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.).

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.

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.

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.

Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy.

Primary polydipsia (PP) has been defined as excessive intake of fluids. However, the pathogenesis of PP remains unexplored. Different theories include a dysfunction in the thirst mechanism, involvement of the hippocampus, stress-reducing behaviour and lesion occurrences in specific areas of the brain. Most studies have been performed in the psychiatric setting, indicating that PP coincides with schizophrenia, anxiety disorder and depression. However, an increasing number of case reports emphasise the incidence of PP in non-psychiatric patients. As often recommended by healthcare professions and in life-style programmes, the phenomenon of excessive fluid intake appears to be growing, especially in health-conscious and active people. PP is part of the polyuria-polydipsia syndrome, so the differential diagnosis diabetes insipidus (central or nephrogenic) must be excluded. The gold standard when differentiating between these disorders has been the water deprivation test. However, new options for distinguishing between these entities have been proposed e.g., measurement of copeptin, a reliable surrogate marker of the hormone arginine vasopressin (AVP). The major risk of excessive drinking is the development of hyponatraemia and the ensuing complications. In patients with PP, factors reducing the renal excretory capacity of the kidney such as acute illness, medications or low solute intake may accumulate in hyponatraemia. Treatment options for PP remain scarce. Different medication and behavioural therapy have been investigated, but never on a large scale and rarely in non-psychiatric patients. This review provides an overview of the pathophysiology, characteristics, complications, and outcomes of patients with PP in the medical and psychiatric patient.

Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'.

OBJECTIVE: Hyponatraemia is common and its differential diagnosis is challenging. Commonly used diagnostic algorithms have limited diagnostic accuracy. Copeptin, the c-terminal portion of the precursor peptide of arginine vasopressin might help in the differential diagnosis of hyponatraemia. DESIGN: Prospective multicentre observational study. PATIENTS/METHODS: A total of 298 patients admitted with profound hypoosmolar hyponatraemia (Na < 125 mmol/l) were evaluated. Three experts uninvolved in the patients' care determined the aetiology of hyponatraemia after standardized diagnostic evaluation. RESULTS: Hyponatraemia differential diagnoses were as follows: syndrome of inappropriate antidiuresis (SIAD), 106 patients (35·6%); 'diuretic-induced', 72 (24·2%); 'hypovolaemic', 59 (19·8%); 'hypervolaemic', 33 (11·1%); primary polydipsia (PP), 24 (8·1%); and cortisol deficiency, 4 (1·3%). Copeptin levels <3·9 pmol/l identified patients with PP with high specificity (91%). Further, copeptin levels >84 pmol/l were highly predictive for hypovolaemic hyponatraemia (specificity: 90%). Urinary sodium levels and copeptin/urinary sodium ratio in patients with SIAD were higher and lower as compared to other hyponatraemia aetiologies (P < 0·0001). However, the specificity to identify SIAD was moderate for both parameters (31% and 61%). Fractional uric acid excretion (FEUA ) and fractional urea excretion (FEurea ) were higher in patients with SIAD compared to other hyponatraemia aetiologies (both P < 0·0001). FEurea values >55% and FEUA values >12% had a specificity of 96% and 77% to detect patients with SIAD. These results remained similar after excluding patients taking diuretics. CONCLUSIONS: Overall, there is only limited diagnostic utility of copeptin in the differential diagnosis of profound hyponatraemia. Very low copeptin levels are seen in patients with PP and highest copeptin levels in hypovolaemic hyponatraemia. To discriminate between SIAD and other hyponatraemia aetiologies, FEurea and FEUA levels are valuable irrespective of diuretics use.

Diagnostic value of the water deprivation test in the polyuria-polydipsia syndrome.

