 PPS (AVP-R excluded) 37 3.5 (100/87)
 AVP-D 21 9.6± ± 4.6 No 1.7 (1.0, 2.0)
 PP 16 3.1±3.8 No 5.6 (5.6, 10.2)
Binder [38]
 Controls (younger) 68 7±2.7

(2 groups)		 Yes 1.3–44.4 6.0 (1.7, 44.4) Arginine 30–60 8.5 (1.6, 39.9) 42
 Controls (older) 27 16.4 ± 1.2 Yes 5.6 (1.3, 43.5) (Same) (Same) 7.3 (2.8, 20.8) 30
 AVP-D 4 NA 1–2.2 1.5 (1.3, 1.7) (Same) (Same) 1.9 (1.6, 2.9) Trivial
Gippert [40] 3.0 (100/97)
 Controls 32 13.0 (10.3, 16.8) Yes 4.5 (3.5, 8.4) Arginine 60 7.0 (4.5, 12.9) 56
 AVP-D 32 13.0 (10.3, 16.8) 1.5 (1.2, 2.1) (Same) (Same) 1.4 (1.1, 1.87) Trivial
 PP 5 6.0 (1.0, 12.5) 4.4 (4.0, 6.3) (Same) (Same) 9.6 (8.2, 11.4) 118
Gippert [39]
 Controls 43 13.0 (range 4–19) No 4.4 (3.4, 6.7) Insulin 30–60 8.4 (4.95, 19.7) 91 2.3 (92/85) 3.0 (92/94)
 AVP-D 25 12.0 (range 5–21) No 1.5 (0.9, 1.95) (Same) (Same) 1.95 (1.3, 2.4) 30
Tuli [64]
 Controls 13 9.9 ± 2.1 Yes 12.9 ± 3.2
 Controls 40 9.9 ± 3.6 No 2.4–8.6 5.2 ± 1.6
 AVPD, established 6 11.7 ± 1.4 2.6 ± 0.5
 AVP-D,new diagnosis(DX) 6 7.1 ± 1.8 WDT (6 h) WDT 2.4 ± 0.4 3.5 (75/83)
 AVP-D, partial, new DX 2 WDT (6 h) (Same) 4.3, 4.9
 PP 6 4.6 ± 1 WDT (6 h) (Same) 6.7 ± 1.7
Tuli [36]
 Controls
 40 8.6 Yes 3.3–14.9 10.6 (IQR NA)
 88 8.7 No 2–10.8 4.9 (IQR NA)
Tuli [65] 3.8 (100/100)
 Controls 50 11.9 ± 0.4 No 6.7 ± 0.6 Arginine 60 12.2 ± 1.4 82
 PPS 13 12.0 ± 1.4
 AVP-D 6 1.4 ± 0.2 (Same) (Same) 2.0 ± 0.3 43
 PP 7 3.8 ± 0.5 (Same) (Same) 7.8 ± 0.8 105
March [44]
 Controls 38 12.4 ± 2.2 Yes 3.0–25.0 9.9 ± 5.0 Arginine 60 13.2 ± 5.8 33
Yes 9.9 ± 5.0 Arg-insulin 90 27.7 ± 14.2 80
March [45] 9.3 (100/80)
 Controls 47 11.4 ± 2.6 Yes <2–17.1 7.0 (5.0–10.0) ALD-ST 60–120 44.0 (21.4, 181) 529
 AVP-D 10 8.2 ± 5.8 No <2.0–5.0 2.5 (2.0–3.1) (Same) (Same) 4.6 (2.4, 6.0) 84
 PP 10 5.7 ± 5.3 No <2.0–17.0 8.5 (8.0, 11.0) (Same) (Same) 125.2 (87.6, 174) 1,373

  1. PPS, polyuria-polydipsia syndrome; AVP-D, AVP deficiency; AVP-R, AVP resistance; PP, primary polydipsia; Sens/Spec, sensitivity/specificity (note, rounded to closest integer); IQR, interquartile range; WDT, water deprivation test; ALD-ST, arginine-levodopa stimulation test; Arg, arginine; NA, not available.

The AVP and copeptin assays

The AVP assay

A dependable radioimmunoassay (RIA) for AVP, a small nonapeptide with a short half-life, was developed in the early 1970s [15] with subsequent modifications [16], 17]. The assay has remained laborious and prone to preanalytical and analytical shortcomings. These include rapid degradation of AVP in plasma by proteases and loss of AVP immunoreactivity in frozen samples, resulting in often substantial underestimation of AVP levels [15], 16]. Rarely, a spurious AVP increase may occur due to leakage of AVP from the (AVP-rich) platelets [18]. With the advent of increasing automation and the demand for faster turnaround times in the clinical laboratory in the 1990s, the AVP RIA became less and less popular and has remained available, as a validated assay, only in few research laboratories.

The copeptin assay

Although this 39 amino acid glycopeptide was discovered in 1972 [19] and first sequenced in 1981 [20], its concentration in serum/plasma was first measured in 2006 [8]. As opposed to AVP, the larger copeptin molecule allows it to be measured by a robust, two-site, “sandwich” immunometric assay, in unextracted plasma or serum. Unlike AVP, copeptin is very stable in plasma/serum for 1 week at room temperature or longer in refrigerated/frozen samples [8]. The rationale for measuring copeptin, which has no known biological function, as a marker of AVP activity is based on the process of AVP production [21], 22] (Figure 1). (Pre)-Pro-AVP, synthesized in the magnocellular neurons of the supraoptic and paraventricular nuclei, is cleaved during its axonal transport toward the storage granules in the posterior hypophysis, from which AVP, copeptin, and neurophysin II are released in equimolar amounts. These 3 peptides are coded for by a single gene on chromosome 20 [23]. Despite copeptin’s half-life (∼26 min) being ∼ twice that of AVP [24], its circulating concentrations are highly correlated with plasma AVP levels and osmolalities [25], 26], making it a good surrogate of AVP. The only copeptin assay that has provided consistently reliable and reproducible results is the immunofluorimetric assay on the Kryptor- B.R.A.H.M.S platform (Thermo-Fisher, Waltham, MA, USA) with Time Resolved Amplified Cryptate Emission (TRACE) technology (also available as an immunoluminometric assay with similar characteristics), based on two proprietary antibodies, while assay kits from other vendors (usually expressing copeptin concentrations in pg/mL) have shown limited reliability [27] and unwieldy conversions to the units (pmol/L) of the Kryptor- B.R.A.H.M.S assay [11]. In this review, we will largely refer to papers (including ours) based on copeptin measurement using the Kryptor/B.R.A.H.M.S platform.

Figure 1: Synthesis and release of AVP and copeptin from common precursor in the hypothalamic-pituitary unit. Adapted from Mu et al. [13], with copyright permission. PVN, SON: paraventricular, supraoptic nuclei. BP: blood pressure.
Figure 1:

Synthesis and release of AVP and copeptin from common precursor in the hypothalamic-pituitary unit. Adapted from Mu et al. [13], with copyright permission. PVN, SON: paraventricular, supraoptic nuclei. BP: blood pressure.

Pre-Pro-AVP is also synthesized in the hypothalamic parvocellular neurons whose axons project to the median eminence, from which AVP (and copeptin) reach the anterior pituitary via the portal circulation. This pathway is considered complementary to the CRH-ACTH pathway, with AVP being synergistic with CRH in stimulating ACTH production by activating pituitary V1b receptors [28], [29], [30], [31] as part of the stress response. In this review, we will discuss mainly the effects of AVP on fluid homeostasis (mediated by the V2 receptors, expressed in the distal and, predominantly, the collecting tubules of the kidneys) and touch briefly on copeptin as a marker of stress for situations encountered in pediatric endocrinology. Copeptin as a stress marker in various pathological conditions in adults is reviewed elsewhere [12], 13], 32].

Tests of AVP reserve

The main physiological stimulus to AVP secretion is an increase in plasma osmolality. As little as a 1–2 % increase in plasma osmolality induces a noticeable, AVP-dependent increase in urine osmolality [33], 34]. A second category of stimuli is mediated by volume receptors, including low pressure volume receptors sensitive to intravascular volume changes and high pressure arterial baroreceptors sensitive to blood pressure changes [35]. These nonosmotic stimuli do not factor into AVP regulation under usual physiologic conditions, though they can trigger AVP secretion when there is a substantial loss of intravascular volume (10 % or greater) or significant hypotension [22]. Thus, tests of AVP reserve have been typically based on osmotic challenges. Recently, another category of nonosmotic stimuli has emerged, following the observation that growth hormone stimulating agents also trigger AVP/copeptin release in both adults and children. These include intravenous (IV) arginine, IV insulin, intramuscular or subcutaneous glucagon, and possibly oral L-Dopa. Below we review the diagnostic utility of measuring random and stimulated copeptin serum concentrations in the evaluation of PPS, with focus on nonosmotic copeptin stimulation tests in children, to include new tests using two agents in combination, which we have developed and used in our pediatric center in the last few years.

Random serum copeptin measurements in assessing AVP secretion in children

Copeptin serum concentrations have been measured in children, usually in fasting samples, at the time of growth hormone stimulation tests with various agents. The variability of the mean baseline copeptin concentrations in different cohorts shown in Table 1 (ranging from 1 to >40 pmol/L) appears to be predominantly related to the different degrees of hydration in the hours before blood sampling [36] and possibly other factors. Even in children allowed “free access to fluids” until the time of testing [37], the duration of time without drinking was not standardized, thus further limiting comparability of baseline copeptin levels in various studies. Another factor affecting variability is sample timing. In some studies, copeptin levels were measured after several minutes of rest following phlebotomy [38], [39], [40], which probably resulted in them being lower than would have been had copeptin been measured immediately after venipuncture. [41]. Additionally, in different cohorts, the variable prevalence of outliers with very high (>20–30 pmol/L) copeptin concentrations, likely related to the stress of the procedure, [42] rather than to the rare AVP-R, may affect the statistical interpretation of the values. Among other variables, obesity has been associated with higher copeptin values in some studies of “control” children [36], 43] but not in others [37]. Age (aside from one study [38]), BMI within the 10–90th percentile, sex, or growth hormone secretory status have not generally shown correlation with baseline or stimulated copeptin concentrations [37], 40], 44], 45], with the exception of one study linking severe growth hormone deficiency to a decreased copeptin response to the insulin tolerance test (ITT) [46]. Similarly, random copeptin concentrations do not seem to differ in boys vs. girls before or during puberty [37], 40], 44], with the possible exception of late puberty, when males may have slightly higher concentrations than females [43], similar to adults [8]. In summary, these studies, not unlike adult data [26], show substantial variability in random copeptin levels among subjects, which may affect its diagnostic sensitivity.

