Arginine vasopressin deficiency: diagnosis, management and the relevance of oxytocin deficiency.

Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution.

Biological Variation Estimates for Plasma Copeptin and Clinical Implications.

BACKGROUND: Plasma copeptin measurement is useful for the differential diagnoses of polyuria-polydipsia syndrome. It has also been proposed as a prognostic marker for cardiovascular diseases. However, limited information is available about the within- (CVI) and between-subject (CVG) biological variation (BV). This study presents BV estimates for copeptin in healthy individuals. METHODS: Samples were collected weekly from 41 healthy subjects over 5 weeks and analyzed using the BRAHMS Copeptin proAVP KRYPTOR assay after at least 8 h of food and fluid abstinence. Outlier detection, variance homogeneity, and trend analysis were performed followed by CV-ANOVA for BV and analytical variation (CVA) estimation with 95% confidence intervals. Reference change values (RCVs), index of individuality (II), and analytical performance specification (APS) were also calculated. RESULTS: The analysis included 178 results from 20 males and 202 values from 21 females. Copeptin concentrations were significantly higher in males than in females (mean 8.5 vs 5.2 pmol/L, P < 0.0001). CVI estimates were 18.0% (95% CI, 15.4%-21.6%) and 19.0% (95% CI, 16.4%-22.6%), for males and females, respectively; RCVs were -35% (decreasing value) and 54% (increasing value). There was marked individuality for copeptin. No result exceeded the diagnostic threshold (>21.4 pmol/L) for arginine vasopressin resistance. CONCLUSIONS: The availability of BV data allows for refined APS and associated II, and RCVs applicable as aids in the serial monitoring of patients with specific diseases such as heart failure. The BV estimates are only applicable in subjects who abstained from oral intake due to the rapid and marked effects of fluids on copeptin physiology.

Diabetes insipidus: Vasopressin deficiency .

Diabetes insipidus is a disorder characterized by hypo-osmotic polyuria secondary to abnormal synthesis, regulation, or renal action of antidiuretic hormone. Recently, an expert group, with the support of patient associations, proposed that diabetes insipidus be renamed to avoid confusion with diabetes mellitus. The most common form of diabetes insipidus is secondary to a dysfunction of the neurohypophysis (central diabetes insipidus) and would be therefore named 'vasopressin deficiency'. The rarer form, which is linked to renal vasopressin resistance (nephrogenic diabetes insipidus), would then be named 'vasopressin resistance'. The etiology of diabetes insipidus is sometimes clear, in the case of a neurohypophyseal cause (tumoral or infiltrative damage) or a renal origin, but in some cases diabetes insipidus can be difficult to distinguish from primary polydipsia, which is characterized by consumption of excessive quantities of water without any abnormality in regulation or action of antidiuretic hormone. Apart from patients' medical history, physical examination, and imaging of the hypothalamic-pituitary region, functional tests such as water deprivation or stimulation of copeptin by hyperosmolarity (induced by infusion of hypertonic saline) can be proposed in order to distinguish between these different etiologies. The treatment of diabetes insipidus depends on the underlying etiology, and in the case of a central etiology, is based on the administration of desmopressin which improves patient symptoms but does not always result in an optimal quality of life. The cause of this altered quality of life may be oxytocin deficiency, oxytocin being also secreted from the neurohypophysis, though this has not been fully established. The possibility of a new test using stimulation of oxytocin to identify alterations in oxytocin synthesis is of interest and would allow confirmation of a deficiency in those patients presenting with diabetes insipidus linked to neurohypophyseal dysfunction.

The diagnostic performance of copeptin in clinical practice: A prospective study.

