Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Hypothalamic-pituitary-adrenal axis activity in patients with primary polydipsia compared to healthy controls.

OBJECTIVE: Primary polydipsia is characterized by excessive fluid intake which may suppress vasopressin levels. It is speculated that suppressed vasopressin levels lead to a dysregulated hypothalamic-pituitary-adrenal (HPA) axis as vasopressin co-modulates the HPA axis. However, data are contradictory. The aim of this study was to investigate markers of the HPA axis in patients with primary polydipsia compared to healthy controls. DESIGN: Exploratory analysis combining data from two different prospective observational studies. PATIENTS: We included 34 patients with primary polydipsia (68% females, median aged 29.5 years (interquartile range, IQR: 26.0, 38.8) and 20 healthy controls (55% females, median age 24.0 years [IQR: 22.0, 27.2]). MEASUREMENTS: The main outcome was difference in HPA axis activity assessed using circadian serum and salivary cortisol, 24-h urinary free cortisol and cortisol levels before and after adrenocorticotropic hormone (ACTH) stimulation; vasopressin suppression was assessed measuring fasting copeptin levels between patients with primary polydipsia and healthy controls using Wilcoxon rank-sum test. RESULTS: No difference was seen in circadian serum cortisol levels (p = .9), urinary free cortisol levels (p = .17) and serum cortisol in response to ACTH stimulation (p = .77) between groups. Circadian salivary cortisol levels were significantly lower in patients with primary polydipsia compared to healthy controls with an estimated difference of -3.7 nmol/L (95% CI: -5.5, -1.8 nmol/L, p < .001). Fasting copeptin levels were significantly lower in patients with primary polydipsia compared to healthy volunteers (p < 0.01). CONCLUSION: Our results suggest no difference in HPA axis activity between patients with primary polydipsia and healthy controls. The observed difference in salivary cortisol levels may be linked to a dilution effect in saliva rather than an altered stress axis considering the other findings.

Severe hyponatremia due to surreptitious water intoxication in a hospitalized patient.

Hyponatremia is a common electrolyte abnormality among hospitalized patients and often present as first sign of other underlying medical conditions. Severe hyponatremia can be life threatening and requires prompt diagnosis and treatment. We present a case of refractory hyponatremia that was a diagnostic challenge requiring a prolonged hospitalization. Diagnosis of primary polydipsia was ultimately suspected due to improbable 24-h urine studies and confirmed through complete removal of free water access in the form of disconnecting the bathroom faucet in the patient's hospital room. Diagnosis and management of primary polydipsia is further discussed.

Machine learning-based algorithm as an innovative approach for the differentiation between diabetes insipidus and primary polydipsia in clinical practice.

Objective: Differentiation between central diabetes insipidus (cDI) and primary polydipsia (PP) remains challenging in clinical practice. Although the hypertonic saline infusion test led to high diagnostic accuracy, it is a laborious test requiring close monitoring of plasma sodium levels. As such, we leverage machine learning (ML) to facilitate differential diagnosis of cDI. Design: We analyzed data of 59 patients with cDI and 81 patients with PP from a prospective multicenter study evaluating the hypertonic saline test as new test approach to diagnose cDI. Our primary outcome was the diagnostic accuracy of the ML-based algorithm in differentiating cDI from PP patients. Methods: The data set used included 56 clinical, biochemical, and radiological covariates. We identified a set of five covariates which were crucial for differentiating cDI from PP patients utilizing standard ML methods. We developed ML-based algorithms on the data and validated them with an unseen test data set. Results: Urine osmolality, plasma sodium and glucose, known transsphenoidal surgery, or anterior pituitary deficiencies were selected as input parameters for the basic ML-based algorithm. Testing it on an unseen test data set resulted in a high area under the curve (AUC) score of 0.87. A further improvement of the ML-based algorithm was reached with the addition of MRI characteristics and the results of the hypertonic saline infusion test (AUC: 0.93 and 0.98, respectively). Conclusion: The developed ML-based algorithm facilitated differentiation between cDI and PP patients with high accuracy even if only clinical information and laboratory data were available, thereby possibly avoiding cumbersome clinical tests in the future.

