Study of endocrine disruptor effects in AVP and OT mediated behavioral and reproductive processes in female rat models.

Environmental exposures may have endocrine disruptor (ED) effects, e.g., a role for halogenated hydrocarbon chlorobenzenes in increasing vasopressin (AVP), oxytocin (OT) secretion and, in association, anxiety and aggression in male rats has been shown. Our aim is to investigate whether 1,2,4-trichlorobenzenehexachlorobenzene= 1:1 (mClB) treatment of female rats also shows ED effects and reproductive biology differences, and whether AVP may have a mediator role in this? Female Wistar rats were treated (0.1; 1.0; 10.0 µg/bwkg/day) with mClB (by gastrictube) and then 30; 60; 90 days after treatment anxiety (open field test) and aggressive (resident intruder test) behaviors AVP, OT concentrations from blood plasma samples were detected by radioimmunoassay on 30; 60; 90 days. Treated female rats were mated with untreated males. Mating success, number of newborn and maternal aggression on the neonates were monitored. Results showed that AVP, OT levels; and anxiety, aggressive behaviors; and mothers' aggression towards their offspring increased significantly in relation to the duration and the dose of mClB treatment. But mating propensity and number of offspring decreased. Patterns of AVP, OT release and anxiety, aggression behaviors, and reproductive-related behaviors were correlated. Consistent with the literature, our studies confirmed the role of AVP and OT in different behavioral effects.

Diurnal rhythm of urinary aquaporin-2 in children with primary monosymptomatic nocturnal enuresis.

Background/aim: Nocturnal enuresis can be frustrating for children and their families as the child ages. Our aim is to evaluate urine aquaporin 2 (AQP-2) as a noninvasive biomarker of water balance in children with primary monosymptomatic nocturnal enuresis (PMNE). Material and methods: The study included 90 children; sixty-eight children suffering from PMNE aged (9.57 ± 2.16) years and 22 healthy children with good toilet control, matched sex and age. All enuretic children were subjected to complete history taking, clinical evaluation, and bed wetting diary. Serum arginine vasopressin (AVP) and urine AQP-2 were tested in the morning (at 9-11 am) and evening (at 9-11 pm). Blood urea, creatinine, Na, glucose, urine osmolality, Ca/Cr, Alb/Cr and specific gravity were tested simultaneously. Results: Serum AVP, urine AQP-2, and urine osmolality were statistically lower in patients than controls. Patients had a significantly lower level of night serum AVP concentrations, urine AQP-2, and urine osmolality than the corresponding morning level. Urine AQP-2 was significantly correlated with urine osmolality (p < 0.05). AQP-2 had a sensitivity of 90% and a specificity of 70%. However, no statistically significant correlation was found between serum AVP and urine AQP-2. Conclusion: Primary monosymptomatic nocturnal enuresis in children could be associated with reduction of urine excretion of AQP-2 at night. Urine AQP-2 is significantly correlated with urine osmolality. Therefore, it may be a noninvasive biomarker of hydration status in children with PMNE, with good sensitivity and specificity.

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.

A cAMP-biosensor-based assay for measuring plasma arginine-vasopressin levels.

Arginine-vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations via the vasopressin V2 receptor (V2R). Plasma AVP is a valuable biomarker for the diagnosis of central diabetes insipidus (CDI) and is commonly measured using radioimmunoassay (RIA). However, RIA has several drawbacks, including a long hands-on time, complex procedures, and handling of radioisotopes with special equipment and facilities. In this study, we developed a bioassay to measure plasma AVP levels using HEK293 cells expressing an engineered V2R and a cAMP biosensor. To achieve high sensitivity, we screened V2R orthologs from 11 various mammalian species and found that the platypus V2R (pV2R) responded to AVP with approximately six-fold higher sensitivity than that observed by the human V2R. Furthermore, to reduce cross-reactivity with desmopressin (DDAVP), a V2R agonist used for CDI treatment, we introduced a previously described point mutation into pV2R, yielding an approximately 20-fold reduction of responsiveness to DDAVP while maintaining responsiveness to AVP. Finally, a comparison of plasma samples from 12 healthy individuals demonstrated a strong correlation (Pearson's correlation value: 0.90) between our bioassay and RIA. Overall, our assay offers a more rapid and convenient method for quantifying plasma AVP concentrations than existing techniques.

The influence of insulin-induced hypoglycemia on copeptin concentrations.

