Arginine Vasopressin Secretion Research Articles

Oral Levodopa Stimulates Copeptin Secretion in Children and Adolescents with Intact Posterior Pituitary Function

BackgroundCopeptin stimulation tests can be used in the differential diagnosis of polyuria polydipsia syndrome. Current stimulation methods rely on intravenous or subcutaneous administration. Oral stimulus can further simplify the diagnostic approach. The levodopa stimulation test is widely used in the evaluation of growth hormone deficiency (GHD), and the dopamine pathway was reported to be associated with arginine vasopressin secretion. The study aimed to investigate the effect of oral levodopa on copeptin secretion. MethodsThe study was a prospective observational single-center cohort study. Patients < 18 years old with short stature and no symptoms of polyuria or polydipsia undergoing levodopa stimulation test for suspected GHD were recruited from May 2023 to Nov 2023. Copeptin and growth hormone (GH) were measured at 0, 30, 60, 90, and 120min in the levodopa test. The insulin tolerance test with copeptin and GH measured at the same time points was conducted in part of patients. ResultsForty-four participants were included in the final analysis. In the levodopa stimulation test, the median (interquartile range, IQR) copeptin concentration increased from 5.20 (3.51, 8.25) pmol/L to maximum 19.36 (8.97, 108.08) pmol/L (P < 0.001), 3.94 (1.41, 13.88) times of the baseline (P < 0.001). Compared with insulin tolerance test, peak copeptin in the levodopa test was significantly higher (34.61 (13.67, 98.96) vs 8.88 (7.14, 15.42) pmol/L, P = 0.009). Higher copeptin was associated with larger dose of levodopa. ConclusionsOral levodopa could be used to stimulate copeptin.

Autoimmunity related to anti-Nax and anti-ZSCAN1 autoantibodies in adipsic hypernatremia.

"Adipsic hypernatremia" is clinically characterized by chronic elevation of plasma [Na+] with an inappropriate lack of thirst and upward resetting of the osmotic set point for arginine vasopressin (AVP) secretion, combined with a relative deficiency of AVP, thereby resulting in persistent hypernatremia. Many cases are accompanied by structural lesions in the hypothalamus, pituitary gland, and circumventricular organs (CVOs). On the other hand, cases without structural lesions have been reported since the 1970s, but the pathophysiology was unknown for a long time. In 2010, Hiyama et al. reported that an anti-Nax antibody response caused adipsic hypernatremia in a pediatric case with ganglioblastoma. In recent years, advances in clinical research have led researchers to recognize that an autoimmunological pathogenic mechanism might be associated with periventricular organs such as the subfornical organ (SFO). In addition, in pediatric cases diagnosed as ROHHAD (rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation) syndrome, it has been reported that half of the cases have abnormal serum Na levels, and some research findings indicated an autoimmune mechanism acting on the organs of the hypothalamus and CVOs. Then, anti-ZSCAN1 antibody response was detected in cases diagnosed as ROHHAD-NET in 2022. In this review, by summarizing a series of studies on Nax and ZSCAN1, which are expressed in the hypothalamus, pituitary gland, and SFO, I would like to describe the current findings of the autoimmune pathogenesis of adipsic hypernatremia.

Renal Afferent Nerve Activity and Association with Neurohumoral Dysregulation in a Model of Autosomal Recessive Polycystic Kidney Disease