Glucagon-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a double-blind, randomized, placebo-controlled study.

Background: The differential diagnosis of diabetes insipidus is challenging. The most reliable approaches are copeptin measurements after hypertonic saline infusion or arginine, which is a known growth hormone secretagogue but has recently also been shown to stimulate the neurohypophysis. Similar to arginine, glucagon stimulates growth hormone release, but its effect on the neurohypophysis is poorly studied. Design: Double-blind, randomized, placebo-controlled trial including 22 healthy participants, 10 patients with central diabetes insipidus, and 10 patients with primary polydipsia at the University Hospital Basel, Switzerland. Methods: Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test. The primary objective was to determine whether glucagon stimulates copeptin and to explore whether the copeptin response differentiates between diabetes insipidus and primary polydipsia. Copeptin levels were measured at baseline, 30, 60, 90, 120, 150, and 180 min after injection. Results: In healthy participants, glucagon stimulated copeptin with a median increase of 7.56 (2.38; 28.03) pmol/L, while placebo had no effect (0.10 pmol/L (-0.70; 0.68); P < 0.001). In patients with diabetes insipidus, copeptin showed no relevant increase upon glucagon, with an increase of 0.55 (0.21; 1.65) pmol/L, whereas copeptin was stimulated in patients with primary polydipsia with an increase of 15.70 (5.99; 24.39) pmol/L. Using a copeptin cut-off level of 4.6pmol/L had a sensitivity of 100% (95% CI: 100-100) and a specificity of 90% (95% CI: 70-100) to discriminate between diabetes insipidus and primary polydipsia. Conclusion: Glucagon stimulates the neurohypophysis, and glucagon-stimulated copeptin has the potential for a safe, novel, and precise test in the differential diagnosis of diabetes insipidus.

Hyponatraemic seizure secondary to primary polydipsia following urological surgery.

An 82-year-old man presented to the emergency department with delirium, vomiting and an initial hyponatraemia of 112 mmol/L the day after successful transurethral vaporisation of the prostate. He had a tonic-clonic seizure in the acute surgical unit and was managed subsequently in the intensive care unit with a controlled rate of hypertonic saline. Initial work-up for the cause of hyponatraemia revealed a low urine osmolality, suggestive of relative excess water intake. Detailed examination of the operation notes revealed no discrepancy between intraoperative irrigating fluid input and output. Careful collateral history revealed that the patient had drunk 8 L of water in the 24 hours following the operation, after taking advice to 'drink plenty of water' literally. This case highlights the importance of conveying specific advice to patient, the lower incidence of transurethral resection syndrome in resections using saline as an irrigation fluid and outlines the pathway for investigation and management for hyponatraemia.

PSYCOGENIC POLYDIPSIA AND SEVERE HYPONATREMIA IN BIPOLAR AFFECTIVE DISORDER.

Psychogenic polydipsia, primary polydipsia or potomania is a disorder of multifactorial etiology which is associated with substantial morbidity and mortality. It occurs frequently in patients with psychiatric diseases, particularly those with schizophrenia, however, it is not exclusive, it has been reported in a lower proportion in patients with anxiety disorders and mood disorders. Although, is still poorly understood and therefore underdiagnosed condition.

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia.

BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Primary polydipsia: Update.

