Vasopressin Research Articles

Real-time intraoperative ultrasound imaging of the posterior pituitary gland during endoscopic endonasal approach.

Pituitary adenomas are amongst the most common benign central nervous system tumors, and often require resection via an endoscopic endonasal approach (EEA). Two of the most common associated complications are central diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Both are thought to be caused by manipulation of the posterior pituitary gland (PPG), making intraoperative visualization and preservation of this structure critical. Intraoperative endoscopic endonasal ultrasound (IEUS) may present an optimal tool for this purpose. This study aims to describe the appearance and morphology of the PPG on IEUS. This study included all pituitary adenoma surgeries during which IEUS was utilized and the PPG was visualized between 1/1/2022, and 12/31/2023. Demographic, clinical, pathological, and radiological data were retrospectively collected. The PPG was described as either hypoechoic, isoechoic, or hyperechoic as compared to the anterior pituitary gland and adenoma, and the morphology of the PPG was further classified as ellipse or crescent shaped. The PPG was hypoechoic in all 43 cases included in our final cohort (100.0%). Morphologically, the PPG appeared elliptical in 27 cases (62.8%), and crescent shaped in 16 cases (37.2%). The PPG can typically be visualized by IEUS as a hypoechoic structure immediately anterior to the posterior wall of the sella turcica, with elliptical morphology being the most common appearance. These characteristics can be used by the skull base surgeon to more confidently identify the position and morphology of the PPG intraoperatively for its' preservation.

Hyponatremia Associated with the Use of Common Antidepressants in the All of Us Research Program.

Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.

Correlation Between Serum Copeptin and NTproBNP Levels in Heart Failure

Introduction: Heart Failure is a leading cause of morbidity and mortality worldwide. It is associated with upregulation and dysfunction of the renin-angiotensin aldosterone system, the sympathetic nervous system and the vasopressin system. In heart failure, the levels of vasopressin are elevated and out of sync with the osmotic status. Arginine Vasopressin has a half-life of only 20 minutes and is bound to circulating platelets. Hence, it is not useful as a biomarker. Copeptin, a by-product of vasopressin metabolism has been used as a surrogate marker for Arginine Vasopressin in clinical practice. Thus, our study aims to find the use of copeptin in studying heart failure and its use in predicting severity. We also sought to correlate copeptin with NTproBNP the standard biomarker used in heart failure. Methods: Our study was a single-centre cross-sectional observational study involving 90 admitted heart failure patients over 18 months. NYHA Class was used to assess the severity of heart failure. Copeptin levels were measured using Human Copeptin ELISA Kit. Results: In these patients, elevated levels of copeptin and NTproBNP were found. In patients with higher NYHA Class, a greater rise in serum copeptin and NTproBNP levels was noted. Moreover, a strong positive correlation between NTproBNP and copeptin (rho = 0.7) was found in our study. Conclusion: Our study puts forward copeptin as a simple additional cost-effective biomarker for predicting the severity of heart failure.

Empagliflozin Raises Sodium in SIADH Patient, Enabling Timely Surgery

AbstractEmpagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, induces osmotic diuresis via glucosuria and may represent a novel therapeutic approach for managing syndrome of inappropriate antidiuretic hormone secretion (SIADH). This case report details the successful use of empagliflozin to correct persistent hyponatremia in a 78-year-old man with SIADH, awaiting elective abdominal surgery for hernia repair over several months. The patient, who had a history of hypertension and multinodular thyroid goiter with normal thyroid function tests, continued to experience low serum sodium levels despite discontinuing enalapril, previously used for hypertension management. An extensive evaluation confirmed a diagnosis of SIADH, with sodium levels initially ranging between 124 and 128 mmol/L. Traditional management, including fluid restriction, failed to normalize his sodium levels, leading to repeated cancellations of his scheduled surgery due to persistent hyponatremia. In October 2023, treatment with empagliflozin was initiated, leading to a gradual increase in sodium levels. Within 3 weeks, his serum sodium had normalized to 134 mmol/L, accompanied by a rise in serum osmolality. As a result, the elective surgery was successfully performed without complications. These findings suggest that empagliflozin, in combination with fluid restriction, offers a promising treatment option for improving sodium levels in patients with SIADH, helping avoid unnecessary delays in elective surgical interventions.