The effect of stress on random copeptin concentrations

In adults, copeptin and/or AVP and can be very elevated during illnesses associated with pain or physical stress, including myocardial infarction, stroke, sepsis, and pneumonia [12], 47], 48]. Copeptin levels are only modestly increased in experimental studies of moderate physical pain [49] or mild psychological stress [50], 51].

With regard to children, copeptin levels are also quite elevated during critical illness [52]. Limited information exists for less severe stressful situations; for example, chronic maltreatment has been associated with increased copeptin levels, but the conclusion is marred by a nonvalidated copeptin assay [53]. We did observe, however, elevated copeptin concentrations in response to phlebotomy in a prospective study of 93 children undergoing growth hormone stimulation testing. Nine percent of these children had high copeptin concentrations (>39 pmol/L) in their initial blood samples obtained 1–3 min after phlebotomy, which decreased rapidly over the subsequent 2 hours [42]. This suggested a marked stress response in a small subgroup of children undergoing venipuncture. In a second study of 51 children, excluding outliers, serum copeptin concentrations levels decreased significantly (Delta −2.7 pmol/L, p<0.001) 20 min after phlebotomy, concordant with a significant decrease in norepinephrine and epinephrine concentrations [41]. Thus, standardization of blood drawing, along with attention to possible outliers, is important to properly interpret copeptin concentrations in children and allow comparison across different studies.

Available tests of copeptin stimulation in children

Osmotic tests of AVP/copeptin secretion

Osmotic tests include the WDT [54] and the hypertonic saline test (HST) [33], 55], both initially described and validated in adults. The HST has been recently updated with measurement of copeptin, rather than AVP, also in adults [26]. These tests achieve stimulation of AVP/copeptin secretion differently. The WDT, while unmasking hypernatremia rapidly in severe AVP-D, induces a slow, modest increase in plasma osmolality over several hours in subjects with PP or partial AVP-D, which, at least in adult studies, has been linked to inadequate AVP stimulation [9]. Conversely, the infusion of 3 % NaCl in the HST achieves a rapid and substantial (≥5 %) increase in serum sodium and plasma osmolality over a few hours [33], resulting in intense stimulation of AVP/copeptin secretion and, unsurprisingly, a much better accuracy than the WDT in adults. [55], [56], [57]. They are reviewed in more detail below.

The water deprivation test

Adult studies: In the original description in adults [54], the WDT was based on measurements of urine volumes and plasma and urine osmolalities in response to water restriction for up to 17 hours, without hormonal measurements, referred to as the “indirect” WDT. Subsequently, measurement of AVP during the WDT (the “direct” WDT) reportedly improved its diagnostic accuracy in adults [58], but these results were difficult to reproduce [9], 59]. The poor reproducibility cannot be explained solely by the difficulty in measuring AVP, given that quantitation of copeptin has, likewise not increased the diagnostic accuracy of the WDT [56], [60], [61], [62], despite early encouraging results [9]. Overall, the WDT was found to have limited diagnostic accuracy, estimated at 70–75 % in large cohorts of adults with PPS, with the main difficulty being differentiating PP from partial AVP-D [9], 56], 63].

Pediatric studies: In children, the WDT has been the gold standard for evaluation of PPS. Its diagnostic accuracy has not been validated in large studies, as most reports involve small cohorts of children [5], [6], [7]. While a serum sodium level ≥147 mEq/L in conjunction with hypotonic urine confirms AVP-D (or AVP-R), our and others’ experience suggests that, similarly to the adult findings, the WDT does not easily differentiate AVP-D from PP in children with PPS [45] due to overlapping laboratory parameters. Likewise, a study of plasma copeptin measurements following a short WDT in children [64] listed in Table 1 showed overlapping copeptin levels (range 2.3–14.5 in PP, 1.4–4.9 pmol/L in AVP-D), leading to suboptimal sensitivity (75 %) and specificity (83 %). Two children with partial AVP-D achieved copeptin levels of 4.3–4.9 pmol/L, which overlapped with those of children with PP. Another report by the same group showed overlapping urine osmolalities as well as fasting serum copeptin levels between partial AVP-D and PP [65]. In a preliminary report [66] of 13 children, ultimately diagnosed with PP, median serum copeptin levels were 8 (IQR 5–16 pmol/L, range 2–45 pmol/L) during the WDT (mean duration 12.8 h). Interestingly, in six of 11 subjects who had serial copeptin levels obtained during the WDT, maximal values (all ≥5 pmol/L) occurred in the second half of the test, rather than at the end. Thus, the utility and the modality of copeptin quantitation during the WDT in children with PPS remain to be defined.

The WDT also has practical shortcomings, as it is taxing for the child and the family, with risks of dehydration or hypoglycemia, particularly in young children. Some centers allow consumption of dry food to prevent hypoglycema [67], though this does not abolish the unpleasant lack of access to water for a thirsty patient. It typically requires hospitalization and close supervision of the child and family to prevent surreptitious fluid intake.

The hypertonic saline test (HST)

Adult studies: The HST has been considered a reliable test for evaluation of PPS in adults for decades, both without [68] or with AVP measurements [57]. More recently, two adult studies (employing copeptin measurements) compared the HST to the WDT and to the arginine stimulation test to differentiate AVP-D from PP. The HST achieved a diagnostic accuracy of ∼95 % vs. ∼70–75 % against both the WDT [56] and the arginine stimulation test [63], at a proposed cutoff between 4.9 and 5.2 pmol/L [26], 56], 63].

Pediatric studies: The HST has been used infrequently in children [69], [70], [71], [72], [73] due to concerns about a rapid increase in plasma osmolality, the local risk of thrombophlebitis/extravasation, the need for close monitoring of serum sodium levels in the hospital/intensive care setting, and reference values on HST-stimulated copeptin levels being available only for adults [56]. It has been shown to be a valuable tool to assess the AVP reserve in children with partial AVP-D [71], 72]. Except for this limited indication, we believe that the HST should be used uncommonly in children, only as an “end of the line” test in particularly challenging cases, at variance with a recently suggested pediatric algorithm [11], and only in centers who are experienced in this procedure.

Nonosmotic tests of AVP reserve: growth-hormone stimulating agents being “redirected” for copeptin stimulation

This category includes single agent tests: insulin-induced hypoglycemia via the ITT, the arginine stimulation test, the glucagon stimulation test (GST), and recently, the oral L-Dopa stimulation test. In pilot studies (unpublished), we found clonidine to have no effect on copeptin stimulation, as recently reported [74], 75]. Macimorelin, likewise, has shown no effect in adult studies [76], 77]. We recently developed tests of copeptin stimulation by 2 combined agents, namely the arginine-insulin tolerance test (AITT), and the arginine-L-Dopa/carbidopa stimulation test (ALD-ST), as discussed below.

Single agent tests of nonosmotic copeptin stimulation (Table 1)

Insulin

Adult studies: Early studies showed stimulation of AVP secretion by the ITT in humans [78]. This effect was confirmed by Katan et al. [79], who showed a robust copeptin response (with peak 30–60 min after IV insulin administration) from a mean ± SD of 3.7 ± 1.5 at baseline to 11.2 ± 4.6 pmol/L (+200 %) in 29 AVP-sufficient adults, albeit with large variability between subjects, and peak levels or delta increase over baseline being often very low (<5 pmol/L) in individual patients. Subsequent studies in adults with normal pituitary or anterior pituitary deficiencies only, the copeptin response to the ITT has ranged from 40 % [74], 80] to 107 % [81].

Pediatric studies: These have shown copeptin responses to the ITT (Table 1) averaging 86–90 % above baseline in normal-short children [39], 46]. In one of these studies, frequently low individual peak or delta responses (<5 pmol/L) to the ITT were reported [46]; in the other one, ITT-stimulated copeptin levels showed considerable overlap of interquartile range values between control and AVP-D children, with a diagnostic sensitivity only marginally better than that of baseline copeptin in differentiating severe AVP-D from PP [39]. Altogether, these studies suggest limited diagnostic utility for the ITT, a test that is often stressful for the patient due to induced hypoglycemia, in the assessment of the AVP/copeptin reserve in children.

Arginine

Adult studies: Winzeler et al. opened a new chapter in posterior pituitary testing by describing the effect of IV arginine as an agent for copeptin stimulation [10]. They noted a copeptin increment of ∼90–116 % in adult controls and subjects with PP, but only a minimal increase in patients with complete or partial AVP-D, for a diagnostic accuracy of 93 % for identifying AVP-D at a proposed cutoff of 3.8 pmol/L for stimulated copeptin. In a follow-up study from the same group, however, this test had limited diagnostic accuracy, similar to that of the WDT in a head-to-head comparison with the current adult “gold standard” of hypertonic saline infusion (∼75 vs. 95 % for the HST). [63].

