Investigation and management of hypotonic polyura is a common challenge in clinical endocrinology. The three main causes, recently renamed to arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus), AVP-resistance (AVP-R, formerly nephrogenic diabetes insipidus), and primary polydipsia (PP) require accurate diagnosis as management differs for each. This new nomenclature more accurately reflects pathophysiology, and has now been adopted by the Systemised Nomenclature of Medicine (SNOMED). Advances in diagnosis over the last few years have centered around the use of copeptin measurement. Here, we use three patient case histories to highlight the use of this approach, and to demonstrate how it can succeed where other approaches, such as the water deprivation test, sometimes fail. We discuss the overall approach to each type of patient and the strengths and limitations of diagnostic strategies, illustrating the use of the new nomenclature.

Nephrogenic diabetes insipidus (NDI) is a rare genetic disorder primarily associated with mutations in the arginine vasopressin receptor 2 (AVPR2) gene or the aquaporin 2 (AQP2) gene, resulting in impaired water reabsorption in the renal tubules. This report describes a case of a young male patient with NDI from China with a history of polydipsia and polyuria for over 15 years. Laboratory examinations of the proband indicated low urine-specific gravity and osmolality. Urologic ultrasound revealed severe bilateral hydronephrosis in both kidneys, bilateral dilatation of the ureters, roughness of the bladder wall, and the formation of muscle trabeculae. The diagnosis of diabetes insipidus was confirmed by water deprivation tests. The administration of posterior pituitary hormone did not alter urine-specific gravity, and osmolality remained at a low level (<300 mOsm/kg). Based on these findings, and the genetic tests of the proband and his parents were performed. A missense mutation (c.616 G>C) in exon 3 of the AVPR2 gene of the proband was found, caused by the substitution of amino acid valine to leucine at position 206 [p.Val206Leu], which was a hemizygous mutation and consistent with X-chromosome recessive inheritance. The administration of oral hydrochlorothiazide improves the symptoms of polydipsia and polyuria in the proband. This novel AVPR2 gene mutation may be the main cause of NDI in this family, which induces a functional defect in AVPR2, and leads to reduced tubular reabsorption of water.

UNASSIGNED: Langerhans cell histiocytosis (LCH) is a rare bone marrow derived neoplasm that mainly affects children. It is a multiorgan disorder and hypothalamic-pituitary involvement is uncommon. LCH reveals a wide spectrum of indications; thus, the diagnosis and treatment are usually challenging.
UNASSIGNED: A 22-year-old male presented with polydipsia, polyuria with nonspecific radiological findings, later on, developed a mandibular lesion and a biopsy was conducted which led to LCH diagnosis. After many improper treatments due to unclear diagnosis, the patient was finally placed on chemotherapy and is now under surveillance.
UNASSIGNED: LCH is a rare disease with diverse clinical manifestations affecting various organs. Associated mutations, such as BRAF V600E, contribute to its complexity. In adults, initial symptoms include pain, weight loss, and fever, with potential pituitary involvement leading to Arginine vasopressin (AVP) deficiency. Commonly affected organs include bone, skin, and the pituitary gland. The disease can be categorized into single-system and multisystem. Pathological diagnosis involves electron microscopy or immunohistochemical staining. Treatment options vary; the presented case utilized Desmopressin acetate and prednisolone before transitioning to cyclophosphamide for multisystemic LCH.
UNASSIGNED: AVP deficiency can suggest hypothalamic-pituitary LCH, and a biopsy, if possible, is recommended to confirm the diagnosis.

Type 2 Diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, resulting from deficits in insulin secretion, insulin action, or both. Whilst the role of insulin in the peripheral nervous system has been ascertained in countless studies, its role in the central nervous system (CNS) is emerging only recently. Brain insulin has been lately associated with brain disorders like Alzheimer\'s disease, obsessive compulsive disorder, and attention deficit hyperactivity disorder. Thus, understanding the role of insulin as a common risk factor for mental and somatic comorbidities may disclose novel preventative and therapeutic approaches. We evaluated general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH, previously reported to constitute a valid experimental model of T2DM due to impaired insulin signaling). Adult TH mice have also been studied for alterations in gut microbiota diversity and composition. While TH mice exhibited profound deficits in cognitive flexibility and altered glucose metabolism, we observed that these alterations emerged either much earlier (males) or independent of (females) a comprehensive constellation of symptoms, isomorphic to an overt T2DM-like phenotype (insulin resistance, polydipsia, higher energy expenditure, and altered lipid metabolism). We also observed significant sex-dependent alterations in gut microbiota alpha diversity and taxonomy in adult TH mice. Deficits in insulin signaling may represent a common risk factor for both T2DM and CNS-related deficits, which may stem from (partly) independent mechanisms.