Serum Sodium Concentration During Arginine Vasopressin Infusion in Critically Ill Children

Background: Intravenous arginine vasopressin is increasingly used for the treatment of critically ill children. It bears the risk of hyponatraemia with potential severe long-term sequelae, but data on hyponatraemia as a side effect of continuous vasopressin infusion for paediatric intensive care patients is scarce. Methods: In this retrospective analysis performed at a tertiary care paediatric intensive care unit with 2000 annual admissions, patients were included if they were treated with intravenous vasopressin between 2016 and 2022. Baseline sodium concentrations, lowest sodium concentrations during arginine vasopressin treatment, and time to lowest sodium concentration (nadir) were derived. Results: In total, 170 patients with a median age of 4 months [interquartile range, IQR, 0–33] were included, 92.4% underwent surgery, and 28.8% died. Median arginine vasopressin dose rate was 0.027 IU/kg/h [0.019–0.036] and arginine vasopressin was started 3.2 [0–26] h after intensive care admission. Median arginine vasopressin application duration was 13.6 h [6.2–32.6]. Baseline sodium was 141 mmol/L [138–145], and lowest median sodium during arginine vasopressin infusion was 137 mmol/L [132–141] (nadir at 8.4 h [1.0–28.1] after arginine vasopressin start). Hyponatraemia (<135 mmol/L) occurred in 38.2% of patients during AVP treatment, and physicians administered a median of 10.2 mmol/kg/d [6.2–16.4] sodium during arginine vasopressin therapy. Conclusions: Under arginine vasopressin infusion, hyponatraemia was common, although high daily doses of sodium were administered to keep the serum values in physiologic ranges. This emphasises the need for close electrolyte monitoring and sodium substitution in children and adolescents under arginine vasopressin treatment to avoid hyponatraemia and related sequelae.

Genetic variations as predictors of dispositional and dyadic empathy—a couple study

Biological drivers of empathy have been explored in an interdisciplinary manner for decades. Research that merges the psychological and genetic perspectives of empathy has recently gained interest, and more complex designs and analyses are needed. Empathy is a multidimensional construct that might be regarded both dispositionally (as a personality trait) and contextually (experienced and/or expressed in a particular relationship/situation). This study analyzed genetic variations associated with genes encoding oxytocin, arginine vasopressin, and receptors that regulate their secretion as predictors of the empathic dimensions of emotional (empathic concern and personal distress) and cognitive (perspective taking) dyadic factors of partners in heterosexual intimate relationships. Machine learning methods to capture both linear and nonlinear relationships between SNPs, RS1 and RS2 repeat polymorphisms and dimensions of empathy in couples were employed. A total of 442 individuals (221 couples) participated in this study. Empathy was measured by the Polish version of the Interpersonal Reactivity Index and the Interpersonal Reactivity Index for Couples. The MassARRAY® 4 instrument, which combines mass spectrometry with endpoint PCR, was used for genotyping all 14 genetic variations. Microsatellite fragment analysis was performed by denaturing polyacrylamide gel electrophoresis. The results confirmed the significance of certain genetic alterations linked to oxytocin, vasopressin, serotonin and estrogen for dispositional and dyadic empathy (mainly rs1884051, rs6311, RS1, rs4686302, and rs1042778) in couples. The effects were stronger for the prediction of emotional and dyadic empathy than for perspective taking. Separate analyses for women and men indicated different predictive effects of genes for empathy (for example, effects of rs53576 were indicated only in women), which are also experienced and expressed in couples. Different dimensions of empathy should be included when the genetic predictors of empathy are examined.