Pediatric studies: The above noted study by Winzeler included a group of control children, and no children with PPS. The copeptin increment was less robust in children (∼50 % over baseline) than the 90+ % increase in adults. Further pediatric reports of the arginine stimulation test in groups of 16–68 short children being tested for growth hormone deficiency showed an increase of copeptin concentrations ranging from 20–86 % from baseline, [38], 40], 44], 65], 74], for an overall increase of ∼50 %, in agreement with the original report [10]. Even though some investigators have claimed a high diagnostic accuracy for various cutoff values of arginine-stimulated copeptin in separating PP from AVP-D [38], 40], these studies suffer from one or more of the following limitations: the number of subjects with PPS is small, the number of subjects with PP and with AVP-D is unevenly matched, or there is a selection bias toward patients with severe (vs. partial) AVP-D. Thus, sensitivity and specificity calculations of cutoff stimulated copeptin values should be interpreted with caution. While the test is easy to perform and with limited side effects, we share with others [11], 38] concerns that arginine is a weak stimulus of copeptin secretion in children, and its diagnostic sensitivity, which is suboptimal in adults [63], would need to be reevaluated in larger cohorts of children with PPS, which should include children with partial AVP-D.

Glucagon

Adult studies: Intramuscular or subcutaneous glucagon (GST) stimulates copeptin secretion in adults [77], [82], [83], [84], with a peak copeptin response at 150–180 min. IV glucagon has no effect [85]. Atila et al. [82] showed a median copeptin increase from 4.4 to 12.1 pmol/L (+175 %) in 22 control adults pretreated with an antiemetic agent. They found that a stimulated copeptin level of 4.6–5.0 pmol/L, similar to the cutoff proposed for the adult HST, had a diagnostic accuracy of 95 % in differentiating PP from AVP-D. In contrast, without antiemetic agents, Lewandoski [83] showed a robust copeptin response to glucagon in healthy controls with a peak of 30–35 pmol/L, significantly higher than in subjects with combined posterior and anterior pituitary deficiencies (peak ∼5 pmol/L). Patients at risk for anterior pituitary dysfunction after trans-sphenoidal pituitary surgery who had normal cortisol and growth hormone response to glucagon had intermediate values (peak copeptin 10–12 pmol/L). Given the more robust and consistent copeptin response to the GST than to arginine or insulin and excellent safety profile, the GST may well become the preferred agent for nonosmotic, single agent copeptin stimulation testing in adults.

Pediatric studies: No pediatric data are available yet for this test.

Levodopa (L-Dopa)

Adult studies: None published.

Pediatric studies: Though one study reported no effect on copeptin secretion by L-Dopa [86], it was hampered by a very small sample size (4 children) and lack of use of the validated Kryptor copeptin assay. More recently, Wang et al. showed that oral L-Dopa at an average dose of 12.7 mg/kg elicited a copeptin response in 40/44 short children [87]. Although the authors stated that children with nausea/vomiting were excluded, only 1 child with these symptoms was found in the medical record in this retrospective study, an unexpectedly very low prevalence of these side effects. Regardless, the median copeptin peak value in this study was 19.4 (IQR: 9,108) pmol/L, which is higher than the peak after single agent tests in children [38], [39], [40, 46], 65]. This promising test awaits validation in children with PPS.

Urea

Adult studies: In a recent open-label study urea (0.5 g/kg), administered orally as a novel osmotic stimulus for copeptin secretion, separated subjects with AVP-D from those with PP in a small (n=26) cohort of adults with PPS, with diagnostic accuracy ~ 90 %, similar to that of the Arginine Stimulation test [88]. Despite the practical advantages of oral administration, the adoption of such a test in children will be limited by the bitter taste of the urea solution.

Pediatric studies: None.

Combined (2-agent) tests of nonosmotic copeptin stimulation (Table 1)

In the last 3 years, we have developed posterior pituitary stimulation tests that combine IV arginine with a) intravenous insulin or b) oral levodopa/carbidopa. Both tests appear to yield a substantially greater copeptin stimulation than that achieved with single (nonosmotic) agent stimulation tests.

Arginine-insulin

Sequential arginine-insulin stimulation test (AITT) induces potent stimulation of copeptin secretion in normal short children, which appears to be greater than the sum of the responses to each agent administered alone [44] (Table 1). In this test, arginine (0.5 g/kg) is infused IV between 0 and 30 min, followed by an IV bolus of regular insulin (0.1 U/kg) at 60 min. Peak copeptin values occur consistently between 80 and 90 min in all subjects and at 90 min in most of them, making the results meaningful with only the 0 and 90 min blood sample drawn. In our series, 97 % of control children achieved a peak copeptin level >10 pmol/L. Although we have used the AITT for growth hormone stimulation without incident in over 1,500 children to date, concerns of patient discomfort and risk of hypoglycemia have prevented approval of its use for children with PPS, for whom it is not standard of care. The most appropriate use of this test at the present time would be in children who have a combined diagnosis of PPS and suspected GH/ACTH deficiencies, for whom the AITT would test both the anterior and posterior pituitary functions, with advantages over the ITT for consistency and robustness of the copeptin response.

Arginine-L-Dopa/carbidopa

Recently, we have adapted the arginine-levodopa/carbidopa stimulation test (ALD-ST), which we have used for growth hormone stimulation for decades, to assess the copeptin response in short-normal children and children with PPS. We modified the test from previous reports [89], 90] by adjusting the dosage of the L-Dopa/carbidopa to the body surface area (BSA). After a baseline blood sample is obtained, L-Dopa [dose 175 (range 150–200) mg/m2 BSA]/carbidopa (10:1 ratio) is given orally at time 0 min, simultaneously with the beginning of a 30-min IV infusion of arginine (0.5 mg/kg, maximum 30 g). This is followed by blood sampling at 60, 90, 120 min, which are optimal times based on preliminary work involving sampling every 15 min. Patients should avoid solids for a minimum of 3 hours and liquids for at least 2 hours before the test to maximize absorption of the L-Dopa/carbidopa, which is affected by food [91]. In our study, the ALD-ST achieved potent stimulation of copeptin release in a cohort of 48 normal-short children [median peak 44 (IQR 21,181) pmol/L] [45] (Table 1). We found peak-stimulated copeptin concentration of 9.3 pmol/L to have the best diagnostic accuracy in differentiating PP from AVP-D, in our cohort (n=20) of children with PPS. [45]. Figure 2 shows the peak copeptin responses to arginine and the AITT in normal short children (controls) and includes the response to the ALD-ST in both controls and children with PPS.

Figure 2: Peak copeptin response to arginine (ARG). Arginine-insulin (AITT) in control children (Cont) [44] and to arginine-levodopa/carbidopa (ALD-ST) [45] in control children, children with primary polydipsia (PP) and AVP deficiency (AVP-D). Bars indicate median and IQR. The whiskers indicate the 5th and 95th percentile. Dots indicate outliers.
Figure 2:

Peak copeptin response to arginine (ARG). Arginine-insulin (AITT) in control children (Cont) [44] and to arginine-levodopa/carbidopa (ALD-ST) [45] in control children, children with primary polydipsia (PP) and AVP deficiency (AVP-D). Bars indicate median and IQR. The whiskers indicate the 5th and 95th percentile. Dots indicate outliers.

Nausea, a well-known side effect, occurred in approximately 50 % of children undergoing the ALD-ST. Children who experienced nausea had a potentiated copeptin response, even more so if associated with vomiting. Regardless, the response was substantial even in children without nausea/vomiting, whose copeptin peak (median 22.7 (IQR 16, 34) pmol/L) was similar to the peak we observed in 38 children (largely unaffected by nausea/vomiting) undergoing the AITT (median 23 (IQR 19, 27.5) pmol/L) [44]. The effect of nausea/vomiting on the copeptin response may be relevant to other tests of copeptin stimulation but has been studied only to a limited extent in adults and not in children. The interesting report by Brooks suggested that nausea/vomiting increased the copeptin response to the HST ∼65 % in adults [92]. Of note, non-nauseous adults in the latter study achieved median copeptin levels of 20 (IQR 1,331) pmol/L, similar to the median of our non-nauseous group of children undergoing the ALD-ST, with the obvious limitations of the comparison of different types of stimuli in cohorts of different age. Unanswered questions at this regard are whether these gastrointestinal side effects may also amplify the copeptin response to stimulation tests in (some) children with partial AVP-D and whether separate cutoff values may be needed for copeptin stimulation tests in patients with or without nausea/vomiting. It is also unclear whether the addition of antiemetics may affect the copeptin response to the ALD-ST or other tests of copeptin reserve, as suggested by experimental studies [93], 94].

The possible mechanisms whereby L-Dopa stimulates AVP/copeptin secretion are unclear. Experimental data on the effect of L-Dopa on AVP secretion suggest a differential effect related to dopamine receptor subtypes D1 and D2 [95], 96] but are overall inconclusive or controversial [97], while clinical reports of SIADH in dopamine-agonist treated patients with Parkinson’s disease are anecdotal [98]. Somatostatin suppression, induced by arginine and, at least partially, by L-Dopa [99], may act as a stimulus for AVP/copeptin secretion, as noted elsewhere [44]. A previously mentioned recent paper does suggest stimulation of AVP/copeptin by L-Dopa alone in children [87], albeit to a lower degree than the L-Dopa/carbidopa/arginine combination. However, the likely under-reporting of nausea vomiting in that retrospective analysis does not allow an accurate comparison with our ALD-ST study, which prospectively documented side effects. Thus, it is unclear whether arginine potentiates the copeptin response to L-Dopa/carbidopa, similar to the postulated arginine augmentation of the insulin response in the AITT [44].

Discussion

The recent availability of the robust copeptin immunometric assay as a reliable surrogate of AVP secretion has reopened a chapter of posterior pituitary endocrinology, which was extensively studied in adults in the 1970–1990 years with a validated RIA and allowed great progress in the understanding of the pathophysiology, diagnosis, and therapy of fluid regulation and dysregulation [33], 57], 100], 101]. Taking advantage of the copeptin assay and our experience with double-agent copeptin stimulation tests, we have recently modified our traditional approach to investigating PPS in pediatrics. We typically perform the ALD-ST in the early phase of the diagnostic evaluation with or without a subsequent WDT – the latter having often been our initial diagnostic mainstay previously. In the proposed diagnostic workup, we assume that a thorough history and physical examination were obtained and a baseline laboratory work-up excluded polyuria secondary to conditions such as diabetes mellitus, hypokalemia, hypercalcemia, renal dysfunction/tubular damage. We also assume that there are no immediate concerns for a CNS lesion, which would require an immediate MRI of the brain. Once hypotonic polyuria (>2 L/m2/day [3]) has been confirmed, the differential diagnosis includes AVP-D, AVP-R ,and PP. Of note, even though the diagnosis of diabetes insipidus is classically associated with a U-Osm below 300 mOsm/kg [102], higher urine osmolalities characterize partial AVP-D in both adults [54] and children [64], 65]. We have summarized our approach below.