OBJECTIVE: Diabetes insipidus (DI) and primary polydipsia (PP) are characterised by polyuria and polydipsia. It is crucial to differentiate between these two disorders since the treatment is different. The aim of this study was to evaluate the diagnostic value of the short and an extended variant of the water deprivation test (WDT) and of measuring urinary vasopressin (AVP) in patients with polyuria and polydipsia. DESIGN: A retrospective, single-centre study based on WDTs performed between 2004 and 2014 including 104 consecutive patients with the polyuria-polydipsia syndrome. During a strict water deprivation, weight, urinary osmolality, urinary vasopressin and specific gravity were collected until one of the following was reached: i) >3% weight reduction, ii) Urinary specific gravity >1.020 or, urinary osmolality >800 mOsm/L, iii) Intolerable adverse symptoms such as excessive thirst. RESULTS: Out of 104 patients (67 women, 37 men), 21 (20%) were diagnosed with DI and 83 (80%) with PP. The median (interquartile range; range) test duration was 14 hours (10-16; 3-36) in patients with DI and 18 hours (14-24; 7-48) in patients with PP (P=0.011). Of those diagnosed with PP, 22 (26%) did not reach urinary specific gravity >1.020 nor urine osmolality >800 mOsm/L. Urine AVP did not overlap between patients with PP and patients with central DI. CONCLUSIONS: The short WDT is of limited value in the diagnostic work-up of polydipsia and polyuria and a partial DI may have been missed in every fourth patient diagnosed with PP. Urinary AVP has excellent potential in discriminating PP from central DI.

[Deleterious Results of Safety Seeking Behaviours in Panic Disorder: Polydipsia and Diabetes Mellitus Type 2]. / Panik Bozuklugunda Güvenlik Saglama Davranislarinin Medikal Sonuçlari: Polidipsi ve Tip 2 Diabetes Mellitus.

Panic disorder is an anxiety disorder that involves recurrent panic attacks, which emerge when a harmless stimulus is interpreted as "catastrophic". In an attempt to avoid the panic attack or prevent confrontation, the patient exhibits a dysfunctional attitude and behavior, such as evasion and safety-seeking behavior (SSB). Dysfunctional behavior leads to an increase in the recurrence of panic attacks and affects the patient's life in a negative way. According to the cognitive behavioral therapy model, SSB contributes to the continuation of unrealistic beliefs (e.g. physical experiences) regarding and prevents the patient from grasping new information that may potentially contradict the unrealistic cognitions. In this paper, we present a case with a primary diagnosis of panic disorder. Interestingly, this patient developed diabetes mellitus (DM) type 2 and psychogenic polydipsia (PPD) as a consequence of his SSB. PPD is a common occurrence in patients with psychiatric disorders, especially in schizophrenia. Up to now, no case of a panic disorder with either DM or PPD has been reported in the literature. While it is accepted that major depression poses a risk for DM type 2, panic disorder may also increase this risk. Treatment of the panic disorder with cognitive behavioral therapy (CBT) resulted in improvement of PPD and DM type 2. In conclusion, the role of SSB in medical disorders accompanied by psychiatric disorders should be kept in mind when treating these patients.

Fulminant crural compartment syndrome preceded by psychogenic polydipsia.

We report a case of bilateral anterolateral crural compartment syndrome elicited by hyponatraemia and psychogenic polydipsia. The unusual constellation of clinical findings and diminished pain expression made initial diagnostic procedures challenging. The possible pathogenesis and treatment options are discussed. Impairment of lower extremity function at follow-up was serious and permanent.

[Compartment syndrome caused by rhabdomyolysis in the context of pychogenic polydipsia]. / Kompartmentsyndrom nach Rhabdomyolyse im Rahmen einer psychogenen Polydipsie.

Psychogenic polydipsia leading to severe hyponatremia is well documented in the literature. This electrolyte disorder can result in encephalopathy, cerebral edema and epileptic seizures. Another rare effect is rhabdomyolysis with all its well known complications (e.g. renal failure, hyperkalemia and cardiac arrhythmia) and even resulting in compartment syndrome due to severe muscle edema. We present the case of a patient with severe hyponatremia caused by psychogenic polydipsia leading to rhabdomyolysis and compartment syndrome.