Role of copeptin as biomarker of volume overload in children with end-stage renal disease

BackgroundChildren who undergo dialysis may develop hypertension and cardiovascular morbidity as a result of fluid overload. The intravascular parameter is clinically relevant in children because it directly influences systemic blood pressure, cardiac output, and cardiovascular squeals. Optimum fluid management is still a chronic clinical challenge, despite recent advances in the care of children with end-stage renal disease (ESRD). The paraventricular and supraoptic nuclei of the hypothalamus emit arginine vasopressin (AVP), a nonapeptide. It is secreted into the bloodstream by the pituitary gland in response to both osmotic and nonosmotic stimuli. Copeptin and AVP are released at equimolar concentrations. The aim of the study is to determine if copeptin, a surrogate marker of AVP, may be used to predict unfavorable outcomes, including chronic volume overload and its impact on hypertension and cardiovascular diseases in children undergoing dialysis.ResultsA cross-sectional study including 65 children: The mean age of the investigated patients was 10.79 ± 2.857 years, with 53% being male. The patient group had significantly greater mean blood levels of AVP and copeptin compared to the control group (P value = 0.0001). 45% of patients experienced cardiac issues, specifically left ventricular hypertrophy. Hypertensive patients accounted for 57%. The mean blood levels of AVP and copeptin were considerably greater in individuals with cardiac problems and hypertension.ConclusionsHemodynamics have a significant influence on cardiac function and hypertension in children receiving hemodialysis. Copeptin is a more appropriate biomarker for evaluating the effects of AVP on hypertension and cardiac problems in children with ESRD.

Implication of vasopressin receptor genes (AVPR1A and AVPR1B) in the susceptibility to polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a complex heterogenous disorder manifesting with various reproductive, endocrine, and metabolic derangements such as insulin resistance and hyperglycemia. The arginine vasopressin peptide (AVP), also called or antidiuretic hormone (ADH), modulates metabolic functions such as glucose hemostasis, insulin sensitivity, and lipid metabolism via binding to two central and peripheral receptors (AVPR1A and AVPR1B). In the present study, we aimed to detect whether the AVPR1A and AVPR1B genes confer risk for PCOS.MethodsIn peninsular Italian families, we tested 7 variants in the AVPR1B gene and 2 variants in the AVPR1A gene via Pseudomarker for linkage and linkage joint to association (i.e.., linkage disequilibrium) with PCOS.ResultsWe identified two risk variants in each gene, significantly associated with the risk of PCOS.ConclusionTo the best of our knowledge, this is the first study to report risk variants in AVPR1A and AVPR1B genes in association with PCOS. However, replication in other ethnic groups as well as functional studies are needed to confirm these results.

Long-term Outcome of a Chihuahua With Idiopathic Syndrome of Inappropriate Antidiuretic Hormone Secretion.

An approximately 3 yr old female Chihuahua was presented for evaluation of polyuria and polydipsia noted by the owner after adoption. Serum biochemistry and urinalysis revealed hyponatremia, hypochloremia, hypo-osmolality, and normal fractional excretion of sodium. Serum antidiuretic hormone concentration was 5.54 pg/mL and serum copeptin concentration was 135.40 pg/mL. The antidiuretic hormone value was above the reported range for healthy dogs and was considered inappropriate in light of serum osmolality. Idiopathic syndrome of inappropriate antidiuretic hormone secretion was considered the most likely diagnosis after excluding other potential causes, such as diuretic use, renal disease, adrenal disease, and thyroid dysfunction. The dog remains clinically well 2 yr after diagnosis without specific treatment other than minimal dietary salt supplementation. This case is unique because of the absence of systemic or neurologic signs, good long-term outcome without treatment, and use of novel diagnostic testing.