Step 1: Clinical assessment

As the first step, polydipsia and polyuria should be confirmed by asking that families measure the total amount of fluids the child drinks over 24 hour, with timing of the drinks (daytime vs. night-time), at least on 2 different days. Nocturnal drinking favors AVP-D vs. PP, at least in adults [56]. Likewise one, or preferably two, 24-hour urine collection at home should be obtained, for total volume and urine osmolality (though the latter is rarely diagnostic). High costs of hospitalization prevent the more accurate inpatient quantification of polyuria and polydipsia in most countries.

Step 2: Fasting serum sodium/electrolytes, copeptin, and urine osmolality

As a second level procedure, the child should go to the laboratory in the early morning in the fasting state, after limiting nocturnal drinking for as long as usually tolerated at home, for measurement of serum sodium/electrolytes, BUN, creatinine, copeptin level, plasma osmolality, and urine osmolality on the first morning urine specimen. Such screening test may suffice to exclude AVP-D if it demonstrates a clearly elevated urine osmolality (>600–800 mOsm/kg as discussed below for the WDT) and/or reassuring serum copeptin values (also discussed below), with normal sodium levels of 143 mEq or less. Unfortunately, a lower urine osmolality with normal serum sodium will not exclude AVP-D.

Regarding fasting copeptin concentrations, proposed cutoff copeptin values to differentiate AVP-D from PP in children have generally been in the 2.9–3.8 pmol/L range [37], 64], 65] (Table 1), with lower values (2.2–2.9 pmol/L range) suggested to separate PP from complete DI [64] (Table 1). Similar cutoffs have been suggested in adults [9], 26]. In the different context of 17 critically ill, hypernatremic children, a cutoff of 4.9 pmol/L had the best diagnostic accuracy to diagnose AVP-D [103].

We [44], 45] and others [36] have observed average copeptin values in the 7–10 pmol/L range (with a wide scatter of values) in children with no access to fluids for ∼ 8 hours, being cognizant that subjects with PPS would not be likely or able to undergo water restriction for so many hours. We and others have also observed copeptin values as high as 4–5 pmol/L in children with partial AVP-D randomly [45] or following water restriction [38], 64]. Acknowledging these limited data indicating overlap of random copeptin concentrations ≤5 pmol/L between subjects with PP and those with partial AVP-D, we have been using 5 pmol/L as reassuring, and 6 pmol/L as very reassuring cutoffs against AVP-D. These cutoff values, while higher than generally proposed for baseline or even arginine- or insulin-stimulated copeptin (Table 1), aim at excluding partial AVP-D, at variance with studies (Table 1) including predominantly subjects with severe AVP-D. Moreover, as an initial screening test, they are meant to favor maximal sensitivity (at the expense of specificity) toward excluding partial AVP-D, in order to minimize the risk of overlooking organic CNS lesions.

With regard to the finding of elevated copeptin values in random blood samples, levels >20–21.4 pmol/L with hypotonic urine have been considered diagnostic of AVP-R in children [64], as well as adults [9], 56]. However, as noted above, very elevated copeptin concentrations occur in a subset of normal children after phlebotomy, possibly owing to the pain/stress of the venipuncture and/or related procedures [42]. Therefore, a high copeptin level may need to be interpreted in the context of the additional clinical and laboratory findings and, if indicated, confirmed by repeat blood sampling to avoid an incorrect diagnosis.

Step 3: The L-Dopa/carbidopa stimulation test

As random laboratory tests, including copeptin measurements, are frequently equivocal, the outpatient ALD-ST is the next step in our evaluation. The cutoff value of 9.3 pmol/L for peak stimulated copeptin concentrations that had the best diagnostic accuracy to differentiate AVP-D from PP in our study [45] is higher than cutoffs proposed for the stimulation tests with other, single agents (Table 1), which is likely related to the intense stimulatory effect of the ALD-ST vis-à-vis the presence of subjects with partial AVP-D in our series, which included 2 patients with stimulated copeptin values ≥10 pmol/L. For comparison, in children with severe AVP-D who underwent the ALD-ST during validation studies, we found very low or undetectable copeptin (<2–3 pmol/L) at baseline (as others did [38], [39], [40]) and throughout the test.

The goal of the diagnostic pathway in Figure 3 is to outline the steps we currently use and recommend in the diagnostic evaluation of PPS in children, based on the initial measurement of fasting serum sodium and copeptin, followed by the ALD-ST as the next step. In our opinion, this test provides a more practical (outpatient) alternative to the WDT; it is as safe as the arginine stimulation test and safer than the ITT. Despite the relatively high cutoff values for baseline and stimulated copeptin levels shown in Figure 3, their usage has undoubtedly decreased the number of patients undergoing a WDT and/or a pituitary MRI in our center. We pursue MRIs, however, in those children with a copeptin response <9.3 pmol/L to the ALD-ST, and even in selected children with slightly higher responses, depending on the other clinical and laboratory findings.

Figure 3: Recommended steps in the diagnostic evaluation of PPS in children. PPS, polyuria-polydipsia syndrome; PP, primary polydipsia; AVP-D: AVP-deficiency; AVP-R: AVP resistance; ALDST, arginine-levodopa stimulation test; WDT, water deprivation test.
Figure 3:

Recommended steps in the diagnostic evaluation of PPS in children. PPS, polyuria-polydipsia syndrome; PP, primary polydipsia; AVP-D: AVP-deficiency; AVP-R: AVP resistance; ALDST, arginine-levodopa stimulation test; WDT, water deprivation test.

Step 4: The water deprivation test and pituitary magnetic resonance imaging (MRI)

As we mentioned above, in children with high presumption of complete AVP-D based on history and preliminary laboratory tests, a short (3–4 hour) period of fluid deprivation in the outpatient setting may confirm the diagnosis without further tests. Barring this scenario, the WDT may be helpful in a (likely small) subgroup of children with equivocal/borderline copeptin response to the ALD-ST. Thus, we have moved the WDT toward the end of the diagnostic pathway for children with PPS. To pass a formal WDT, we have been using a urine osmolality >800 mOsm/Kg in children aged 2 years or older, as in adults [54], 104]. For younger children, we have used a cutoff of >600 mOsm/kg due to the substantial variability for this parameter during the first few years of life, partially related to protein intake [105] even though full urine concentrating capacity should be achieved by 6–12 months of age [106]. Other pediatric investigators have proposed urine Osm >750 mOsm/kg or>1,000 in a single specimen or >600 mOsm/kg in 2 subsequent specimens [107], 108]. Regardless of the cutoff chosen, even the conservative value of 800 mOsm/Kg could theoretically be exceeded in rare cases of very partial AVP-D. As we noted above, measurement of copeptin levels during the WDT has not improved the diagnostic accuracy of the test in adults, while data are limited in children. Though the WDT may be nondiagnostic, it still serves the important role of providing useful physiological information about the tolerance to water deprivation in children diagnosed with, or suspected to have, partial AVP-D and gives a valuable input on the risk of dehydration for families and providers, in the event of vomiting or diarrhea.

Pituitary/brain MRI has become a very important tool in the evaluation of children and adults with PPS [109], as the posterior pituitary hyperintense signal (“bright spot” or “PPBS”) in T1-weighed images is believed to reflect the AVP content of the posterior pituitary [110]. Pediatric studies suggest that the diagnostic sensitivity of an absent PPBS to indicate AVP-D in children is higher (>90 %) [111], 112] than in adults (∼70 %) [56]; however, data are overall limited, with absence of large series comparing the diagnostic accuracy of MRI, in the differential diagnosis of pediatric AVP-D vs. PP. Additional drawbacks of this procedure, limiting its use as a first-line test, are the need for sedation in young children and limited access to obtaining an MRI expeditiously in many countries and healthcare systems. However, a pituitary and brain MRI with gadolinium contrast is clearly indicated during the investigation of PPS, at least under these circumstances: A) In children with neurological or other findings suspicious for an organic brain lesion (the MRI should be obtained immediately after the initial clinical and laboratory evaluation). B) In neonates/infants with unexplained hypernatremia and nonelevated copeptin level (due to high probability of anatomical hypothalamic–pituitary/CNS abnormalities). C) In all children diagnosed with AVP-D by clinical and laboratory assessment, to clarify the etiology. If no lesion is visualized initially, leading to a provisional diagnosis of “idiopathic” AVP-D, our practice is to reimage in 3–6 months (to exclude rapidly growing germ-cell tumors), followed by bi-annual MRIs for at least 3–5 years, given that germ-cell tumors may appear with several years’ delay after the onset of DI [113], [114], [115]. Even longer-term MRI monitoring is suggested for Langerhans Cell histiocytosis, which may remain undiagnosed after 7 years of initial manifestations in 20 % of cases [116]. D) If the diagnosis is unclear (typically between partial AVP-D and PP), the MRI may clarify the diagnosis.

In conclusion, we have found that, among the nonosmotic copeptin stimulation tests that have been used in children, the dual-agent tests induce a substantially stronger stimulus of copeptin secretion than single agent tests. Further and larger studies are needed to validate our assumption that the ALD-ST provides a better separation between children with PP and those with partial AVP-D than single agent tests. We believe the ALD-ST can be used safely and effectively in the early workup of PPS in children [45]. With any test, however, the possibility remains of an overlap in values between subjects with PP and those on the spectrum of partial AVP-D, which underlines the need for a comprehensive evaluation of clinical, MRI, and biochemical findings in equivocal cases of children with PPS.