OBJECTIVE: Plasma copeptin is a relatively new biomarker for evaluation of arginine vasopressin (AVP) secretion. The aim of this study was to test the diagnostic performance of copeptin in patients with polyuria-polydipsia syndrome. DESIGN, PATIENTS AND MEASUREMENTS: This was a prospective study where 88 patients with polyuria-polydipsia syndrome were evaluated with a water deprivation test (WDT). Weight, urine osmolality, urine specific gravity, and plasma copeptin were collected at baseline, after 8 h, and at termination of the WDT when one of the following had been reached: (i) >3% weight reduction, (ii) urine specific gravity >1.017 or urine osmolality >600 mOsm/kg, or (iii) intolerable adverse symptoms. RESULTS: Of 88 patients (57 women), 21 (24%) were diagnosed with central diabetes insipidus (cDI), 5 (6%) with nephrogenic DI (nDI), and 62 (71%) with primary polydipsia (PP). Median (interquartile range) copeptin at baseline was 1.7 (1.4-2.5) pmol/L in cDI, 22 (18-65) pmol/L in nDI, and 2.7 (2-4) pmol/L in PP. After 8 h of WDT, the highest copeptin in patients with cDI was 4.0 pmol/L. In patients with PP: (i) 41 had urine osmolality <600 mOsm/kg, 7 (17%) of these had copeptin >4.0 pmol/L, (ii) 21 had urine osmolality ≥600 mOsm/kg, 14 (67%) of these had copeptin >4.0 pmol/L. CONCLUSIONS: Copeptin >4.0 pmol/L after an overnight WDT can be used to rule out cDI and copeptin ≥21 pmol/L at baseline to diagnose nDI. The diagnostic performance of copeptin in the context of the WDT is otherwise limited in the diagnostic work-up of patients with polyuria-polydipsia syndrome.

An exceptional cause of polyuria-polydipsia syndrome in a 10-year-old boy.

Polyuria-polydipsia syndrome is a frequent symptom in pediatrics, primarily attributed to diabetes mellitus. In the context of diabetes insipidus, this syndrome can stem from central or nephrogenic factors. Sjögren's syndrome, an uncommon autoimmune disease in children, can affect multiple organs. Kidney involvement as described in adults is usually related to glomerular or tubular impairment, often linked to distal tubular acidosis. As a kidney involvement during childhood, Sjögren's syndrome has rarely been reported. Hereby, we present the case of Sjögren's syndrome revealed by polyuria-polydipsia syndrome in a 10-year-old boy.

The diagnostic role of arginine-stimulated copeptin in the differential diagnosis of polyuria-polydipsia syndrome (PPS) in pediatric age.

PURPOSE: In recent years, copeptin stimulation through arginine administration has been evaluated as a new potential tool in the differential diagnosis of polyuria-polydipsia syndrome (PPS) in adults; to date very few data, all retrospective, exist in pediatric age. The aim of this prospective study is to evaluate the diagnostic performance of the arginine-stimulation test for copeptin in a cohort of pediatric patients affected by PPS. METHODS: All children (<18 years) referred to the Department of Pediatric Endocrinology of the Regina Margherita Children Hospital for polyuria-polydipsia in the period January 2021-June 2023 were enrolled. The Arginine-stimulation test for copeptin was performed in all patients presenting PPS after water deprivation test (WDT). Patients with polyuria-polydipsia were then classified as having primary polyuria (PP), complete and partial central diabetes insipidus (CDI), according to the standardized interpretation. Arginine-stimulation test for copeptin was also performed in a control cohort. RESULTS: A significant difference in arginine-stimulated copeptin values was observed at baseline (p = 0.005), at 60 min (p = 0.01), and at 90 min (p = 0.005) in 7 subjects presenting PP, 6 patients affected by CDI and 50 subjects of the control cohort. Plasma osmolality values remained stable at all measurements. The arginine-stimulated copeptin test demonstrated sensitivity and specificity of 100%, whereas the sensitivity of the WDT test was 83.3% and the specificity was 85.7%. CONCLUSION: Given the reliability and the minor adverse effects and costs, the copeptin level after arginine administration could replace the WDT in the diagnostic workup of these in pediatric age.

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.).

Hypodipsic hypernatremia after long-standing polydipsia in a cat with suspect neonatal head trauma.