In primary polydipsia pathologically high levels of water intake physiologically lower arginine vasopressin (AVP) secretion, and in this way mirror the secondary polydipsia in diabetes insipidus in which pathologically low levels of AVP (or renal responsiveness to AVP) physiologically increase water intake. Primary polydipsia covers several disorders whose clinical features and significance, risk factors, pathophysiology and treatment are reviewed here. While groupings may appear somewhat arbitrary, they are associated with distinct alterations in physiologic parameters of water balance. The polydipsia is typically unrelated to homeostatic regulation of water intake, but instead reflects non-homeostatic influences. Recent technological advances, summarized here, have disentangled functional neurocircuits underlying both homeostatic and non-homeostatic physiologic influences, which provides an opportunity to better define the mechanisms of the disorders. We summarize this recent literature, highlighting hypothalamic circuitry that appears most clearly positioned to contribute to primary polydipsia. The life-threatening water imbalance in psychotic disorders is caused by an anterior hippocampal induced stress-diathesis that can be reproduced in animal models, and involves phylogenetically preserved pathways that appear likely to include one or more of these circuits. Ongoing translational neuroscience studies in these animal models may potentially localize reversible pathological changes which contribute to both the water imbalance and psychotic disorder.

Effect of Arginine on the Hypothalamic-Pituitary-Adrenal Axis in Individuals With and Without Vasopressin Deficiency.

CONTEXT: Arginine stimulates pituitary hormones, like growth hormone and vasopressin, but its effect on the hypothalamic-pituitary-adrenal (HPA) axis is unknown. Arginine may also stimulate the HPA axis, possibly through a mechanism involving vasopressin. OBJECTIVE: To investigate the effect of arginine on adrenocorticotropic hormone (ACTH) and cortisol in subjects with and without vasopressin deficiency. DESIGN: Prospective study, University Hospital Basel. PARTICIPANTS: 38 patients with central diabetes insipidus, 58 patients with primary polydipsia, and 50 healthy controls. INTERVENTION: Arginine infusion with measurement of ACTH, cortisol and copeptin at baseline and 30, 45, 60, 90, and 120 minutes. RESULTS: We found different response patterns to arginine: in patients with diabetes insipidus (and low stimulated copeptin levels) median (interquartile range [IQR]) ACTH and cortisol increased from 22.9 (16.8, 38.7) to 36.6 (26.2, 52.1) ng/L and from 385 (266, 463) to 467 (349, 533) nmol/L, respectively. In contrast, median (IQR) ACTH and cortisol levels decreased in patients with primary polydipsia (despite high stimulated copeptin levels): ACTH from 17.3 (12.3, 23) to 14.8 (10.9, 19.8) ng/L and cortisol from 343 (262, 429) to 272 (220.8, 360.3) nmol/L; likewise, in healthy controls: ACTH from 26.5 (17.6, 35.7) to 14.8 (12.1, 22.7) ng/L and cortisol from 471 (393.3, 581.8) to 301.5 (206.5, 377.8) nmol/L. CONCLUSION: Diabetes insipidus is associated with increased responsiveness of ACTH/cortisol to arginine. In contrast, arginine does not stimulate the HPA axis in healthy controls or in primary polydipsia.

[Psychogenic polydipsia†: a (still) unknown psychosomatic entity]. / Polydipsie psychogène†: une entité somato-psychiatrique (encore) méconnue.

Psychogenic polydipsia, as well referred to as «â€…potomania ¼, is a clinical entity that can be found in psychiatric as well as in physical care settings. Its diagnosis is based on the detection of an excessive fluid intake along with a polyuria, after excluding any potential somatic cause of this clinical presentation. Given the different somatic complications and care complexity, early detection and multidisciplinary interventions are necessary. This article offers a literature review on this topic.

La polydipsie psychogène, également dénommée «â€…potomanie ¼, est une entité clinique que l'on rencontre en milieu psychiatrique, ainsi qu'en milieu somatique. Son diagnostic se base sur la détection d'une consommation excessive d'eau et d'une polyurie, après exclusion de toute cause somatique pouvant être à l'origine du tableau clinique. Vu les diverses complications somatiques et la complexité de la prise en charge, la nécessité de la détection précoce et d'une approche pluridisciplinaire est primordiale. Cet article propose une revue de la littérature scientifique sur ce sujet.