Corresponding authors: Luigi R. Garibaldi, MD and Christine A. March, MD MS, Division of Pediatric Endocrinology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA; and Department of Pediatrics, University of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA, E-mail: (L. R. Garibaldi), (C. A. March).

Funding source: NIDDK

Award Identifier / Grant number: 1K23135800

Acknowledgments

We are indebted to testing nurses of the Endocrine Division at the UPMC Children’s Hospital of Pittsburgh for their skills and help with many copeptin stimulation tests, which have made this and previous papers possible.

  1. Research ethics: Not applicable (Review paper).

  2. Informed consent: Not applicable (Review paper).

  3. Author contributions: Dr. Garibaldi conceptualized the manuscript and wrote the initial draft. Dr. March and McPhaul contributed to revising the draft and structuring the manuscript. Dr Sastry reviewed publications and advised how to integrate our results with previously published results. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: Dr. Garibaldi, March and Sastry: No conflict. Dr. McPhaul, Dr. Michael J McPhaul is a consultant for Quest Diagnostics- Nichols Institute (where copeptin measurements for our previous papers were performed) and owns stock in the company.

  6. Research funding: Dr. March has funding through NIDDK 1K23135800.

  7. Data availability: Not applicable.

References

1. Christ-Crain, M. EJE award 2019: new diagnostic approaches for patients with polyuria polydipsia syndrome. Eur J Endocrinol 2019;181:R11–21. https://doi.org/10.1530/eje-19-0163.Suche in Google Scholar

2. Arima, H, Cheetham, T, Christ-Crain, M, Cooper, D, Drummond, J, Gurnell, M, et al.. Changing the name of diabetes insipidus: a position statement of the working group for renaming diabetes insipidus. J Clin Endocrinol Metab 2022;108:1–3. https://doi.org/10.1210/clinem/dgac547.Suche in Google Scholar PubMed PubMed Central

3. Patti, G, Napoli, F, Fava, D, Casalini, E, Di Iorgi, N, Maghnie, M. Approach to the pediatric patient: central diabetes insipidus. J Clin Endocrinol Metab 2022;107:1407–16. https://doi.org/10.1210/clinem/dgab930.Suche in Google Scholar PubMed

4. Bockenhauer, D, Bichet, DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol 2015;11:576–88. https://doi.org/10.1038/nrneph.2015.89.Suche in Google Scholar PubMed

5. Frasier, SD, Kutnik, LA, Schmidt, RT, Smith, FGJr. A water deprivation test for the diagnosis of diabetes insipidus in children. Am J Dis Child 1967;114:157–60. https://doi.org/10.1001/archpedi.1967.02090230087009.Suche in Google Scholar PubMed

6. Wong, LM, Man, SS. Water deprivation test in children with polyuria. J Pediatr Endocrinol Metab 2012;25:869–74. https://doi.org/10.1515/jpem-2012-0092.Suche in Google Scholar PubMed

7. Czernichow, P, Pomarede, R, Basmaciogullari, A, Rappaport, R. Diabetes insipidus in children. I. Arginine-vasopressin determination in plasma during short dehydration test. Acta Paediatr Scand Suppl 1979;277:64–8.10.1111/j.1651-2227.1979.tb06194.xSuche in Google Scholar PubMed

8. Morgenthaler, NG, Struck, J, Alonso, C, Bergmann, A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 2006;52:112–9. https://doi.org/10.1373/clinchem.2005.060038.Suche in Google Scholar PubMed

9. Fenske, W, Quinkler, M, Lorenz, D, Zopf, K, Haagen, U, Papassotiriou, J, et al.. Copeptin in the differential diagnosis of the polydipsia-polyuria syndrome–revisiting the direct and indirect water deprivation tests. J Clin Endocrinol Metab 2011;96:1506–15. https://doi.org/10.1210/jc.2010-2345.Suche in Google Scholar PubMed

10. Winzeler, B, Cesana-Nigro, N, Refardt, J, Vogt, DR, Imber, C, Morin, B, et al.. Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study. Lancet 2019;394:587–95. https://doi.org/10.1016/s0140-6736(19)31255-3.Suche in Google Scholar PubMed

11. Huynh, T, Signal, D, Christ-Crain, M. Paediatric perspectives in the diagnosis of polyuria-polydipsia syndrome. Clin Endocrinol 2024. https://doi.org/10.1111/cen.15011.Suche in Google Scholar PubMed

12. Christ-Crain, M. Vasopressin and Copeptin in health and disease. Rev Endocr Metab Disord 2019;20:283–94. https://doi.org/10.1007/s11154-019-09509-9.Suche in Google Scholar PubMed

13. Mu, D, Ma, C, Cheng, J, Zou, Y, Qiu, L, Cheng, X. Copeptin in fluid disorders and stress. Clin Chim Acta 2022;529:46–60. https://doi.org/10.1016/j.cca.2022.02.002.Suche in Google Scholar PubMed

14. Di Iorgi, N, Morana, G, Napoli, F, Allegri, AE, Rossi, A, Maghnie, M. Management of diabetes insipidus and adipsia in the child. Best Pract Res Clin Endocrinol Metabol 2015;29:415–36. https://doi.org/10.1016/j.beem.2015.04.013.Suche in Google Scholar PubMed

15. Robertson, GL, Mahr, EA, Athar, S, Sinha, T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Investig 1973;52:2340–52. https://doi.org/10.1172/jci107423.Suche in Google Scholar PubMed PubMed Central

16. Kluge, M, Riedl, S, Erhart-Hofmann, B, Hartmann, J, Waldhauser, F. Improved extraction procedure and RIA for determination of arginine8-vasopressin in plasma: role of premeasurement sample treatment and reference values in children. Clin Chem 1999;45:98–103. https://doi.org/10.1093/clinchem/45.1.98.Suche in Google Scholar

17. Ysewijn-Van Brussel, KA, De Leenheer, AP. Development and evaluation of a radioimmunoassay for Arg8-vasopressin, after extraction with Sep-Pak C18. Clin Chem 1985;31:861–3.10.1093/clinchem/31.6.861Suche in Google Scholar

18. Preibisz, JJ, Sealey, JE, Laragh, JH, Cody, RJ, Weksler, BB. Plasma and platelet vasopressin in essential hypertension and congestive heart failure. Hypertension 1983;5:I129–38. https://doi.org/10.1161/01.hyp.5.2_pt_2.i129.Suche in Google Scholar PubMed

19. Holwerda, DA. A glycopeptide from the posterior lobe of pig pituitaries. I. Isolation and characterization. Eur J Biochem 1972;28:334–9. https://doi.org/10.1111/j.1432-1033.1972.tb01918.x.Suche in Google Scholar PubMed

20. Seidah, NG, Benjannet, S, Chretien, M. The complete sequence of a novel human pituitary glycopeptide homologous to pig posterior pituitary glycopeptide. Biochem Biophys Res Commun 1981;100:901–7. https://doi.org/10.1016/s0006-291x(81)80258-6.Suche in Google Scholar PubMed

21. Bankir, L, Bichet, DG, Morgenthaler, NG. Vasopressin: physiology, assessment and osmosensation. J Intern Med 2017;282:284–97. https://doi.org/10.1111/joim.12645.Suche in Google Scholar PubMed

22. Robinson, AG. Chapter 5: The posterior pituitary (Neurohypophysis). In: Gardner GG, Shobac D, editor. Greenspan's basic & clinical endocrinology, 10th ed. New York: McGraw-Hill; 2017.Suche in Google Scholar

23. Christ-Crain, M, Refardt, J, Winzeler, B. Approach to the patient: “utility of the copeptin assay”. J Clin Endocrinol Metab 2022;107:1727–38. https://doi.org/10.1210/clinem/dgac070.Suche in Google Scholar PubMed PubMed Central

24. Fenske, WK, Schnyder, I, Koch, G, Walti, C, Pfister, M, Kopp, P, et al.. Release and decay kinetics of copeptin vs AVP in response to osmotic alterations in healthy volunteers. J Clin Endocrinol Metab 2018;103:505–13. https://doi.org/10.1210/jc.2017-01891.Suche in Google Scholar PubMed

25. Balanescu, S, Kopp, P, Gaskill, MB, Morgenthaler, NG, Schindler, C, Rutishauser, J. Correlation of plasma copeptin and vasopressin concentrations in hypo-iso-and hyperosmolar States. J Clin Endocrinol Metab 2011;96:1046–52. https://doi.org/10.1210/jc.2010-2499.Suche in Google Scholar PubMed

26. Timper, K, Fenske, W, Kuhn, F, Frech, N, Arici, B, Rutishauser, J, et al.. Diagnostic accuracy of copeptin in the differential diagnosis of the polyuria-polydipsia syndrome: a prospective multicenter study. J Clin Endocrinol Metab 2015;100:2268–74. https://doi.org/10.1210/jc.2014-4507.Suche in Google Scholar PubMed

27. Sailer, CO, Refardt, J, Blum, CA, Schnyder, I, Molina-Tijeras, JA, Fenske, W, et al.. Validity of different copeptin assays in the differential diagnosis of the polyuria-polydipsia syndrome. Sci Rep 2021;11:10104. https://doi.org/10.1038/s41598-021-89505-9.Suche in Google Scholar PubMed PubMed Central

28. Aguilera, G, Subburaju, S, Young, S, Chen, J. The parvocellular vasopressinergic system and responsiveness of the hypothalamic pituitary adrenal axis during chronic stress. Prog Brain Res 2008;170:29–39. https://doi.org/10.1016/s0079-6123(08)00403-2.Suche in Google Scholar PubMed PubMed Central

29. Gillies, GE, Linton, EA, Lowry, PJ. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 1982;299:355–7. https://doi.org/10.1038/299355a0.Suche in Google Scholar PubMed