Polycystic kidney disease (PKD) is a rare, genetic kidney disease characterized by cyst growth that leads to kidney failure. Renal nerves play an important role in the development and maintenance of hypertension and other renal diseases. Afferent (sensory) nerves convey information to the central nervous system in response to intrarenal stimuli. Our laboratory demonstrated that afferent renal nerve activity (ARNA) is elevated in 10-week-old PCK rats compared to non-cystic, age-matched Sprague-Dawley (SD) controls. Furthermore, ARNA positively correlated with cystic index (CI; a measure of cyst growth). To further elucidate the relationship between renal nerve activity, age, and cyst progression, we aimed to quantify both ARNA and renal sympathetic nerve activity (RSNA) in PCK and SD rats. We hypothesized that ARNA and RSNA would be greater in PCK than SD. Furthermore, arginine vasopressin (AVP) is elevated in PKD and increases cyst growth. There is evidence that activation of the afferent renal nerves can contribute to secretion of AVP. Thus, we propose that elevated ARNA increases AVP secretion, thereby increasing cyst growth. We also hypothesized that ARNA would positively correlate with age, CI, and copeptin (an indirect marker of AVP) in young PCK rats. To test our first hypothesis, we conducted direct renal nerve recordings in 10- to 12-week-old PCK (n=16;11M/5F) and 10-week-old SD (n=9;7M/2F) rats. For our second hypothesis, we conducted nerve recordings in 4- to 10-week-old PCK rats to evaluate the correlation of nerve activity with age, cystic index, and copeptin in animals ages 4- to 12-weeks-old (n=28;21M/7F). Multiunit nerve recording was performed under inactin anesthesia. As we previously published, a renal nerve bundle is isolated, placed on an iridium bipolar electrode, and encased in silicone. Resting RSNA was recorded following 10-minute stabilization period, then the nerve bundle was severed proximal to the electrode to isolate ARNA. ARNA recordings were normalized to maximal ARNA evoked by intrarenal 50 μM capsaicin. Comparisons between PCK and SD were analyzed by Student’s t-test (p&lt;.05). Linear regression analyses were used to assess variable correlation (p&lt;.05). Data presented as mean ± SEM. In contrast to our first hypothesis, RSNA did not differ between 10- to 12-week-old SD and PCK rats, whether measured via burst frequency (SD 6.92 ± 0.82; PCK *6.97 ± 0.34 Hz) or bursts/heart beat (SD 1.36±0.16; PCK 1.28 ± 0.06). ARNA was calculated as a percentage of maximal ARNA using either integrated ARNA (ARNAInt) or spikes/s (ARNASpikes). Baseline ARNAInt was greater in PCK rats (29.14±3.35%) than SD (13.46±2.08%, n=4), whereas PCK ARNASpikes trended (p=.06) higher than SD controls (SD 5.57±2.21; PCK 13.90±2.21%). In correlative analysis, RSNA trended (p=.05) to correlate with age in the PCK rat. However, there was no relationship between RSNA and (1) CI (p=0.29) or (2) copeptin (p=0.15). Similarly, there was no correlation detected between ARNA and age (ARNAInt: p=0.41; ARNASpikes: p=0.16) or serum copeptin (ARNAInt: p=0.96; ARNASpikes: p=0.20). ARNAInt trended (p=.07) to correlate with CI, but ARNASpikes did not correlate with CI (p=0.48). Overall, these data partially support our hypotheses. RSNA did not differ between SD and PCK rats, but ARNAInt was increased in PCK rats vs. SD. We failed to detect a correlation between either ARNA or RSNA and age, CI, or copeptin in PCK rats though, ARNAInt trended to correlate with CI. As ARNA does not appear to be correlated with serum copeptin, further studies are required to uncover the relationship between afferent renal nerves and cystogenesis in this model of PKD. PKD Foundation Research Award 1022534 (CB) NIDDK/PKD RRC Pilot and Feasibility Award U24DK126110 (CB) AHA 21PRE0000216068 (MG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Generation of an Inducible Avp Knockout Mouse Line Using CRISPR/Cas9 and Cre/LoxP