ПАЦИЕНТ С ГИДРОПЕРИКАРДОМ, ГИДРОТОРАКСОМ, АСЦИТОМ – КЛИНИЧЕСКИЙ КВЕСТ ДЛЯ ТЕРАПЕВТА

Hypothyroidism is caused by a deficiency of thyroid hormones and presents various clinical manifestations. The possibility of tissue edema should be mentioned in addition to the classic symptoms, such as cold intolerance, fatigue, constipation, bradycardia, depression, drowsiness, hoarseness, weight gain. Tissues edema and the formation of isolated effusions in the cavities (abdominal, pleural and pericardial) are not unusual in hypothyroidism. These manifestations are caused by increased vascular permeability and transudation of fluid and albumin into the interstitial and other spaces (pericardium, pleura), inadequate secretion of antidiuretic hormone, accumulation of hydrophilic glycosaminoglycans in the intercellular spaces of the dermis and various tissues. Multiple effusions in the body cavities and tissue edema are rare to happen simultaneously. The nonspecific nature of these symptoms requires a differential diagnosis, in which hypothyroidism is not always taken into consideration. This situation leads to delay in making a diagnosis and treatment administration, especially in comorbid patients. It is advisable to pay attention to the necessity of thorough analysis of the obtained data and the use of simple differential diagnosis algorithms for the hypothyroidism.

Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion in a patient with neuropathic pain.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induces hyponatremia accompanied by uric acid reduction. We report a case of a patient with small-cell lung cancer who developed SIADH with hypouricemia after duloxetine treatment and discuss the potential underlying mechanisms. SIADH and hypouricemia improved after duloxetine was switched to mirogabalin.

The glycoprotein hormone receptor (LGR1) influences Malpighian tubule secretion rate in Rhodnius prolixus.

In the hemipteran Rhodnius prolixus, successful post-prandial diuresis is accomplished through the synergistic actions of the peptidergic diuretic hormone RhoprCRF/DH and the biogenic amine 5-hydroxytryptamine (5-HT), and by an antidiuretic hormone RhoprCAPA-2 that terminates diuresis by inhibiting this synergy. Lateral neurosecretory cells (NSCs) in the mesothoracic ganglionic mass release RhoprCRF/DH, while midline NSCs release RhoprCAPA-2 during blood feeding. These NSCs co-express GPA2/GPB5, a conserved glycoprotein hormone involved in various physiological processes across bilaterians. This study investigates the influence of GPA2/GPB5 signaling on Malpighian tubule (MT) fluid secretion in R. prolixus. GPB5-like immunoreactivity in lateral and midline NSCs decreases following a blood meal, suggesting release and a role in diuresis. Downregulating the GPA2/GPB5 receptor LGR1 via RNA interference results in an increased basal fluid secretion rate in MTs, which is inhibited by the antidiuretic hormone RhoprCAPA-2. dsLGR1 treatment reduces the effects of RhoprCRF/DH and 5-HT on MT secretion and eliminates their synergism. RT-qPCR reveals that the transcript expression of the diuretic and antidiuretic hormone receptors are decreased in MTs of dsLGR1 injected insects, indicating that GPA2/GPB5 influences the expression of these other receptor transcripts. Downregulating LGR1 results in a smaller blood meal size and disrupts the normal time-course of diuresis. As LGR1 is the most abundantly expressed G protein-coupled receptor transcript in R. prolixus MTs, our results suggest that GPA2/GPB5 signaling has a critical role in regulating the timing and success of water retention in the unfed state, and in the complex processes associated with feeding and diuresis in R. prolixus.

The participation of monoamines in the realization of vasopressin analgesic effects during electrical stimulation of paws in rats