A 16-month-old neutered male domestic shorthair cat weighing 2.7 kg was referred for further evaluation of acute generalized muscle weakness and paraparesis after a long-standing history of polyuria-polydipsia. The diagnosis of hypodipsic/adipsic hypernatremia relied on the key findings of absent spontaneous drinking despite hypernatremia and a hyperosmolar state (444.8 mOsm/kg, reference interval 280 to 310 mOsm/kg). Brain MRI revealed severe multifocal anatomic anomalies of the rostral calvarium and the forebrain, suggestive of encephaloclastic porencephaly. Involvement of the thalamic and hypothalamic regions could have been responsible for the cat's adipsic hypernatremia. The unique aspects of this case were the rare description of central nervous system disease leading to hypodipsia, and the history of chronic polydipsia before the acute onset of hypodipsia. Key clinical message: Multifocal abnormalities of the forebrain can present with polyuria-polydipsia syndrome, hypodipsia/adipsia, or both, depending on the stage of the disease. This likely happens when the hypothalamic and thalamic regions are affected, since they regulate antidiuretic hormone release and thirst, respectively.

Hypernatrémie hypodipsique après polydipsie ancienne chez un chat suspect de traumatisme crânien néonatal. Un chat domestique à poil court mâle castré âgé de 16 mois et pesant 2,7 kg a été référé pour une évaluation plus approfondie de faiblesse musculaire aiguë généralisée et de paraparésie après une longue histoire de polyurie-polydipsie. Le diagnostic d'hypernatrémie hypodipsique/adipsique reposait sur les principales conclusions de l'absence d'abreuvement spontané malgré l'hypernatrémie et un état hyperosmolaire (444,8 mOsm/kg, intervalle de référence de 280 à 310 mOsm/kg). L'IRM du cerveau a révélé des anomalies anatomiques multifocales sévères de la calotte crânienne rostrale et du prosencéphale évoquant une porencéphalie encéphaloclastique. L'atteinte des régions thalamique et hypothalamique pourrait être responsable de l'hypernatrémie adipsique du chat. Les aspects uniques de ce cas étaient la description rare d'une maladie du système nerveux central conduisant à l'hypodipsie, et l'histoire de la polydipsie chronique avant l'apparition aiguë de l'hypodipsie.Message clinique clé :Les anomalies multifocales du cerveau antérieur peuvent présenter un syndrome de polyurie-polydipsie, une hypodipsie/adipsie, ou les deux, selon le stade de la maladie. Cela se produit probablement lorsque les régions hypothalamique et thalamique sont affectées, car elles régulent respectivement la libération d'hormone antidiurétique et la soif.(Traduit par Dr Serge Messier).

Iatrogenic Cushing syndrome in a child due to erroneous compounding of omeprazole containing glucocorticoid: A case report and literature review.

A 3-month-old infant was examined for inconsolable crying with polydipsia, polyuria, and rapid weight gain. Unexpectedly, the symptoms resolved spontaneously during hospitalization but were aggravated 2 weeks after discharge, with the patient presenting a Cushingoid appearance. Investigations ruled out diabetes mellitus and nephrogenic diabetes insipidus but indicated adrenocortical suppression by exogenous glucocorticoids, which were discovered via toxicologic analysis of her previously compounded omeprazole suspension. After discontinuing the omeprazole suspension, the infant recovered fully and the laboratory results normalized. This case shows us that the assumption of appropriate medication intake may conceal unexpected medication errors. Following this case, the current literature on the benefits and risks of compounding and its impact on patient health is discussed.

[Diagnosis of psychogenic polydipsia in the type of clinical case].