Background: Arginine vasopressin (AVP) is a peptide hormone coded by the Avp gene, synthesized in the hypothalamus and secreted by the posterior pituitary. Dysregulation of AVP secretion contributes to a variety of human diseases. Previous studies of functional roles of AVP have been largely dependent on the use of Brattleboro rats, which manifest a spontaneous mutation in the Avp gene and lack circulating AVP. Despite their utility, Brattleboro rats are diffcult to breed owing largely to the fixed nature of the Avp mutation, resulting in increased neonatal death and behavioral effects in the adults. Consequently, commercial breeders have ceased production, despite a continued need. To fill this need, we have now created a mouse model with a tamoxifen-inducible deletion of AVP. Methods: We employed CRISPR/Cas9 to target the desired regions (first intron and 3' downstream) within the Avp gene. Successful insertion of the two loxP sites was confirmed by PCR using primers flanking the targeted regions. Restriction enzymes BamHI or EcoRI were used to confirm correct targeting. For additional confirmation, PCR products were cloned into the TA-cloning vector and sequenced. Mice harboring the floxed allele were mated to B6.Cg-Tg(CAG-cre/Esr1*)5Amc/J mice that globally express a tamoxifen-inducible Cre recombinase. Results: The resultant homozygous conditional knockout mice ( Cre+ Avpflx/ flx) are viable, fertile, and show no signs of polydipsia or polyuria prior to induction, indicating that the conditional alleles retain their wild-type function. Induction of Cre-mediated recombination by administration of tamoxifen (2-3 mg q.d., i.p. for 5 days) in 8-week-old mice resulted in a decrease in urine osmolality from 2076±138 to 122±6 mOsm/kgH2O on day 31 after induction (p&lt;0.0001). Sanger sequencing demonstrated the expected 1245 bp deletion at the Avp locus. The kidney parenchyma was structurally normal with no evidence of medullary atrophy 6 weeks after induction. Immunoblotting of AQP2 in the inner medulla showed a significant decrease in AQP2 band density in Cre+ Avpflx/ flx mice to 27±14 % of values in Cre− floxed control mice (p&lt;0.05). Conclusion: We developed an inducible AVP knockout mouse line ( Cre+ Avpflx/ flx) that will be shared with the research community and are likely to be useful for further study of regulation of water balance and polycystic kidney disease, as well as neural, vascular, and metabolic roles of vasopressin. The work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon’s impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.

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.

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

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. 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. 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. 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.

Paediatric perspectives in the diagnosis of polyuria-polydipsia syndrome.

The elucidation of the underlying cause of polyuria-polydipsia syndrome (PPS)is a challenging-especially in the differentiation of partial defects of arginine vasopressin (AVP)secretion or action from primary polydipsia. The water deprivation test has been utilized for many decades, and its application in the paediatric population has been applied using parameters predominantly established in adult cohorts. In more recent times, the development of automated commercial assays for copeptin, a surrogate marker for AVP, has represented a significant advancement in the diagnostic approach to PPS. Measurement of copeptin concentrations has major advantages and has essentially superseded measurement of AVP in diagnostic protocols for PPS. Additionally, stimulated-copeptin protocols utilizing hypertonic saline infusion, arginine, and glucagon have been investigated, and are promising. However, further studies are required in the population-incorporating the differences in physiological regulation of water homeostasis, and safety requirements-before there is widespread adoption into clinical practice.

Hyponatremia due to preserved non-osmotic arginine vasopressin secretion in adipsic diabetes insipidus: a case report with review of literature.

Adipsic diabetes insipidus (ADI) is characterized by central diabetes insipidus and an impaired thirst response to hyperosmolality, leading to hypernatremia. Hyponatremia observed in patients with ADI has been considered a complication of desmopressin therapy. Herein, we present a case of impaired thirst sensation and arginine vasopressin (AVP) secretion without desmopressin therapy, in which hyponatremia developed due to preserved non-osmotic AVP secretion. A 53-year-old woman with hypopituitarism, receiving hydrocortisone and levothyroxine, experienced hyponatremia three times over 5 months without desmopressin treatment. The first hyponatremic episode (120 mEq/L) was complicated by a urinary tract infection with a plasma AVP level of 33.8 pg/mL. Subsequent hyponatremia episodes occurred after administration of antipsychotic (124 mEq/L) and spontaneously (125 mEq/L) with unsuppressed plasma AVP levels (1.3 and 1.8 pg/mL, respectively). Hypertonic saline infusion did not affect AVP or copeptin levels. Regulating water intake using a sliding scale based on body weight prevented the recurrence of hyponatremia without the use of desmopressin. Except during infection, plasma AVP levels (1.3 ± 0.4 pg/mL) were not significantly correlated with serum sodium levels (rs = -0.04, p = 0.85). In conclusion, we present a unique case of impaired thirst sensation and AVP secretion in which hyponatremia developed without desmopressin therapy. Preserved non-osmotic AVP secretion, possibly stimulated by glucocorticoid deficiency, may contribute to the development of hyponatremia in patients with ADI.