BACKGROUND: Arginine vasopressin has been implicated in the modulation of stress and pain. The influence of a synthetic analogue of arginine vasopressin, 1-deamino-8-D-arginine-vasopressin, оn pain sensitivity, stress reactivity, levels of monoamines and brain neurotrophic factor in a model of paw electrical stimulation in rats has not been studied. AIM: The aim was to evaluate the effect of a synthetic vasopressin analog, 1-deamino-8-D-arginine-vasopressin, on pain sensitivity and the content of norepinephrine, serotonin, dopamine, brain neurotrophic factor in the parietal cortex and spinal cord in electrocutaneous paw stimulation test in rats. MATERIALS AND METHODS: The study was conducted on male Wistar rats who were injected with 1-deamino-8-D-arginine-vasopressin intranasally once a day for 5 days in small (single 20 ng, course 100 ng) and large doses (single 2 ug, course 10 ug). The content of brain neurotrophic factor in the parietal cortex and spinal cord, and corticosterone in blood serum were determined using enzyme immunoassay. The levels of norepinephrine, serotonin, dopamine and their metabolites in the brain were evaluated using high-performance liquid chromatography. RESULTS: 1-Deamino-8-D-arginine-vasopressin in different doses reduced pain sensitivity in rats, more pronounced when administered in large doses. The peptide in small doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid, a metabolite of serotonin; in the spinal cord, it reduced the content of 5-hydroxyindolacetic acid. 1-Deamino-8-D-arginine-vasopressin in high doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid; in the spinal cord ― reduced the content of serotonin and 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine; increased the levels of norepinephrine and homovanilic acid, a metabolite of dopamine. The peptide had no effect on corticosterone levels in the blood and brain neurotrophic factor levels in the brain in rats. CONCLUSIONS: The analgesic effects of 1-deamino-8-D-arginine-vasopressin were revealed with intranasal administration in different subendocrine doses. Regardless of the administered doses, dopamine and serotonin at the supraspinal level were involved in peptide-induced anesthesia; serotonin at the spinal cord level. More pronounced analgesia with the administration of 1-deamino-8-D-arginine-vasopressin in high doses was due to the additional involvement of dopamine and norepinephrine at the spinal cord level.

Investigation of Fibrillar Aggregates Formed by Pathogenic Pre-Pro-Vasopressin Mutants that Cause ADNDI.

Aggregations of unfolded or misfolded proteins, both inside and outside cells, are implicated in numerous diseases, collectively known as amyloidosis. Particularly, Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a rare disease caused by mutations in the AVP-NPII gene, leading to the inability to secrete arginine vasopressin (AVP). These misfolded proteins accumulate within the endoplasmic reticulum (ER), causing cellular dysfunction. This study aimed to investigate the formation of amyloid-like aggregates within the cell resulting from misfolded mutant precursor proteins, which induce disulfide-linked oligomers due to the G45C, 207_209delGGC, G88V, C98X, C104F, E108D-1, E108D-2 and R122H mutations identified by our group in the AVP-NPII gene of ADNDI patients. De-glycosylation studies were performed to analyze the glycosylation patterns of mutant protein precursors. The involvement of these precursors in the ER-related degradation pathway was studied by conducting protease inhibition experiments. Disulfide-linked oligomer analysis determined the oligomerization status of the mutant precursors. Immunofluorescence and electron microscopy studies provided evidence of aggregate structures in the ER lumen. In vitro studies involving bacterial expression and fibril formation in E. coli. Our findings demonstrated that the N-glycan structure of mutant precursors remains intact within the ER. Protease inhibition experiments indicated the involvement of these precursors in the ER-related degradation pathway. Disulfide-linked oligomer analysis revealed homo-oligomer structures in mutations. Immunofluorescence and electron microscopy studies confirmed the presence of aggregate structures in the ER lumen. In vitro studies showed that mutant precursors could form fibril structures in E. coli. Our study may support the idea that ADNDI belongs to the group of neurodegenerative diseases due to the formation of fibrillar amyloid aggregates in the cell.

63 Utilization of vasopressin and norepinephrine in neonates with cardiorespiratory compromise: A multicenter retrospective cohort study in Canada