Plasma copeptin is a biomarker that reflects arginine vasopressin (AVP) secretion. In this study we measured copeptin during insulin tolerance test (ITT) in 65 patients referred to our department for evaluation of anterior pituitary function. Plasma for measurements of copeptin were collected at the start of the test and regurarly up to 120 minutes thereafter. Of 60 patients who developed significant hypoglycemia and were included in the analyses, 13 (22%) had corticotropic deficiency, 11 (18%) had thyreotropic deficiency, 33 (55%) had growth hormone deficiency and 4 (6%) had AVP deficieny (AVPD). Thirty-seven (62%) patients had at least one anterior pituitary deficiency. In patients without AVPD, median (range) copeptin increased from 4.5 pmol/L (1.3-33.0) to a maximum of 6.2 pmol/L (2.0-34.4; p<0.001). Baseline copeptin was similar in men and women, but maximal copeptin during ITT was higher in men. Copeptin concentrations were not affected by age, BMI, somatotropic, or corticotropic function. Copeptin concentrations were lower in patients with AVPD than patiets without AVPD, and in patients with thyrotropic deficiency, compared to patients with intact thyrotropic function, both at baseline and during ITT. In conclusion, copeptin increases significantly during insulin induced hypoglycemia but is of limited value in predicting anterior pituitary hormonal function.

Evaluation of copeptin in children after stimulation with clonidine or L-Dopa.

OBJECTIVES: Arginine-stimulated serum copeptin has been proposed as a new method to diagnose arginine vasopressin (AVP) deficiency in children and adolescents. Herein we investigated the secretagogic potential of clonidine or L-Dopa on the copeptin serum levels in children. METHODS: Eight stimulation tests (4 with clonidine and 4 with L-Dopa) were performed in eight children (5 boys and 3 girls) with a median age of 6.5 years-old, evaluated for short stature due to possible growth hormone deficiency. Serum copeptin levels were measured at 30, 60, 90, and 120 min after administration of clonidine or L-Dopa. RESULTS: Copeptin levels in serum did not show any significant change in either test (clonidine or L-Dopa). The values of copeptin levels compared to the baseline value did not deviate more than 5 % in the clonidine arm (p=0.60) or 8 % in the L-Dopa arm (p=0.75) respectively. CONCLUSIONS: Data do not support the use of L-Dopa or clonidine as stimulants for evaluating AVP relating disorders in clinical pediatric practice.

Impact of urine cyclic AMP relative to plasma arginine vasopressin on response to tolvaptan in patients with chronic kidney disease and heart failure.

BACKGROUND: The clinical utility of tolvaptan in chronic kidney disease (CKD) patients with heart failure remains uncertain. The level of urine cyclic adenosine monophosphate (AMP) relative to plasma arginine vasopressin (AVP) indicates the residual function of the collecting ducts in response to AVP stimulation and might be a key to predicting response of tolvaptan. METHODS: CKD patients who were hospitalized to treat their congestive heart failure refractory to conventional loop diuretics were considered to receive tolvaptan and included in this prospective study. The impact of urine cyclic AMP/plasma AVP ratio for prediction of response to tolvaptan, which was defined as any increase in urine volume at day 7 from day 0, was investigated. RESULTS: A total of 30 patients (median 75 years old, 24 men, and median estimated glomerular filtration rate 14.4 mL/min/1.73 m2) were included. As compared to baseline, urine volume increased at day 7 in 17 responders, whereas urine volume decreased at day 7 in 13 non-responders. Baseline urine cyclic AMP/plasma AVP ratio distributed between 0.25 and 4.01 with median 1.90. The urine cyclic AMP/plasma AVP ratio was a significant predictor of response to tolvaptan, which was adjusted for 6 potential confounders with a cutoff of 1.24. CONCLUSIONS: Baseline urine cyclic AMP/plasma AVP ratio is an independent predictor of response to tolvaptan in advanced CKD patients with heart failure. CLINICAL TRIAL REGISTRATION: UMIN000022422.

Recovery from Liver Failure and Fibrosis in a Rat Portacaval Anastomosis Model after Neurointermediate Pituitary Lobectomy.