Bimatoprost Ophthalmic Solution (BOS) 0.3 mg w/v for 1 Open Trial of Long-term Preventive Therapy of Migraine in 3 patients with Pathophysiologic Shift from Brain to Eye

Known since antiquity, migraine is a complex primary disorder, an episodic painful Autonomic Nervous System (ANS) storm, generally following the stress/post-stress phase. Despite exhaustive study of neuropeptides, neurochemicals, molecules, neurogenetics, neuroimaging along with animal and human experiments over the last 50 years, the scientific basis of migraine remains unknown. Straddling eight decades from Cortical Spreading Depression (CSD) to Calcitonin-Gene Related Peptide (CGRP) and its antagonists, exponentially increasing data have failed to create a gestalt synthesis. This article lays cohesive and robust fundamental principles for the comprehension and management of migraine. The continuum between migraine and non-congestive Primary Open-Angle Glaucoma (POAG), Normal Tension Glaucoma (NTG), or Low-Tension Glaucoma (LTG) is advancing. The case of sustained remission of migraine attacks (&gt; 75%) over 3 years - 5 years with ocular hypotensive topical Bimatoprost Ophthalmic Solution (BOS) 0.3% in an N-of-1 trial in 3 patients with refractory migraine is presented. A cause-effect-adaptive process underlies the ANS-stress/post-stress-linked biology of migraine. Vasopressin-serotonin-norepinephrine ‘homeostatic-adaptive system’ Lowers Intraocular Pressure (IOP), while enhancing anti-stress, antinociception, vasomotor, and behaviour control functions, thereby selectively decreasing algogenic neural traffic in the ophthalmic division of trigeminal nerve (V1), and, raising the threshold to develop migraine. Striking migraine headache-aborting feature of vomiting is also likely linked to a several hundred-fold increase in arginine-vasopressin secretion. Eye-cover tests and self-ocular digital displacement are essential to studying the visual aura. Real-time physical displacement of Scintillating Scotoma (SS) and floating ‘stars’ is reported. The basis of spontaneous onset and offset, self-limited duration of migraine attacks, as well as female preponderance, and age/menopause decline in prevalence, are elucidated. Intraocular implants with long-term ocular hypotensive effects, including bimatoprost, are the future of migraine management. Controlled trials are required to establish the migraine-preventive effect of topical bimatoprost, a revolutionary advance in neuroscience.

Serum Copeptin, Perceived Stress, and Pain in Patients Living with Sickle Cell Disease