Abstract Background Data regarding neonatal clinical experience with Vasopressin (VA) and Norepinephrine (NE) are limited to small studies. The lack of large-scale studies with safety and efficacy data is preventing the widespread adoption of these agents. Objectives To describe epidemiological data on utilization of NE and VA in neonates including their indications, effectiveness and overall outcomes across 3 tertiary Neonatal Intensive Care Units (NICU) in Canada. Design/Methods This retrospective cohort study involved neonates who received NE or VA between January 1, 2015-December 31, 2020 at 3 tertiary NICUs. Data regarding demographic information, indications of use, dosing details, and clinical outcomes were described using mean, standard deviations (SD), frequencies and percentages. When appropriate, a comparative analysis was performed using Mann-Whitney U tests or the chi-square test as appropriate. Post-initiation changes in physiological variables and laboratory parameters over time were analyzed using repeated measure ANOVA. Results 133 neonates (VA:70, NE:63) were included in this study. Baseline demographic features, clinical characteristics at initiation, indication of use, dosing details and clinical response in neonates exposed to both agents are summarized in Table 1. VA was commonly used for oxygenation failure due to persistent pulmonary hypertension of the newborn (PPHN), while NE was commonly used for hypotension due to septic shock. NE was frequently used as a 1st line inotropic agent, whereas VA was used more as an additive agent [30 (47.6%) vs 12 (18.6%); p=<0.001]. During treatment, lower sodium levels were recorded in the VA group vs the NE group [126.5 (8.6) vs 132 (7); p=.035], but other safety parameters were similar. The time to reach predefined stability parameters were similar in both groups. Significant improvement in physiological parameters were seen over time with both agents (Figure 1). Mortality within 7 days of use was high in the cohort, but comparable between VA and NE groups [18 (25.7%) vs 22 (34.9%), p=0.206]. Other neonatal morbidities were comparable between groups (Table 1). Conclusion This multicenter study provides pragmatic insights into the current use of NE and VA in neonates. Our study reports the effective use of each agent in distinct patient subgroups. This cohort represented neonates with high illness severity; however, exposure to either agent did not independently increase the risk of mortality or adverse outcomes. Further prospective studies exploring its optimal use and cardiopulmonary effects would be interesting.

Arginine vasopressin induces analgesic effects and inhibits pyramidal cells in the anterior cingulate cortex in spared nerve injured mice.

Neuropathic pain (NP) is a severe disease caused by a primary disease or lesion affecting the somatosensory nervous system. It`s reported that NP is related to the increased activity of glutamatergic pyramidal cells and changed neural oscillations in the anterior cingulate cortex (ACC). Arginine vasopressin (AVP), a neurohypophyseal hormone, has been shown to cause pain-alleviating effects when applied to peripheral system. However, the extent to which, and the mechanisms by which, AVP induces analgesic effects in the central nervous system remain unclear. In the present study, we observed that intranasal delivery of AVP inhibited mechanical pain, thermal pain and spontaneous pain sensitivity in mice with spared nerve injury. Meanwhile, AVP application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the ACC. In vivo electrophysiological recording of the ACC further showed that AVP application not only inhibited the theta oscillation in local field potential analysis, but also reduced the firing rate of spikes of pyramidal cells in the ACC in neuropathic pain mice. In summary, AVP induce analgesic effects by inhibiting neural theta oscillations and the spiking of pyramidal cells of the ACC in mice with neuropathic pain, which should provide new potential noninvasive methods for clinical treatment of chronic pain.

Exogenous Opioids and the Human Endocrine System: An Endocrine Society Scientific Statement.

The use and misuse of opioids are a growing global problem. Although the effects of these drugs on the human endocrine system have been studied for decades, attention on their related clinical consequences, particularly on the hypothalamic-pituitary system and bone health, has intensified over recent years. This Statement appraises research data related to the impact of opioids on the gonadal and adrenal function. Whereas hypogonadism is well recognized as a side effect of opioids, the significance of their inhibitory actions on the hypothalamic-pituitary-adrenal system and the occurrence of clinically relevant adrenal insufficiency is not fully elucidated. The often-inconsistent results of studies investigating how opioids affect the secretion of GH, prolactin, arginine vasopressin, and oxytocin are assessed. The accumulating evidence of opioid actions on bone metabolism and their negative sequelae on bone mineral density and risk of fracture are also reviewed. In each section, available data on diagnostic and management approaches for opioid endocrine sequelae are described. This Statement highlights a plethora of gaps in research associated with the effects and clinical consequences of opioids on the endocrine system. It is anticipated that addressing these gaps will improve the care of people using or misusing opioids worldwide. The Statement is not intended to serve as a guideline or dictate treatment decisions.