Diabetes Insipidus: New Concepts for Diagnosis.

Diabetes insipidus (DI), be it from central or from nephrogenic origin, has to be differentiated from primary polydipsia. This differentiation is crucial since wrong treatment can have dangerous consequences. For decades, the "gold standard" for differential diagnosis has been the standard water deprivation test. However, this test has several limitations leading to an overall limited diagnostic accuracy. In addition, the test has a long duration of 17 h and is cumbersome for patients. Also clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia. Direct measurement of arginine vasopressin (AVP) upon osmotic stimulation was first shown to overcome these limitations, but failed to enter clinical practice mainly due to technical limitations of the AVP assay. Copeptin is secreted in equimolar ratio to AVP, mirroring AVP concentrations in the circulation. We have shown that copeptin, without prior fluid deprivation, identifies patients with nephrogenic DI. For the more difficult differentiation between central DI and primary polydipsia, a copeptin level of 4.9 pmol/L stimulated with hypertonic saline infusion differentiates between these 2 entities with a high diagnostic accuracy and is superior to the water deprivation test. However, it is important to note that close and regular sodium monitoring every 30 min during the hypertonic saline test is a prerequisite, which is not possible in all hospitals. Furthermore, side effects are common. Therefore, a nonosmotic stimulation test would be advantageous. Arginine significantly stimulates copeptin and therefore is a novel, so far unknown stimulus of this peptide. Consequently, infusion of arginine with subsequent copeptin measurement was shown to be an even simpler and better tolerated test, but head to head comparison is still lacking.

Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis.

Copeptin is secreted in an equimolar amount to arginine vasopressin (AVP) but can easily be measured in plasma or serum with a sandwich immunoassay. The main stimuli for copeptin are similar to AVP, that is an increase in osmolality and a decrease in arterial blood volume and pressure. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation. Copeptin has, therefore, been evaluated as diagnostic biomarker in vasopressin-dependent disorders of body fluid homeostasis. Disorders of body fluid homeostasis are common and can be divided into hyper- and hypoosmolar circumstances: the classical hyperosmolar disorder is diabetes insipidus, while the most common hypoosmolar disorder is the syndrome of inappropriate antidiuresis (SIAD). Copeptin measurement has led to a "revival" of the direct test in the differential diagnosis of diabetes insipidus. Baseline copeptin levels, without prior thirsting, unequivocally identify patients with nephrogenic diabetes insipidus. In contrast, for the difficult differentiation between central diabetes insipidus and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is clearly superior to the classical water deprivation test. On the contrary, in the SIAD, copeptin measurement is of only little diagnostic value. Copeptin levels widely overlap in patients with hyponatraemia and emphasize the heterogeneity of the disease. Additionally, a variety of factors lead to unspecific copeptin elevations in the acute setting further complicating its interpretation. The broad use of copeptin as diagnostic marker in hyponatraemia and specifically to detect cancer-related disease in SIADH patients can, therefore, not be recommended.

Diagnosis and management of central diabetes insipidus in adults.

Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless they are treated with lithium salts, the practical challenge is how to differentiate between CDI and clinical disorders of excess thirst. The differential diagnosis is usually straight forward, but the recommended gold standard test, the water deprivation test, is not without interpretative pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a few specialized centres. More recently, the measurement of plasma copeptin concentrations has been claimed to provide a reliable alternative to measurement of plasma AVP, without the sampling handling challenges. In addition, the measurement of thirst ratings can help the differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically certain, investigations to determine the cause of AVP deficiency are needed. In this review, we will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test and review recent data on value of adding AVP/copeptin measurement. We will also discuss treatment strategies for CDI, with analysis of potential complications of treatment.

A COMBINED OUTPATIENT AND INPATIENT OVERNIGHT WATER DEPRIVATION TEST IS EFFECTIVE AND SAFE IN DIAGNOSING PATIENTS WITH POLYURIA-POLYDIPSIA SYNDROME.