Sickle cell disease (SCD) is a hereditary blood disorder characterized by intense acute and chronic pain episodes, resulting in a complex interplay of negative physical and emotional experiences. One of the main barriers to addressing pain in this disease state is the limited information about the mechanisms affecting the variable degree and types of pain and stress that impact patients in this population. The arginine vasopressin receptor1a gene (AVPR1A) single nucleotide polymorphism (rs10877969) is associated with aspects of acute pain and stress related pain in patients living with SCD. Arginine vasopressin (AVP) is a hormone known for its role in regulating extracellular fluid, vasoconstriction, and the endocrine stress response. However, due to its short half-life, AVP is difficult to measure. Thus, copeptin, the stable biologically inactive C-terminal portion of pro-vasopressin, is often used as a surrogate marker for AVP secretion. Copeptin is a marker of hypothalamic-pituitary-adrenal axis activation, however, its levels have not been studied in patients living with SCD. Psychological stress has been associated with changes in circulating copeptin concentrations. Considering the relationship between pain, stress, and copeptin, it is important to investigate their relationship in the context of SCD. The primary objective of this study was to examine serum copeptin levels with reports of perceived stress and pain in this patient population. In this cross-sectional study, we investigated serum copeptin levels, perceived stress, and pain experiences in a cohort of 50 adults living with SCD. Th participants had a mean age of 39.8±8.5 years, ranging from 29 to 59 years. Ninety-six percent of the participants were of African ancestry and 62% were female. Participants had the following hemoglobin genotypes: 68% had SS, 24% had SC, and 8% had other Hgb genotypes. To assess pain experiences, participants responded to questionnaires, including the Average Pain Intensity (API, average of current, least, and worst pain experienced within a 24-hour period, measured on a scale from 0 to 10). The Adult Sickle Cell Quality of Life Measure (ASCQ-Me) was used to measure number of vaso-occlusive crises (VOC). Perceived stress was assessed using the Perceived Stress Scale (PSS). Serum copeptin levels were quantified using a well-established laboratory. All the participants provided blood samples and completed psychological scales. Descriptive statistics and bivariate associations were conducted using R statistical software package. The study received approval from the Institutional Review Board at the University of Tennessee Health Science Center. We observed no significant differences in mean copeptin levels by sex ( p=.33) or associations between copeptin levels and age ( p=.66), weight ( p=.81), number of hospitalizations due to pain crisis ( p=.23), and the number of pain crisis managed at home ( p=0.07). The coefficients for API .92 ( p=.05) and PSS .97 ( p=.03) exhibited statistically significant positive association with copeptin levels. Our findings provide insights into the relationship between serum copeptin levels, perceived stress, and pain intensity in patients with sickle cell disease (SCD). The positive associations observed between copeptin levels and both perceived stress and average pain intensity underscore the potential interchange of pain and psychological stress in the regulation of copeptin secretion in this patient population. Our results indicate that copeptin levels are not significantly influenced by sex, age, or weight suggesting that these demographic factors may not be major determinants of copeptin viability in patients living with SCD. While sickle cell severity indicators did not show significant associations with copeptin levels, further investigation with larger sample sizes is needed to validate these findings and explore additional factors contributing to pain and psychological stress in individuals living with SCD. Ultimately, understanding the complexities of copeptin regulation may lead to improved pain management strategies and enhanced overall well-being for patients with this challenging disorder.

Diagnostic and Therapeutic Strategies to Severe Hyponatremia in the Intensive Care Unit.

Hyponatremia is the most common electrolyte abnormality encountered in critically ill patients and is linked to heightened morbidity, mortality, and healthcare resource utilization. However, its causal role in these poor outcomes and the impact of treatment remain unclear. Plasma sodium is the main determinant of plasma tonicity; consequently, hyponatremia commonly indicates hypotonicity but can also occur in conjunction with isotonicity and hypertonicity. Plasma sodium is a function of total body exchangeable sodium and potassium and total body water. Hypotonic hyponatremia arises when total body water is proportionally greater than the sum of total body exchangeable cations, that is, electrolyte-free water excess; the latter is the result of increased intake or decreased (kidney) excretion. Hypotonic hyponatremia leads to water movement into brain cells resulting in cerebral edema. Brain cells adapt by eliminating solutes, a process that is largely completed by 48 h. Clinical manifestations of hyponatremia depend on its biochemical severity and duration. Symptoms of hyponatremia are more pronounced with acute hyponatremia where brain adaptation is incomplete while they are less prominent in chronic hyponatremia. The authors recommend a physiological approach to determine if hyponatremia is hypotonic, if it is mediated by arginine vasopressin, and if arginine vasopressin secretion is physiologically appropriate. The treatment of hyponatremia depends on the presence and severity of symptoms. Brain herniation is a concern when severe symptoms are present, and current guidelines recommend immediate treatment with hypertonic saline. In the absence of significant symptoms, the concern is neurologic sequelae resulting from rapid correction of hyponatremia which is usually the result of a large water diuresis. Some studies have found desmopressin useful to effectively curtail the water diuresis responsible for rapid correction.

A case of IgG4-related hypophysitis maintained remission of diabetes insipidus for over 3 months after completion of steroid treatment.