30. Rivier, C, Vale, W. Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 1983;305:325–7. https://doi.org/10.1038/305325a0.Suche in Google Scholar PubMed

31. Watabe, T, Tanaka, K, Kumagae, M, Itoh, S, Kogure, M, Hasegawa, M, et al.. Role of endogenous arginine vasopressin in potentiating corticotropin-releasing hormone-stimulated corticotropin secretion in man. J Clin Endocrinol Metab 1988;66:1132–7. https://doi.org/10.1210/jcem-66-6-1132.Suche in Google Scholar PubMed

32. Martino, MAG, Arnaldi, G. Copeptin and stress. Endocrine 2021;2:384–404. https://doi.org/10.3390/endocrines2040035.Suche in Google Scholar

33. Robertson, GL, Athar, S. The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man. J Clin Endocrinol Metab 1976;42:613–20. https://doi.org/10.1210/jcem-42-4-613.Suche in Google Scholar PubMed

34. Schrier, RW, Berl, T, Anderson, RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol 1979;236:F321–32. https://doi.org/10.1152/ajprenal.1979.236.4.f321.Suche in Google Scholar PubMed

35. Thrasher, TN. Baroreceptor regulation of vasopressin and renin secretion: low-pressure versus high-pressure receptors. Front Neuroendocrinol 1994;15:157–96. https://doi.org/10.1006/frne.1994.1007.Suche in Google Scholar PubMed

36. Tuli, G, Munarin, J, Tessaris, D, Einaudi, S, Matarazzo, P, de Sanctis, L. Distribution of plasma copeptin levels and influence of obesity in children and adolescents. Eur J Pediatr 2021;180:119–26. https://doi.org/10.1007/s00431-020-03777-3.Suche in Google Scholar PubMed PubMed Central

37. Bonnet, L, Marquant, E, Fromonot, J, Hamouda, I, Berbis, J, Godefroy, A, et al.. Copeptin assays in children for the differential diagnosis of polyuria-polydipsia syndrome and reference levels in hospitalized children. Clin Endocrinol 2022;96:47–53. https://doi.org/10.1111/cen.14620.Suche in Google Scholar PubMed

38. Binder, G, Weber, K, Peter, A, Schweizer, R. Arginine-stimulated copeptin in children and adolescents. Clin Endocrinol 2023;98:548–53. https://doi.org/10.1111/cen.14880.Suche in Google Scholar PubMed

39. Gippert, S, Brune, M, Choukair, D, Bettendorf, M. Insulin-induced copeptin response in children and adolescents to diagnose arginine vasopressin deficiency. Horm Res Paediatr 2024:1–8. https://doi.org/10.1159/000541330.Suche in Google Scholar PubMed

40. Gippert, S, Brune, M, Dirksen, RL, Choukair, D, Bettendorf, M. Arginine-stimulated copeptin-based diagnosis of central diabetes insipidus in children and adolescents. Horm Res Paediatr 2024;97:270–8. https://doi.org/10.1159/000532015.Suche in Google Scholar PubMed

41. Sastry, STE, Filingeri, D, McCann, E, Amruthapuri, R, McPhaul, MJ, Garibaldi, L, et al.. The effect of phlebotomy and placement of an intravenous catheter on plasma catecholamine and serum copeptin concentrations. J Pediatr Endocrinol Metab 2024;38:110–5. https://doi.org/10.1515/jpem-2024-0422.Suche in Google Scholar PubMed

42. Sastry, S, March, CA, McPhaul, MJ, Garibaldi, LR. Very elevated serum copeptin concentrations occur in a subset of healthy children in the minutes after phlebotomy. J Pediatr Endocrinol Metab 2024;37:8–14. https://doi.org/10.1515/jpem-2023-0390.Suche in Google Scholar PubMed PubMed Central

43. Rothermel, J, Kulle, A, Holterhus, PM, Toschke, C, Lass, N, Reinehr, T. Copeptin in obese children and adolescents: relationships to body mass index, cortisol and gender. Clin Endocrinol 2016;85:868–73. https://doi.org/10.1111/cen.13235.Suche in Google Scholar PubMed

44. March, CA, Sastry, S, McPhaul, MJ, Wheeler, SE, Garibaldi, L. Combined arginine and insulin stimulation elicits a robust and consistent copeptin response in short children. Horm Res Paediatr 2023;96:395–403. https://doi.org/10.1159/000528661.Suche in Google Scholar PubMed PubMed Central

45. March, CA, Sastry, S, McPhaul, MJ, Wheeler, SE, Garibaldi, L. Copeptin stimulation by combined intravenous arginine and oral LevoDopa/carbidopa in healthy short children and children with the polyuria-polydipsia syndrome. Horm Res Paediatr 2024:1–11. https://doi.org/10.1159/000539208.Suche in Google Scholar PubMed

46. Drummond, JB, Soares, BS, Pedrosa, W, Vieira, ELM, Teixeira, AL, Christ-Crain, M, et al.. Copeptin response to hypoglycemic stress is linked to prolactin activation in children. Pituitary 2020;23:681–90. https://doi.org/10.1007/s11102-020-01076-6.Suche in Google Scholar PubMed

47. Jalleh, R, Torpy, DJ. The emerging role of copeptin. Clin Biochem Rev 2021;42:17–25. https://doi.org/10.33176/AACB-20-00001.Suche in Google Scholar PubMed PubMed Central

48. Katan, M, Morgenthaler, N, Widmer, I, Puder, JJ, Konig, C, Muller, B, et al.. Copeptin, a stable peptide derived from the vasopressin precursor, correlates with the individual stress level. Neuro Endocrinol Lett 2008;29:341–6.Suche in Google Scholar

49. Blum, CA, Velly, L, Brochet, C, Ziegler, F, Tavolacci, MP, Hausfater, P, et al.. Relevance of cortisol and copeptin blood concentration changes in an experimental pain model. Sci Rep 2022;12:4767. https://doi.org/10.1038/s41598-022-08657-4.Suche in Google Scholar PubMed PubMed Central

50. Siegenthaler, J, Walti, C, Urwyler, SA, Schuetz, P, Christ-Crain, M. Copeptin concentrations during psychological stress: the PsyCo study. Eur J Endocrinol 2014;171:737–42. https://doi.org/10.1530/eje-14-0405.Suche in Google Scholar PubMed

51. Urwyler, SA, Schuetz, P, Sailer, C, Christ-Crain, M. Copeptin as a stress marker prior and after a written examination--the CoEXAM study. Stress 2015;18:134–7. https://doi.org/10.3109/10253890.2014.993966.Suche in Google Scholar PubMed

52. Saleh, NY, Aboelghar, HM, Garib, MI, Rizk, MS, Mahmoud, AA. Pediatric sepsis diagnostic and prognostic biomarkers: pancreatic stone protein, copeptin, and apolipoprotein A-V. Pediatr Res 2023;94:668–75. https://doi.org/10.1038/s41390-023-02499-0.Suche in Google Scholar PubMed PubMed Central

53. Coelho, R, Levandowski, ML, Mansur, RB, da, CGR, Asevedo, E, Zugman, A, et al.. Serum copeptin in children exposed to maltreatment. Psychiatr Clin Neurosci 2016;70:434–41. https://doi.org/10.1111/pcn.12412.Suche in Google Scholar PubMed

54. Miller, M, Dalakos, T, Moses, AM, Fellerman, H, Streeten, DH. Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 1970;73:721–9. https://doi.org/10.7326/0003-4819-73-5-721.Suche in Google Scholar PubMed

55. Baylis, PH, Robertson, GL. Plasma vasopressin response to hypertonic saline infusion to assess posterior pituitary function. J R Soc Med 1980;73:255–60. https://doi.org/10.1177/014107688007300408.Suche in Google Scholar PubMed PubMed Central

56. Fenske, W, Refardt, J, Chifu, I, Schnyder, I, Winzeler, B, Drummond, J, et al.. A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med 2018;379:428–39. https://doi.org/10.1056/nejmoa1803760.Suche in Google Scholar

57. Robertson, GL, Shelton, RL, Athar, S. The osmoregulation of vasopressin. Kidney Int 1976;10:25–37. https://doi.org/10.1038/ki.1976.76.Suche in Google Scholar PubMed

58. Zerbe, RL, Robertson, GL. A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med 1981;305:1539–46. https://doi.org/10.1056/nejm198112243052601.Suche in Google Scholar PubMed

59. Pedrosa, W, Drummond, JB, Soares, BS, Ribeiro-Oliveira, AJr. A combined outpatient and inpatient overnight water deprivation test is effective and safe in diagnosing patients with polyuria-polydipsia syndrome. Endocr Pract 2018;24:963–72. https://doi.org/10.4158/ep-2018-0238.Suche in Google Scholar

60. de Fost, M, Oussaada, SM, Endert, E, Linthorst, GE, Serlie, MJ, Soeters, MR, et al.. The water deprivation test and a potential role for the arginine vasopressin precursor copeptin to differentiate diabetes insipidus from primary polydipsia. Endocr Connect 2015;4:86–91. https://doi.org/10.1530/ec-14-0113.Suche in Google Scholar PubMed PubMed Central

61. Rowe, M, Patel, N, Jeffery, J, Flanagan, D. Use of copeptin in interpretation of the water deprivation test. Endocrinol Diabetes Metab 2023;6:e399. https://doi.org/10.1002/edm2.399.Suche in Google Scholar PubMed PubMed Central

62. Trimpou, P, Bounias, I, Ehn, O, Hammarsten, O, Ragnarsson, O. The diagnostic performance of copeptin in clinical practice: a prospective study. Clin Endocrinol 2024;101:23–31. https://doi.org/10.1111/cen.15018.Suche in Google Scholar PubMed

63. Refardt, J, Atila, C, Chifu, I, Ferrante, E, Erlic, Z, Drummond, JB, et al.. Arginine or hypertonic saline-stimulated copeptin to diagnose AVP deficiency. N Engl J Med 2023;389:1877–87. https://doi.org/10.1056/nejmoa2306263.Suche in Google Scholar PubMed