UNASSIGNED: Hyponatremia is a common electrolyte disorder. The severe hyponatremia has a mortality rate of 4%-40%. Psychiatric patients are likely to develop the condition because of polydipsia or the adverse effects of antipsychotics. We investigated the characteristics of patients with and without psychiatric diseases who developed severe hyponatremia.
UNASSIGNED: We retrospectively investigated cases admitted to our hospital (all departments) between October 2012 and November 2015 with a serum sodium concentration of ≤125 mmol/l on admission. We compared patient characteristics, etiology, and clinical course between psychiatric and nonpsychiatric patients.
UNASSIGNED: In total, 123 cases (62 female) were analyzed. Psychiatric disorders were present in 69 cases (56%), including schizophrenia (n = 19), anorexia (n = 16), mood disorders (n = 14), and organic mental disorders (n = 9). The mean patient age was 63 years. The mean serum sodium concentration on admission was 119 mmol/l, and the main causes of hyponatremia were polydipsia (20%), insufficient sodium intake (18%), and syndrome of inappropriate antidiuretic hormone secretion (16%). Compared with the nonpsychiatric group, the psychiatric group was significantly younger (55 vs. 74 years), was more likely to have polydipsia (30% vs. 6%), and had a lower in-hospital mortality (0% vs. 17%).
UNASSIGNED: Our study found differences in the clinical picture between psychiatric and nonpsychiatric patients with severe hyponatremia. Clinicians need to monitor serum sodium because the symptoms of hyponatremia can mimic those of psychiatric diseases.

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.

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.

Diabetes mellitus (DM) is an uncommon, poorly documented metabolic disorder of birds. Extrapolating knowledge from DM in mammals is challenging because of marked differences in avian physiology and metabolism. A literature review from December 1991 to January 2022 identified 14 publications covering 16 diabetic birds, 63% (10/16) of which belonged to the order Psittaciformes with Ara as the predominant genus. No sex predilection was noted, but males generally presented at a younger age. Commonly reported clinical signs included polyuria 94% (15/16), polydipsia 88% (14/16), weight loss 75% (12/16), lethargy 63% (10/16), and polyphagia 38% (6/16). Diagnosis of DM was based on the presence of clinical signs and persistent hyperglycemia 100% (16/16), often with glucosuria 93% (13/14), response to insulin therapy 80% (8/10), and pancreatic pathology 90% (9/10). Specific treatment for DM was initiated in 14 patients, but blood glucose regulation for 6 months or longer was only achieved in 6 birds. Five of the regulated birds were managed with injectable long-acting insulin and 1 with oral glipizide combined with dietary modifications. However, glipizide yielded poor results in other cases, likely attributable to a lack of functional beta cells. Three diabetic birds progressed to remission. Treatment proved unsuccessful for 7 patients with a mean survival time of 36 days from diagnosis. One patient was lost to follow-up, and 2 were euthanized immediately following diagnosis. Histological examination of the pancreas frequently (90%, 9/10) revealed abnormalities including atrophy, fibrosis, and vacuolization of the endocrine islets with or without lymphoplasmacytic pancreatitis. Comorbidities, including hemosiderosis and infection, were common. This review suggests that birds diagnosed with DM are primarily affected by a type I diabetes as observed in dogs and humans. In contrast to mammalian species, avian DM is often associated with underlying disease and a complete clinical workup is essential to diagnose and address secondary disease conditions prior to initiating long-term insulin therapy.

X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP-intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the β3-adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the β3-AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X-NDI. Here we demonstrate that the β3-AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X-NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow-release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X-NDI mice. Taken together, these data suggest that human β3-AR agonists might represent an effective possible treatment strategy for X-NDI.

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.