IgG4-related disease is a multiorgan disorder in which nodules and hypertrophic lesions are observed simultaneously, or separately, in areas including the pancreas, liver, lungs, salivary glands, thyroid glands, and pituitary glands. IgG4-related hypophysis is one of several IgG4-related diseases and is characterized by pituitary gland and pituitary stalk thickening, various degrees of hypopituitarism, and increased serum IgG4 levels. Steroid therapy is effective for patients with IgG4-related hypophysis, but the reported effectiveness of steroid therapy for restoring pituitary function differs between studies. Following an episode of autoimmune pancreatitis 10 years prior, enlargement of the pituitary gland and stalk along with panhypopituitarism and polyuria developed in a 73-year-old male. A high serum IgG4 level and biopsy of the submandibular gland showing infiltration of IgG4-positive plasma cells led to a clinical diagnosis of IgG4-related hypophysitis. Prednisolone treatment reduced the swelling of the pituitary gland and stalk and improved anterior pituitary function. Although arginine vasopressin secretion remained insufficient, polyuria was relieved and kept in remission even after prednisolone treatment was completed. This is the first reported case in which prednisolone was able to maintain both normal anterior pituitary function and remission of polyuria caused by IgG4-related hypophysitis. IgG4-related hypophysitis has previously been associated with a relapse of symptoms during treatment. However, the patient reported in this case study remained in remission for over 3 months after completion of steroid treatment and should be monitored closely for changes in pituitary function. Steroid therapy is the first-line therapy for pituitary dysfunction and pituitary stalk swelling in IgG4-related hypophysitis. In this case, although posterior pituitary function remained insufficient, polyuria was relieved and kept in remission for over 3 months even after prednisolone treatment was completed. IgG4-related hypophysitis has been associated with the relapse of symptoms during steroid tapering, and changes in pituitary function and symptoms should be monitored closely. When we encounter cases of adrenal insufficiency and polyuria during observation of autoimmune pancreatitis or other IgG4-related disease, we should consider the possibility of IgG4-related hypophysitis in mind.

A Case Report of an Effective Treatment for Syndrome of Inappropriate Secretion of Antidiuretic Hormone with Integration of Western Medicine and Traditional Chinese Medicine

Background: Syndrome of Inappropriate secretion of Antidiuretic Hormone (SIADH) is a group of disorders in which free water excretion is impaired due to increased Arginine Vaso Pressin (AVP) secretion in the absence of renal or endocrine dysfunction, which in turn leads to hypotonic hyponatremia. In this case report, we describe the diagnostic process of a patient with SIADH and the treatment with integration of Western and Chinese medicine. Case Presentation: A 69-year-old man was admitted to our hospital for intermittent hand tremors. He was diagnosed with hyponatremia based on laboratory tests. However, after 2 weeks of sodium supplementation, his condition did not improve. Combined with Pituitary MRI, 24h urine sodium and other laboratory tests, he was diagnosed with SIADH. After taking oral tolvaptan and traditional Chinese medicine Rehmanniae Decoction of Six Ingredients granules, his symptoms were alleviated and the serum sodium normalized. Conclusion: SIADH could be as an etiology for hyponatremia that is difficult-to-correct, and traditional Chinese medicine may have some efficacy and advantages.

Copeptin levels increase in response to both insulin-induced hypoglycemia and arginine but not to clonidine: data from GH-stimulation tests.

The diagnosis of the polyuria-polydipsia syndrome is challenging. Copeptin is a robust biomarker of arginine vasopressin (AVP) secretion. Arginine, which stimulates growth hormone (GH), has been shown also to stimulate copeptin secretion via unknown mechanisms. The aim was to investigate copeptin levels in response to three different GH stimulation tests in patients suspected of GH deficiency. In this cross-sectional study, we measured plasma copeptin levels at baseline and at 60, 105, and 150 min in patients undergoing a stimulation test for growth hormone deficiency with either arginine (n = 16), clonidine (n = 8) or the insulin tolerance test (ITT) (n = 10). In patients undergoing the arginine test, the mean age was 9 years, and 10 years for clonidine. The ITT was only performed in adult patients (>18 years) with a mean age of 49 years. Copeptin level increased significantly from baseline to 60 min after arginine (P <0.01) and ITT (P < 0.01). By contrast, copeptin level tended to decrease after clonidine stimulation (P = 0.14). These data support that infusion of arginine increases plasma copeptin levels and reveal a comparable response after an ITT. We hypothesize that the underlying mechanism is abrogation of somatostatin-induced AVP suppression.