OBJECTIVE: The water deprivation test (WDT) is widely used for the differential diagnosis of the polyuria-polydipsia syndrome (PPS). However, it is inconvenient and may not always be precise in differentiating partial forms of diabetes insipidus (DI) from primary polydipsia (PP). The aim of this study was to evaluate the results of a combined outpatient and inpatient overnight WDT protocol that included an overnight unsupervised period concerning its feasibility and safety. METHODS: We performed a retrospective analysis of clinical data and laboratory results of 52 patients with PPS undergoing WDT at a single center. RESULTS: PP was the most frequent diagnosis, followed by complete central DI (cCDI), partial central DI (pCDI), and nephrogenic DI (NDI). Over 90% of the patients showed an expected increase in serum osmolality at the end of the dehydration period. There were no reports of complications during the overnight deprivation period. Post-dehydration urine osmolality and urine-to-serum osmolality ratio significantly differentiated all the groups ( P<.05), except for cCDI and NDI, which could be differentiated by basal and post-dehydration vasopressin (AVP) levels ( P<.05 for both). Although these measurements were useful for differentiating patients according to their allocation groups, results from WDT and direct AVP levels may often require a comprehensive diagnostic approach, particularly in the challenging groups of PP and pCDI. CONCLUSION: A combined outpatient and inpatient overnight WDT protocol is safe and feasible when the test is performed with special care at experienced centers. Newer diagnostic tools are expected to improve the accuracy of PPS diagnosis. ABBREVIATIONS: AQP2 = aquaporin-2; AVP = vasopressin; CDI = central diabetes insipidus; cCDI = complete central diabetes insipidus; DDAVP = desmopressin; DI = diabetes insipidus; IQR = interquartile range; MRI = magnetic resonance imaging; Na+ = sodium; NDI = nephrogenic diabetes insipidus; pCDI = partial central diabetes insipidus; PP = primary polydipsia; PPS = polyuria-polydipsia syndrome; S_osm = serum osmolality; U_osm = urine osmolality; WDT = water deprivation test.

Do psychoactive drugs have a therapeutic role in compulsivity? Studies on schedule-induced polydipsia.

RATIONALE: Clinical studies have shown that some psychoactive recreational drugs have therapeutic applications in anxiety, depression, and schizophrenia. However, to date, there are few studies on the therapeutic potential efficacy of recreational drugs in compulsive neuropsychiatric disorders. OBJECTIVES: We explored the therapeutic potential of different psychoactive and psychedelic drugs in a preclinical model of compulsive behavior. METHODS: Outbred male Wistar rats were selected as either high (HD) or low (LD) drinkers according to their behavior in schedule-induced polydipsia (SIP). Subsequently, we assessed the effects of acute administration of scopolamine (0.125, 0.25, and 0.5 mg/kg), methamphetamine (0.25, 0.5, 1.25, and 2.5 mg/kg), ketamine (1.25, 2.5, 5, and 10 mg/kg), cannabidiol (1 and 3 mg/kg), WIN21255-2 (0.5, 075, and 1 mg/kg), and AM404 (0.25 and 0.5 mg/kg) on compulsive drinking in SIP. RESULTS: Scopolamine reduced dose-dependent compulsive drinking in HD compared with LD rats in SIP. Methamphetamine induced a dose-dependent inverted U-curve effect in both groups, in which lower doses increased and higher doses reduced compulsive drinking in SIP. Ketamine, cannabidiol, WIN21255-2, and AM404 did not have any relevant effects in SIP. CONCLUSIONS: These data provide new evidence that low doses of scopolamine and intermediate doses of methamphetamine might therapeutically reduce compulsive behaviors and suggest that there is not a direct participation of the endocannabinoid system in compulsive behavior on SIP. The research in the underlying neurochemical mechanisms of these psychoactive drugs might provide an additional insight on new therapeutic targets in compulsive neuropsychiatric disorders.