International expert consensus statement on the diagnosis and management of congenital nephrogenic diabetes insipidus (arginine vasopressin resistance).

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehydration. The diagnosis and management of NDI are very challenging and require an integrated, multidisciplinary approach. Here, we present 36 recommendations for diagnosis, treatment and follow-up in both children and adults, as well as emergency management, genetic counselling and family planning, for patients with NDI. These recommendations were formulated and graded by an international group of experts in NDI from paediatric and adult nephrology, urology and clinical genetics from the European Rare Kidney Disease Reference Network and the European Society of Paediatric Nephrology, as well as patient advocates, and were validated by a voting panel in a Delphi process. The goal of these recommendations is to provide guidance to health care professionals who care for patients with NDI and to patients and their families. In addition, we emphasize the need for further research on different aspects of this potentially life-threatening disorder to support the development of evidence-based guidelines in the future.

Impact of Hyponatremia and ADH Secretion in MIS-C and COVID-19: An Integrative Approach of Prognostic and Diagnostic Markers

The COVID-19 pandemic has introduced challenges in pediatric care, especially due to the emergence of Multisystem Inflammatory Syndrome in Children (MIS-C), a severe condition associated with SARS-CoV-2 infection. This study investigated the impact of hyponatremia and antidiuretic hormone (ADH) secretion corelated to clinical outcomes in these patients. We conducted a retrospective cohort study, including 118 pediatric patients, with a detailed sub-cohort analysis of 53 patients for ADH secretion markers. Hyponatremia, defined by age-specific sodium thresholds, was present in 47.22% of MIS-C cases and 28.04% of COVID-19 cases. Ordinal logistic regression analysis revealed that severe hyponatremia significantly increased the likelihood of more severe clinical outcomes (β = 3.514, p < 0.001). A significant correlation was found between hyponatremia and prolonged hospitalization. For ADH secretion, a predictive model using ridge regression was analysed, which demonstrated that serum sodium level, U/P ratio, and hospitalization duration are key predictors of SIADH. This model fit was assessed using the ROC curve with an AUC of 0.96, indicating reliable model performance. Our findings underscore the significant role of hyponatremia on the clinical severity and hospitalization outcome of COVID-19 and MIS-C in pediatric patients.

The biology of water homeostasis.

Water homeostasis is controlled by a brain-kidney axis that consists of central osmoreceptors, synthesis and secretion of arginine vasopressin (AVP) and AVP-responsive aquaporin-2 (AQP2) water channels in kidney collecting duct principal cells that facilitate water reabsorption. In addition to AVP, thirst represents a second line of defense to maintain water balance. Water balance disorders arise because of deficiency, resistance or inappropriate secretion of AVP or disturbances in thirst sensation (hypodipsia, polydipsia). People with water balance disorders are prone to develop hyponatremia or hypernatremia, which expose cells to osmotic stress and activate cell volume regulation mechanisms. This review covers several recent insights that have expanded our understanding of central osmoregulation, AQP2 regulation and cell volume regulation. This includes the role of with-no-lysine kinase 1 (WNK1) as a putative central osmolality sensor and, more generally, as an intracellular crowding sensor that coordinates the cell volume rescue response by activating sodium and potassium cotransporters. Furthermore, several new regulators of AQP2 have been identified, including for AVP-dependent AQP2 regulation (yes-associated protein, nuclear factor of activated T-cells, microRNAs) and AVP-independent AQP2 regulation (epidermal growth factor receptor, fluconazole, prostaglandin E2). It is also becoming increasingly clear that long-term cell volume adaptation to chronic hypotonicity through release of organic osmolytes comes at the expense of compromised organ function. This potentially explains the complications of chronic hyponatremia, including cognitive impairment, bone loss and vascular calcification. This review will illustrate why these new insights derived from basic science are also relevant for developing new approaches to treat water balance disorders.