Single-nucleus RNA and ATAC sequencing reveals marked changes and sex differences in the kidney collecting duct principal cell in response to mild dehydration

The kidney principal cells in the connecting tubule (CNTPCs) and collecting duct (CDPCs) function to fine-tune water reabsorption and concentrate the urine upon activation of arginine vasopressin (AVP) receptor-2. Our study aimed to determine the kidney single-nucleus transcriptome and DNA accessibility in response to dehydration, a potent physiological stimulus for AVP secretion. We hypothesized that dehydrated male and female mice would have different responses in the PCs.Male and female C57BL/6J mice at 11 weeks old were subjected to either ad libitum (ad lib) or 9hr of dehydration (n = 1 per group) with samples taken at midnight. 10X Genomics Chromium Next GEM Single Cell Multiome ATAC+Gene Expression Kit was used. The fastq files were processed using CellRanger ARC pipeline and downstream analyses completed with the R packages Seurat and Signac. Gene set enrichment analyses were performed with ToppGene Suite.A total of 22,821 nuclei (median fragments per nucleus = 12,961 ± 336) were sequenced and 34 clusters identified with 586 and 129 nuclei annotated as CDPC and CNTPC, respectively. We found more DEGs in CDPC than in CNTPC (106 vs. 13). The common top 5 most highly expressed genes in both CDPC and CNTPC in the dehydrated state compared to ad lib were Grem2, Pde10a, Pappa, Fam129a, Scg5 (adjusted P values &lt; 0.01). Grem2 encodes a cytokine known to antagonize the bone morphogenic protein family (log2FC adlib/dehydrated for CDPC = -2.18 and CNTPC -1.96). Pde10a is a gene related to cAMP-mediated signaling (log2FC for CDPC = -2.17 and CNTPC -2.02). Pappa encodes a metalloproteinase (log2FC for CDPC = -1.36 and CNTPC -1.24). Fam129a encodes a protein that regulates protein phosphorylation (log2FC for CDPC = -1.17 and CNTPC -1.20). Finally, Scg5 encodes a chaperone protein that regulates pituitary hormone secretion (log2FC for CDPC = -0.84 and CNTPC -0.92). As expected, Aqp2 and Aqp3 were significantly higher in CDPCs from the dehydrated male and female mice. When stratifying by sex, we found more DEGs in female CDPCs than in males (79 vs. 54, χ2 p = 2.68E-8), but in CNTPC there were less in females than in males (1 vs 14, Fisher’s Exact p = 0.016). Pathway analyses determined that in dehydrated male DEGs that were highly expressed were enriched in circulatory system development and response to cAMP signaling pathways. In dehydrated female highly expressed DEGs were enriched in pathways related to renal development. Overall, chromatin analysis showed that changes in gene expression were not driven by changes in accessibility of chromatin.In conclusion, these findings suggest that CDPCs are more responsive to dehydration and that although there are common DEGs in dehydrated male and female mice, unique genes are enriched in different biological processes. NIDDK 1R01DK128001 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Relationship Between Copeptin Level and Enuresis in Children Aged 5 - 15 Years