Polydipsia is a pathologically increased thirst, satisfied by the intake of water in large quantities, which can manifest itself in various somatic or mental diseases and at first glance is similar to a true vasopressin deficiency. Central diabetes insipidus (CDI) is a disease of the hypothalamic-pituitary region characterized by the inability of the kidneys to reabsorb water and concentrate urine, which is based on a defect in the synthesis or secretion of vasopressin and is manifested by severe thirst and excretion of large amounts of hypotonic urine. The prevalence of the disease in the population is 1:25,000, which characterizes it as a fairly rare pathology of the hypothalamic-pituitary region. The peak incidence is between 30 and 40 years of age. According to various literary sources, the disease is not characterized by gender differences in prevalence, however, on the example of the Moscow population, women prevailed in the incidence structure of CND in a ratio of 2.2:1. Insidiousness, with apparent absences in the difficulty of diagnosing primary polydipsia, lies in the manifestations of water intoxication, thus this condition requires knowledge of clear diagnostic criteria by healthcare professionals and an interdisciplinary approach in the treatment of this condition. On the example of this clinical case, we will try to highlight the differential diagnostic criteria for psychogenic polydipsia in comparison with the true deficiency of arginine vasopressin (AVP) or central diabetes insipidus (CDI), which can be applied in real clinical practice.

A 75-Year-Old Woman with a 5-Year History of Controlled Type 2 Diabetes Mellitus Presenting with Polydipsia and Polyuria and a Diagnosis of Central Diabetes Insipidus.

BACKGROUND Central diabetes insipidus (CDI) is a rare disorder characterized by large volumes of dilute urine because of a lack of antidiuretic hormone. Co-existing CDI and diabetes mellitus without inherited disorders such as Wolfram syndrome are rare. It is both important and challenging to diagnose this combination because the 2 conditions present with thirst, polydipsia, and polyuria. A few cases of CDI developing in patients with type 2 diabetes mellitus (T2D) have been reported. We report an unusual case of CDI that developed in an older patient with T2D. The aims of this report are to share the clinical course and discuss clues to the early diagnosis of CDI in T2D. CASE REPORT A 70-year-old Japanese woman developed T2D with hyperglycemia symptoms, including thirst, polydipsia, and polyuria. After starting medical treatment, the hyperglycemia and its symptoms improved. The glycated hemoglobin level decreased from 9% to 6%. However, 5 years later (at 75 years of age), she re-exhibited thirst, polydipsia, and polyuria despite stable glycemic control. Her urine volume was large (6.3 L/day). A urine glucose test was negative. The plasma osmolality was high (321 mOsm/kg), while the urinary osmolality was low (125 mOsm/kg). A significant increase in urinary osmolality following vasopressin administration indicated a diagnosis of CDI. Desmopressin therapy effectively relieved the symptoms. CONCLUSIONS This case highlights the need to consider CDI as a rare but important comorbid disorder in patients with diabetes mellitus, including T2D, particularly those presenting with thirst, polydipsia, and polyuria despite well-controlled glycemia.

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.

Polyuria and Polydipsia in Horses.

Polyuria and polydipsia are rare, but significant, manifestations of several different diseases of horses. Causes can be endocrine, iatrogenic, psychogenic, infectious, or toxic in nature and can also be due to primary renal disease or diseases of other organs, such as the liver. Although numerous causes of polyuria and polydipsia in horses exist, the most common conditions include chronic kidney disease, pituitary pars intermedia dysfunction, and psychogenic polydipsia with secondary polyuria. Additional testing is dictated by history, other clinical signs, and the results of blood work and/or urinalysis. Prognosis for horses with polyuria and/or polydipsia varies significantly based on the underlying cause.

Ketoacidosis, Hypertriglyceridemia and Acute Pancreatitis Induced by Soft Drink Polydipsia in a Patient with Occult Central Diabetes Insipidus.

A 21-year-old Japanese man without known diabetes mellitus had abdominal pain. The diagnosis was ketoacidosis and hypertriglyceridemia-induced acute pancreatitis. He had polydipsia and polyuria and had habitually drunk several soft drinks every day for two years. After hospitalization, despite adequate liquid intake, dehydration remained with hypotonic polyuria. Further examinations revealed the coexistence of central diabetes insipidus (CDI), possibly caused by lymphocytic infundibulo-neurohypophysitis, based on anti-rabphilin-3A antibody positivity. Although CDI had been undiagnosed for two years, over-consumption of sugar-rich soft drinks to ease thirst caused ketoacidosis, hypertriglyceridemia, and acute pancreatitis. There are no previous reports of this three-part combination of symptoms caused by CDI.