64. Tuli, G, Tessaris, D, Einaudi, S, Matarazzo, P, De Sanctis, L. Copeptin role in polyuria-polydipsia syndrome differential diagnosis and reference range in paediatric age. Clin Endocrinol 2018;88:873–9. https://doi.org/10.1111/cen.13583.Suche in Google Scholar PubMed

65. Tuli, G, Munarin, J, De Sanctis, L. The diagnostic role of arginine-stimulated copeptin in the differential diagnosis of polyuria-polydipsia syndrome (PPS) in pediatric age. Endocrine 2024;84:677–82. https://doi.org/10.1007/s12020-023-03671-6.Suche in Google Scholar PubMed

66. Sastry, SMM, Garibaldi, L. Serum copeptinconcentrationsduring water deprivation test in children with primary polydipsia (abstract). Horm Res Paediatr 2023;96:1–399.Suche in Google Scholar

67. unlisted, A. Information for families: the water deprivation test 2024. [cited 2024. Available from: https://www.gosh.nhs.uk/about-us/contact-us-hospital.Suche in Google Scholar

68. Hickey, RC, Hare, K. The renal excretion of chloride and water in diabetes insipidus. J Clin Investig 1944;23:768–75. https://doi.org/10.1172/jci101549.Suche in Google Scholar PubMed PubMed Central

69. Mohn, A, Acerini, CL, Cheetham, TD, Lightman, SL, Dunger, DB. Hypertonic saline test for the investigation of posterior pituitary function. Arch Dis Child 1998;79:431–4. https://doi.org/10.1136/adc.79.5.431.Suche in Google Scholar PubMed PubMed Central

70. Davies, JH, Penney, M, Abbes, AP, Engel, H, Gregory, JW. Clinical features, diagnosis and molecular studies of familial central diabetes insipidus. Horm Res 2005;64:231–7. https://doi.org/10.1159/000089291.Suche in Google Scholar PubMed

71. Secco, A, Allegri, AE, di Iorgi, N, Napoli, F, Calcagno, A, Bertelli, E, et al.. Posterior pituitary (PP) evaluation in patients with anterior pituitary defect associated with ectopic PP and septo-optic dysplasia. Eur J Endocrinol 2011;165:411–20. https://doi.org/10.1530/eje-11-0437.Suche in Google Scholar PubMed

72. Yamanaka, C, Momoi, T, Fujisawa, I, Kikuchi, K, Kaji, M, Yorifuji, T, et al.. Neurohypophyseal function of an ectopic posterior lobe in patients with growth hormone deficiency. Acta Endocrinol 1990;122:664–70. https://doi.org/10.1530/acta.0.1220664.Suche in Google Scholar PubMed

73. Kitamura, M, Nishioka, J, Matsumoto, T, Umino, S, Kawano, A, Saiki, R, et al.. Estimate incidence and predictive factors of pediatric central diabetes insipidus in a single-institute study. Endocrine and Metabolic Science 2022;7:100119. https://doi.org/10.1016/j.endmts.2022.100119.Suche in Google Scholar

74. Stankovic, J, Kristensen, K, Birkebaek, N, Jorgensen, JOL, Sondergaard, E. Copeptin levels increase in response to both insulin-induced hypoglycemia and arginine but not to clonidine: data from GH-stimulation tests. Endocr Connect 2023;12. https://doi.org/10.1530/ec-23-0042.Suche in Google Scholar PubMed PubMed Central

75. Binder, G, Weber, K, Peter, A, Schweizer, R. Does clonidine stimulate copeptin in children? J Pediatr Endocrinol Metab 2025;38:172–5. https://doi.org/10.1515/jpem-2024-0498.Suche in Google Scholar PubMed

76. Urwyler, SA, Lustenberger, S, Drummond, JR, Soares, BS, Vogt, DR, Ammer, N, et al.. Effects of oral macimorelin on copeptin and anterior pituitary hormones in healthy volunteers. Pituitary 2021;24:555–63. https://doi.org/10.1007/s11102-021-01132-9.Suche in Google Scholar PubMed PubMed Central

77. Atila, C, Monnerat, S, Urwyler, SA, Refardt, J, Winzeler, B, Christ-Crain, M. The effect of glucose dynamics on plasma copeptin levels upon glucagon, arginine, and macimorelin stimulation in healthy adults : data from: glucacop, Macicop, and CARGO study. Pituitary 2022;25:636–44. https://doi.org/10.1007/s11102-022-01240-0.Suche in Google Scholar PubMed PubMed Central

78. Baylis, PH, Zerbe, RL, Robertson, GL. Arginine vasopressin response to insulin-induced hypoglycemia in man. J Clin Endocrinol Metab 1981;53:935–40. https://doi.org/10.1210/jcem-53-5-935.Suche in Google Scholar PubMed

79. Katan, M, Morgenthaler, NG, Dixit, KC, Rutishauser, J, Brabant, GE, Muller, B, et al.. Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay. J Clin Endocrinol Metab 2007;92:2640–3. https://doi.org/10.1210/jc.2006-2046.Suche in Google Scholar PubMed

80. Trimpou, P, Bounias, I, Ehn, O, Hammarsten, O, Ragnarsson, O. The influence of insulin-induced hypoglycemia on copeptin concentrations. Peptides 2024;176:171185. https://doi.org/10.1016/j.peptides.2024.171185.Suche in Google Scholar PubMed

81. Kacheva, S, Kolk, K, Morgenthaler, NG, Brabant, G, Karges, W. Gender-specific co-activation of arginine vasopressin and the hypothalamic-pituitary-adrenal axis during stress. Clin Endocrinol 2015;82:570–6. https://doi.org/10.1111/cen.12608.Suche in Google Scholar PubMed

82. Atila, C, Gaisl, O, Vogt, DR, Werlen, L, Szinnai, G, Christ-Crain, M. Glucagon-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a double-blind, randomized, placebo-controlled study. Eur J Endocrinol 2022;187:65–74. https://doi.org/10.1530/eje-22-0033.Suche in Google Scholar PubMed

83. Lewandowski, KC, Lewinski, A, Skowronska-Jozwiak, E, Stasiak, M, Horzelski, W, Brabant, G. Copeptin under glucagon stimulation. Endocrine 2016;52:344–51. https://doi.org/10.1007/s12020-015-0783-7.Suche in Google Scholar PubMed PubMed Central

84. Malicka, K, Horzelski, W, Lewinski, A, Lewandowski, KC. Limited role of endogenous vasopressin/copeptin in stimulation of ACTH-cortisol secretion during glucagon stimulation test in humans. Biomedicines 2022;10. https://doi.org/10.3390/biomedicines10112857.Suche in Google Scholar PubMed PubMed Central

85. Stangerup, I, Kjeldsen, SAS, Richter, MM, Jensen, NJ, Rungby, J, Haugaard, SB, et al.. Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin. Peptides 2024;176:171213. https://doi.org/10.1016/j.peptides.2024.171213.Suche in Google Scholar PubMed

86. Giannakopoulos, A, Kritikou, D, Chrysis, D. Evaluation of copeptin in children after stimulation with clonidine or L-Dopa. J Pediatr Endocrinol Metab 2024;37:441–4. https://doi.org/10.1515/jpem-2024-0062.Suche in Google Scholar PubMed

87. Wang, S, Zhou, X, Zhang, Y, Zhang, Q, Huang, B, Wang, Y, et al.. Oral levodopa stimulates copeptin secretion in children and adolescents with intact posterior pituitary function. Endocr Pract 2024;30:1059–65. https://doi.org/10.1016/j.eprac.2024.08.006.Suche in Google Scholar PubMed

88. Lustenberger, S, Atila, C, Baumgartner, J, Monnerat, S, Beck, J, Santos de Jesus, J, et al.. Urea-stimulated copeptin: a novel diagnostic approach in polyuria polydipsia syndrome. Eur J Endocrinol 2025;192:437–44.10.1093/ejendo/lvaf058Suche in Google Scholar PubMed

89. Fevang, FO, Stoa, RF, Thorsen, T, Aarskog, D. The effect of L-dopa with and without decarboxylase inhibitor on growth hormone secretion in children with short stature. Acta Paediatr Scand 1977;66:81–4. https://doi.org/10.1111/j.1651-2227.1977.tb07811.x.Suche in Google Scholar PubMed

90. Weldon, VV, Gupta, SK, Klingensmith, G, Clarke, WL, Duck, SC, Haymond, MW, et al.. Evaluation of growth hormone release in children using arginine and L-dopa in combination. J Pediatr 1975;87:540–4. https://doi.org/10.1016/s0022-3476(75)80816-x.Suche in Google Scholar PubMed

91. Contin, M, Martinelli, P. Pharmacokinetics of levodopa. J Neurol 2010;257:S253–61. https://doi.org/10.1007/s00415-010-5728-8.Suche in Google Scholar PubMed

92. Brooks, E, Bachmeier, C, Vorster, J, Sorbello, J, Peer, F, Chikani, V, et al.. Copeptin is increased by nausea and vomiting during hypertonic saline infusion in healthy individuals. Clin Endocrinol 2021;94:820–6. https://doi.org/10.1111/cen.14417.Suche in Google Scholar PubMed

93. Kenward, H, Elliott, J, Lee, T, Pelligand, L. Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study. BMC Vet Res 2017;13:244. https://doi.org/10.1186/s12917-017-1156-7.Suche in Google Scholar PubMed PubMed Central

94. Coiro, V, Maffei, ML, Volta, E, Cataldo, S, Minelli, R, Vacca, P, et al.. Effect of serotonergic system on AVP secretion induced by physical exercise. Neuropeptides 2010;44:53–6. https://doi.org/10.1016/j.npep.2009.10.004.Suche in Google Scholar PubMed

95. Renaud, LP, Bourque, CW. Neurophysiology and neuropharmacology of hypothalamic magnocellular neurons secreting vasopressin and oxytocin. Prog Neurobiol 1991;36:131–69. https://doi.org/10.1016/0301-0082(91)90020-2.Suche in Google Scholar PubMed