Background: Enuresis is bedwetting that occurs during sleep in children over five years old. If left untreated, it can lead to social and psychological problems for children and their parents. The role of copeptin in patients with primary monosymptomatic nocturnal enuresis (PMNE) has been reported in several studies. Due to the favorable structural properties of copeptin and the reflection of arginine vasopressin (AVP) concentration, it can be used as an alternative marker for AVP secretion. Objectives: This study aims to compare the levels of copeptin in healthy and enuresis children aged 5 - 15 years. Methods: This case-control study was performed on 42 children with primary monosymptomatic enuresis and 42 children without enuresis who were referred to the clinic of Taleghani hospital in Gorgan in 2020. Copeptin levels were measured by the enzyme-linked immunosorbent assay (ELISA) method. Results: Out of 84 patients, an equal proportion of girls (21 patients) and boys (21 patients) participated in both the case and control groups. The age of the children was 8.05 ± 2.46 years, and there was no statistically significant difference between the two groups (P = 0.16). The mean level of copeptin in the case and control groups were 6.7 ± 4.27 and 6.87 ± 8.52 pg/mL, respectively, significantly lower in the case group (P = 0.03). There was a statistically significant difference in the level of copeptin between the boys in the two groups (P = 0.03). Although the mean level of copeptin in the girls in the patient group was lower than that in the control group, this difference was not statistically significant (P = 0.35). Conclusions: In this study, the mean level of copeptin in PMNE was significantly lower than that in the control group, which suggests it may be considered as a probable biomarker for the prediction of response to treatment with desmopressin, but further study is required to confirm this hypothesis.

Hyponatremia and Cancer: From Bedside to Benchside

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients. This applies also to cancer patients. Multiple causes can lead to hyponatremia, but most frequently this electrolyte disorder is due to the syndrome of inappropriate antidiuresis. In cancer patients, this syndrome is mostly secondary to ectopic secretion of arginine vasopressin by tumoral cells. In addition, several chemotherapeutic drugs induce the release of arginine vasopressin by the hypothalamus. There is evidence that hyponatremia is associated to a more negative outcome in several pathologies, including cancer. Many studies have demonstrated that in different cancer types, both progression-free survival and overall survival are negatively affected by hyponatremia, whereas the correction of serum [Na+] has a positive effect on patient outcome. In vitro studies have shown that cells grown in low [Na+] have a greater proliferation rate and motility, due to a dysregulation in intracellular signalling pathways. Noteworthy, vasopressin receptors antagonists, which were approved more than a decade ago for the treatment of euvolemic and hypervolemic hyponatremia, have shown unexpected antiproliferative effects. Because of this property, vaptans were also approved for the treatment of polycystic kidney disease. In vitro evidence indicated that this family of drugs effectively counteracts proliferation and invasivity of cancer cells, thus possibly opening a new scenario among the pharmacological strategies to treat cancer.

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency.

The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophyseal diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

Limited Role of Endogenous Vasopressin/Copeptin in Stimulation of ACTH-Cortisol Secretion during Glucagon Stimulation Test in Humans.

Copeptin is a stable part of a vasopressin precursor that closely mirrors arginine vasopressin (AVP) secretion. It is known that AVP/copeptin is also released in response to nonosmotic stimuli, such as stress evoked during anterior pituitary dynamic testing. In order to examine the role of AVP in challenging the hypothalamo-pituitary-adrenal axis, we assessed adrenocorticotropic hormone (ACTH), cortisol, copeptin and growth hormone (GH) during a glucagon stimulation test (GST) in 10 patients with satisfactory initial cortisol concentrations (mean ± SD: 20.34 ± 5.10 µg/dL) and failure to show any further cortisol increment on stimulation. For comparison, we measured copeptin in two subjects during an insulin tolerance test (ITT). During GST, there was an increase in copeptin (p = 0.02, average individual increase of 98%, range 10% to 321%). There was a robust increase in GH (p = 0.002, average increase 3300%), a decline in cortisol (p = 0.02, average decline 21.8%) and a fall in ACTH (p = 0.06). The relative increase in copeptin during ITT (176% and 52.2%) overlapped with increments observed during GST; however, here there was an increase in cortisol (20.45→24.26 µg/dL and 4.23→29.29 µg/dL, respectively). There was a moderate correlation between copeptin and GH concentrations (r = 0.4235, p = 0.0007). These results confirm that AVP is not crucial for ACTH-cortisol stimulation, though it might be an important factor in GH secretion.