Liver diseases, including cirrhosis, viral hepatitis, and hepatocellular carcinoma, account for approximately two million annual deaths worldwide. They place a huge burden on the global healthcare systems, compelling researchers to find effective treatment for liver fibrosis-cirrhosis. Portacaval anastomosis (PCA) is a model of liver damage and fibrosis. Arginine vasopressin (AVP) has been implicated as a proinflammatory-profibrotic hormone. In rats, neurointermediate pituitary lobectomy (NIL) induces a permanent drop (80%) in AVP serum levels. We hypothesized that AVP deficiency (NIL-induced) may decrease liver damage and fibrosis in a rat PCA model. Male Wistar rats were divided into intact control (IC), NIL, PCA, and PCA+NIL groups. Liver function tests, liver gene relative expressions (IL-1, IL-10, TGF-ß, COLL-I, MMP-9, and MMP-13), and histopathological assessments were performed. In comparison with those in the IC and PCA groups, bilirubin, protein serum, and liver glycogen levels were restored in the PCA+NIL group. NIL in the PCA animals also decreased the gene expression levels of IL-1 and COLL-I, while increasing those of IL-10, TGF-ß, and MMP-13. Histopathology of this group also showed significantly decreased signs of liver damage with lower extent of collagen deposition and fibrosis. Low AVP serum levels were not enough to fully activate the AVP receptors resulting in the decreased activation of cell signaling pathways associated with proinflammatory-profibrotic responses, while activating cell molecular signaling pathways associated with an anti-inflammatory-fibrotic state. Thus, partial reversion of liver damage and fibrosis was observed. The study supports the crucial role of AVP in the inflammatory-fibrotic processes and maintenance of immune competence. The success of the AVP deficiency strategy suggests that blocking AVP receptors may be therapeutically useful to treat inflammatory-fibrotic liver diseases.

Peak Lag Between Plasma Vasopressin and Urine Aquaporin-2 Following Cardiac Surgery.

Tolvaptan, a vasopressin type-2 receptor antagonist, is utilized to ameliorate fluid retention following cardiac surgery. However, the optimal timing of tolvaptan administration considering novel biomarkers remains unknown. We prospectively included patients who underwent cardiac surgery between 2016 and 2020. We measured perioperative trends of free water reabsorption mediators including plasma arginine vasopressin and urine aquaporin-2. A total of 20 patients (68 [60, 75] years old, 18 men) were included. Urine volume decreased gradually after the initial 3 hours following cardiac surgery. The plasma arginine vasopressin level increased significantly with a peak at postoperative 6 hours, whereas the urine aquaporin-2 level increased later with a delayed peak at postoperative 12 hours. As a result, urine aquaporin-2 relative to the plasma arginine vasopressin level, which represents the activity of the collecting ducts and indicates predicted responses to tolvaptan, was a minimum at postoperative 6 hours. Tolvaptan administration immediately after cardiac surgery might not be recommended given the transient refractoriness to tolvaptan probably due to the stunning of kidney collecting ducts.

Copeptin as a novel biomarker of cardiometabolic syndrome.

Arginine vasopressin (AVP), which is also called antidiuretic hormone (ADH), is a neurohormone synthetized from a pre-pro-hormone precursor in the supraoptic and paraventricular nuclei of the hypothalamus in response to increased plasma osmolality and decreased blood volume. AVP exerts several effects by binding to three different receptors: V1aR, V1bR, and V2R. In recent years, it has been suggested that increased plasma concentration of AVP may play a causal role in the development of type 2 diabetes, the metabolic syndrome, renal dysfunction and cardiovascular disease by influencing glucose homeostasis and lipid metabolism through several possible mechanisms involving V1aR and V1bR. V1aR located in the liver is involved in hepatic glycogenolysis and gluconeogenesis. V1bR, found in the pituitary gland and pancreas, mediates secretion of adrenocorticotrophic hormone (ACTH), insulin, and glucagon. However, AVP's clinical use as a biomarker is limited due to its short half-life in plasma (16-20 minutes), small size, and poor stability, which make direct measurement difficult. Copeptin, the biologically inactive, stable, C-terminal part of pro-vasopressin, is co-secreted with AVP in equimolar amounts and thus is considered an adequate and clinically useful surrogate marker of AVP. The aim of this review is to assess the current state of knowledge about the potential role of copeptin as a novel biomarker of cardiometabolic syndrome on the basis of recent scientific literature published up to December 2020 and searches of the PubMed, Google Scholar, and Web of Science databases.

Development of a sensitive liquid chromatography-tandem mass spectrometry method for quantification of human plasma arginine vasopressin.

BACKGROUND AND AIMS: Direct measurement of arginine vasopressin (AVP) via immunoassays is not widely conducted, mainly because of technical constraints. Liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been widely used as the gold standard in clinical chemistry. Here, we aimed to develop an MS-based assay to determine human plasma AVP and compare the results with those obtained using a conventional immunoassay. MATERIALS AND METHODS: We developed a protocol using triple quadrupole MS coupled with LC for the measurement of human plasma AVP. Analytical evaluations of the method were performed, and the results obtained using LC/MS/MS and radioimmunoassay (RIA) were compared. RESULTS: The lower limit of quantification (LLOQ) for plasma AVP obtained using LC/MS/MS and RIA were 0.2 and 0.4 pg/mL, respectively. Although there was a weak overall correlation between the results obtained using the two different methods, the RIA results did not agree with the LC/MS/MS results, particularly at low concentrations. CONCLUSIONS: AVP detection through RIA is not satisfactory compared with that using LC/MS/MS. Diagnostic values of direct AVP measurements must be evaluated based on the results obtained via sensitive and accurate MS-based methods rather than those obtained through RIA.