96. Rossi, NF. Dopaminergic control of angiotensin II-induced vasopressin secretion in vitro. Am J Physiol 1998;275:E687–93. https://doi.org/10.1152/ajpendo.1998.275.4.e687.Suche in Google Scholar

97. Lightman, SL, Forsling, M. Evidence for dopamine as an inhibitor of vasoprotein release in man. Clin Endocrinol 1980;12:39–46. https://doi.org/10.1111/j.1365-2265.1980.tb03130.x.Suche in Google Scholar PubMed

98. Arai, M. Increased plasma arginine vasopressin levels in dopamine agonist-treated Parkinson’s disease patients. Neuro Endocrinol Lett 2011;32:39–43.Suche in Google Scholar

99. Masuda, A, Shibasaki, T, Hotta, M, Yamauchi, N, Ling, N, Demura, H, et al.. Insulin-induced hypoglycemia, L-dopa and arginine stimulate GH secretion through different mechanisms in man. Regul Pept 1990;31:53–64. https://doi.org/10.1016/0167-0115(90)90195-3.Suche in Google Scholar PubMed

100. Oiso, Y, Robertson, GL, Norgaard, JP, Juul, KV. Clinical review: treatment of neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab 2013;98:3958–67. https://doi.org/10.1210/jc.2013-2326.Suche in Google Scholar PubMed

101. Robertson, GL. Physiology of ADH secretion. Kidney Int Suppl 1987;21:S20–6.Suche in Google Scholar

102. Gubbi, S, Hannah-Shmouni, F, Koch, CA, Verbalis, JG. Diagnostic testing for diabetes insipidus. Feingold, KR, Anawalt, B, Blackman, MR, Boyce, A, Chrousos, G, Corpas, E, et al., editors. South Dartmouth (MA): Endotext; 2000.Suche in Google Scholar

103. Al Nofal, A, Hanna, C, Lteif, AN, Pittock, ST, Schwartz, JD, Brumbaugh, JE, et al.. Copeptin levels in hospitalized infants and children with suspected vasopressin-dependent disorders: a case series. J Pediatr Endocrinol Metab 2023;36:492–9. https://doi.org/10.1515/jpem-2022-0525.Suche in Google Scholar PubMed

104. Edelmann, CMJr, Barnett, HL, Stark, H, Boichis, H, Soriano, JR. A standarized test of renal concentrating capacity in children. Am J Dis Child 1967;114:639–44. https://doi.org/10.1001/archpedi.1967.02090270095009.Suche in Google Scholar PubMed

105. Marild, S, Jodal, U, Jonasson, G, Mangelus, L, Oden, A, Persson, NG. Reference values for renal concentrating capacity in children by the desmopressin test. Pediatr Nephrol 1992;6:254–7. https://doi.org/10.1007/bf00878361.Suche in Google Scholar

106. Atiyeh, BA, Dabbagh, SS, Gruskin, AB. Evaluation of renal function during childhood. Pediatr Rev 1996;17:175–80. https://doi.org/10.1542/pir.17.5.175.Suche in Google Scholar

107. Dabrowski, E, Kadakia, R, Zimmerman, D. Diabetes insipidus in infants and children. Best Pract Res Clin Endocrinol Metabol 2016;30:317–28. https://doi.org/10.1016/j.beem.2016.02.006.Suche in Google Scholar PubMed

108. Di Iorgi, N, Napoli, F, Allegri, AE, Olivieri, I, Bertelli, E, Gallizia, A, et al.. Diabetes insipidus–diagnosis and management. Horm Res Paediatr 2012;77:69–84. https://doi.org/10.1159/000336333.Suche in Google Scholar PubMed

109. Fujisawa, I. Magnetic resonance imaging of the hypothalamic-neurohypophyseal system. J Neuroendocrinol 2004;16:297–302. https://doi.org/10.1111/j.0953-8194.2004.01183.x.Suche in Google Scholar PubMed

110. Kurokawa, H, Fujisawa, I, Nakano, Y, Kimura, H, Akagi, K, Ikeda, K, et al.. Posterior lobe of the pituitary gland: correlation between signal intensity on T1-weighted MR images and vasopressin concentration. Radiology 1998;207:79–83. https://doi.org/10.1148/radiology.207.1.9530302.Suche in Google Scholar PubMed

111. Maghnie, M, Cosi, G, Genovese, E, Manca-Bitti, ML, Cohen, A, Zecca, S, et al.. Central diabetes insipidus in children and young adults. N Engl J Med 2000;343:998–1007. https://doi.org/10.1056/nejm200010053431403.Suche in Google Scholar PubMed

112. Maghnie, M, Villa, A, Arico, M, Larizza, D, Pezzotta, S, Beluffi, G, et al.. Correlation between magnetic resonance imaging of posterior pituitary and neurohypophyseal function in children with diabetes insipidus. J Clin Endocrinol Metab 1992;74:795–800. https://doi.org/10.1210/jcem.74.4.1548343.Suche in Google Scholar PubMed

113. Sethi, RV, Marino, R, Niemierko, A, Tarbell, NJ, Yock, TI, MacDonald, SM. Delayed diagnosis in children with intracranial germ cell tumors. J Pediatr 2013;163:1448–53. https://doi.org/10.1016/j.jpeds.2013.06.024.Suche in Google Scholar PubMed

114. Takami, H, Graffeo, CS, Perry, A, Giannini, C, Daniels, DJ. Epidemiology, natural history, and optimal management of neurohypophyseal germ cell tumors. J Neurosurg 2021;134:437–45. https://doi.org/10.3171/2019.10.jns191136.Suche in Google Scholar

115. Tong, T, Zhong, LY. Intracranial germ cell tumors: a view of the endocrinologist. J Pediatr Endocrinol Metab 2023;36:1115–27. https://doi.org/10.1515/jpem-2023-0368.Suche in Google Scholar PubMed

116. Marchand, I, Barkaoui, MA, Garel, C, Polak, M, Donadieu, J, Writing, C. Central diabetes insipidus as the inaugural manifestation of Langerhans cell histiocytosis: natural history and medical evaluation of 26 children and adolescents. J Clin Endocrinol Metab 2011;96:E1352–60. https://doi.org/10.1210/jc.2011-0513.Suche in Google Scholar PubMed

Received: 2025-01-22
Accepted: 2025-03-17
Published Online: 2025-05-23
Published in Print: 2025-07-28

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Sunlight, supplements, and science: vitamin D as a tool for pediatric health care
  4. Mini Review
  5. Physical activity and vitamin D in children: a review of impacts on bone health and fitness
  6. Original Articles
  7. Association between overweight or obesity and vitamin D status in preschool children: an epidemiological survey in Beijing, China, 2021–2023
  8. Association between partial remission phase in type 1 diabetes and vitamin D receptor Fok1 rs2228570 polymorphism
  9. Optimal vitamin D status for Chinese infants in Hong Kong: insights from the relationship between serum 25-hydroxyvitamin D and parathyroid hormone levels
  10. Reviews
  11. The changing landscape in the evaluation of hypotonic polyuria in children and adolescents: the role of the new copeptin stimulation tests
  12. A systematic review and meta-analysis of the self-reported Pubertal Development Scale’s applicability to children
  13. Original Articles
  14. Assessing prediabetes and cardiometabolic risk in Danish youth with obesity
  15. Endocrinopathies in children with inborn errors of immunity: a single-center experience
  16. Relationship between blood lipids and bone mineral density in healthy preschoolers: a 12-month cohort study
  17. The causal role of endocrine disrupting chemicals in pubertal timing: a Mendelian randomization study
  18. Case Reports
  19. Vitamin D dependent rickets type 2A: a case series of two siblings with novel mutation in vitamin D receptor gene responded to high dose oral calcium and calcitriol
  20. Emergence of osteolysis as a new radiological feature in a case with a novel BMP2 gene variant
  21. Rare case of ACTH-independent Cushing syndrome: diagnostic challenges and management
https://doi.org/10.1515/jpem-2025-0046
Schlagwörter für diesen Artikel
copeptin; vasopressin (AVP); diabetes insipidus; AVP-deficiency; polyuria-polydipsia syndrome; primary polydipsia
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Sunlight, supplements, and science: vitamin D as a tool for pediatric health care
  4. Mini Review
  5. Physical activity and vitamin D in children: a review of impacts on bone health and fitness
  6. Original Articles
  7. Association between overweight or obesity and vitamin D status in preschool children: an epidemiological survey in Beijing, China, 2021–2023
  8. Association between partial remission phase in type 1 diabetes and vitamin D receptor Fok1 rs2228570 polymorphism
  9. Optimal vitamin D status for Chinese infants in Hong Kong: insights from the relationship between serum 25-hydroxyvitamin D and parathyroid hormone levels
  10. Reviews
  11. The changing landscape in the evaluation of hypotonic polyuria in children and adolescents: the role of the new copeptin stimulation tests
  12. A systematic review and meta-analysis of the self-reported Pubertal Development Scale’s applicability to children
  13. Original Articles
  14. Assessing prediabetes and cardiometabolic risk in Danish youth with obesity
  15. Endocrinopathies in children with inborn errors of immunity: a single-center experience
  16. Relationship between blood lipids and bone mineral density in healthy preschoolers: a 12-month cohort study
  17. The causal role of endocrine disrupting chemicals in pubertal timing: a Mendelian randomization study
  18. Case Reports
  19. Vitamin D dependent rickets type 2A: a case series of two siblings with novel mutation in vitamin D receptor gene responded to high dose oral calcium and calcitriol
  20. Emergence of osteolysis as a new radiological feature in a case with a novel BMP2 gene variant
  21. Rare case of ACTH-independent Cushing syndrome: diagnostic challenges and management
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 19.11.2025 von https://www.degruyterbrill.com/document/doi/10.1515/jpem-2025-0046/html
Button zum nach oben scrollen