Coregulation Analysis of Mechanistic Biomarkers in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

Is PTSD-Phenotype Associated with HPA-Axis Sensitivity? Feedback Inhibition and Other Modulating Factors of Glucocorticoid Signaling Dynamics.

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.

A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia.

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

Birth signalling hormones and the developmental consequences of caesarean delivery.

Rates of delivery by caesarean section (CS) are increasing around the globe and, although several epidemiological associations have already been observed between CS and health outcomes in later life, more are sure to be discovered as this practice continues to gain popularity. The components of vaginal delivery that protect offspring from the negative consequences of CS delivery in later life are currently unknown, although much attention to date has focused on differences in microbial colonisation. Here, we present the case that differing hormonal experiences at birth may also contribute to the neurodevelopmental consequences of CS delivery. Levels of each of the 'birth signalling hormones' (oxytocin, arginine vasopressin, epinephrine, norepinephrine and the glucocorticoids) are lower following CS compared to vaginal delivery, and there is substantial evidence for each that manipulations in early life results in long-term neurodevelopmental consequences. We draw from the research traditions of neuroendocrinology and developmental psychobiology to suggest that the perinatal period is a sensitive period, during which hormones achieve organisational effects. Furthermore, there is much to be learned from research on developmental programming by early-life stress that may inform research on CS, as a result of shared neuroendocrine mechanisms at work. We compare and contrast the effects of early-life stress with those of CS delivery and propose new avenues of research based on the links between the two bodies of literature. The research conducted to date suggests that the differences in hormone signalling seen in CS neonates may produce long-term neurodevelopmental consequences.

Copeptin response to hypoglycemic stress is linked to prolactin activation in children.

PURPOSE: The physiological role of arginine vasopressin (AVP) in the acute stress response in humans and especially in children is unclear. The aim of this study was to explore the interaction between copeptin, a well-established surrogate marker of AVP release, and anterior pituitary hormone activation in response to acute hypoglycemic stress in children and adolescents. METHODS: We conducted an exploratory single center study involving 77 children and adolescents undergoing insulin-induced hypoglycemia. Blood levels of copeptin, ACTH, cortisol, GH, prolactin, interleukin-6 (IL-6), adrenaline and noradrenaline were determined at baseline and after insulin-induced hypoglycemia. RESULTS: Basal plasma levels of copeptin (median: 5.2 pmol/L) increased significantly after hypoglycemia (median 9.7 pmol/L; P < 0.0001). Subjects with insufficient HPA axis response or severe GH deficiency had lower hypoglycemia-induced copeptin increase (median: 2.3 pmol/L) compared with individuals with intact pituitary response (median: 5.2 pmol/L, P = 0.02). Copeptin increase correlated significantly with the maximal increase of ACTH (rs = 0.30; P = 0.010), cortisol (rs = 0.33; P = 0.003), prolactin (rs = 0.25; P = 0.03), IL-6 (rs = 0.35; P = 0.008) and with BMI-SDS (rs = - 0.28, P = 0.01). In multivariate regression analysis, prolactin increase was the only independent variable associated with copeptin increase (P = 0.0004). CONCLUSION: Our data indicate that: (1) hypoglycemic stress elicits a marked copeptin response in children and adolescents, pointing out its role as an acute stress marker in this population; (2) stress-induced AVP/copeptin release is associated with anterior pituitary activation, mainly a prolactin response.

Copeptin Kinetics and Its Relationship to Osmolality During Rehydration for Diabetic Ketoacidosis in Children.

CONTEXT: Copeptin is a surrogate marker for arginine vasopressin (AVP) release in response to hyperosmolal stimuli such as diabetic ketoacidosis (DKA). OBJECTIVE: The objective of this work is to characterize kinetics of copeptin and osmolality, and their dynamic relationship during rehydration and insulin therapy in children with type 1 diabetes (T1D) and DKA. DESIGN AND SETTING: A prospective, observational, multicenter study was conducted. PATIENTS AND INTERVENTION: Children with T1D admitted for DKA underwent serial serum copeptin and osmolality measurements from start of rehydration at 14 time points during 72 hours. MAIN OUTCOME MEASURES: Measurements included temporal course of copeptin and osmolality (kinetics), relationship between both (dynamics), and association between-subject variability (BSV) (coefficient of variation, CV%). RESULTS: Twenty-eight children (20 newly diagnosed T1D) aged 1 to 16 years were included. Copeptin decreased from 95 pmol/L (95% CI, 55-136 pmol/L) (CV%, 158%) to 9.7 pmol/L (95% CI, 8.1-11.4 pmol/L) (CV%, 31%) with a 50% recovery time (t1/2) of 7.1 hours (range, 5.1-11.5 hours) (114%). Serum osmolality decreased from 321 mOsm/kg (range, 315-327 mOsm/kg) (4%) to 294 mOsm/kg (range, 292-296 mOsm/kg) (1%) with a t1/2 of 4.3 hours (range, 3.0-5.6 hours) (64%). Copeptin levels doubled with each osmolality increase by 15 mOsm/kg (range, 10-21 mOsm/kg) (59%), from 9.8 pmol/L (range, 7.3-12.3 pmol/L) (48%) to 280 mOsm/kg. Copeptin kinetics differed between newly diagnosed and known T1D patients (P = .001), and less between mild vs moderate-severe DKA (P = .04). CONCLUSIONS: First, this study characterized for the first time copeptin kinetics and dynamics in the high hyperosmolar range in children with DKA. Second, it revealed significant differences in copeptin kinetics between newly diagnosed and known T1D patients that may be explained by changes at the osmoreceptor and renal AVP receptor level due to longstanding osmotic diuresis and DKA.

Central diabetes insipidus related to anti-programmed cell-death 1 protein active immunotherapy.

Cancer immunotherapy is a breakthrough strategy entwined with toxicity. Immune-related hypophysitis is conventionally considered distinctive of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. Immune-related central diabetes insipidus (CDI) is exceptional. CDI rarely manifests as hypernatremia, which is almost always euvolemic. We report a 71-years-old male patient with advanced lung cancer who experienced severe chronic hypernatremia presented as alterations in mental status five months after initiation of treatment with the anti-PD-1 checkpoint inhibitor nivolumab. Combination of persistenthypernatremia, polyuria, high plasma osmolality and hyposthenuria raised suspicion of diabetes insipidus, prompting measurement of serum concentration of arginine vasopressin(AVP). The inappropriately undetectable serum levels of AVP confirmed central diabetes insipidus (CDI). Nivolumab-related hypophysitis was recognized as possible cause of CDI. Further hormonal assessment excluded any endocrinopathy indicating disorder of posterior pituitary. Pituitary MRI was normal with persistence of hyperintensity of posterior pituitary on T1-weighted images (bright spot). The patient was scheduled to receive 1-deamino-8-D-arginine vasopressin (DDAVP), but he died suddenly due to cardiac arrest before initiation of treatment. Our report describes the first case of nivolumab related CDI, building on existing literature through: (I) underscoring hypovolemic hypernatremia as CDI manifestation; (ii) bringing into spotlight the rare anti-PD-1 treatment related hypophysitis; (iii) enriching the limited evidence on immune-related CDI. Increased awareness of nivolumab related CDI will enable prompt recognition and therapeutic intervention.

Distinguishing Low and High Water Consumers-A Paradigm of Disease Risk.

A long-standing body of clinical observations associates low 24-h total water intake (TWI = water + beverages + food moisture) with acute renal disorders such as kidney stones and urinary tract infections. These findings prompted observational studies and experimental interventions comparing habitual low volume (LOW) and high volume (HIGH) drinkers. Investigators have learned that the TWI of LOW and HIGH differ by 1-2 L·d-1, their hematological values (e.g., plasma osmolality, plasma sodium) are similar and lie within the laboratory reference ranges of healthy adults and both groups appear to successfully maintain water-electrolyte homeostasis. However, LOW differs from HIGH in urinary biomarkers (e.g., reduced urine volume and increased osmolality or specific gravity), as well as higher plasma concentrations of arginine vasopressin (AVP) and cortisol. Further, evidence suggests that both a low daily TWI and/or elevated plasma AVP influence the development and progression of metabolic syndrome, diabetes, obesity, chronic kidney disease, hypertension and cardiovascular disease. Based on these studies, we propose a theory of increased disease risk in LOW that involves chronic release of fluid-electrolyte (i.e., AVP) and stress (i.e., cortisol) hormones. This narrative review describes small but important differences between LOW and HIGH, advises future investigations and provides practical dietary recommendations for LOW that are intended to decrease their risk of chronic diseases.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.