Vasopressin Release Research Articles

Management of Low Sodium in AMU

Hyponatremia is a common finding in acutely ill patients and is defined as serum sodium (Na) level less than 135 mEq/L which is due to a relative excess of water in relation to serum sodium. Reasons for hyponatremia are increase in water intake (hypotonic intravenous fluid therapy or primary polydipsia) or impaired water excretion due to renal failure or increase release of antidiuretic hormone. Optimum management depends on the duration and severity of hyponatremia and involves close monitoring and accurate fluid balance assessment. We will discuss in this article the basics of management, pitfalls to avoid in Hyponatremia and recommended approach based on literature review when reviewing a patient with Hyponatremia, firstly to enquire about the duration of Hyponatremia to differentiate acute from chronic as the threshold for treatment is different, following duration is assessment of severity (clinically by symptoms and signs as well as biochemistry) as severity will affect the management. Following duration and severity the acute physician should assess the volume status of the patient to hypovolemic, euvolemic or hypervolemic Hyponatremia which aids in reaching the possible cause of Hyponatremia and the right treatment.

Comparing Effects of Tolvaptan and Instruction to Increase Water Consumption in ADPKD: Post Hoc Analysis of TEMPO 3:4.

In addition to decreasing water excretion and increasing urinary concentration, the antidiuretic hormone vasopressin plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). It has been hypothesized that by suppressing vasopressin release, drinking large amounts of water might exert therapeutic effects in ADPKD similar to those of tolvaptan, an antagonist of the vasopressin type 2 receptor, but evidence is lacking. We analyzed data from tolvaptan clinical trials to evaluate relationships among water intake, urine osmolality (Uosm), and change in total kidney volume (TKV). Analysis of the TEMPO 3:4 clinical trial in which participants were randomized to tolvaptan or placebo and instructed to drink large amounts of water. The relationship between change in spot Uosm from baseline to Week 3 and change in TKV to Month 12 was assessed using linear regression modeling. Two short-term tolvaptan trials were analyzed to explore relationships between intermittent Uosm sampling and 24-hour Uosm suppression. With both tolvaptan and placebo (i.e., mandated high water intake alone), Uosm reduction at Week 3 was associated with reduction in TKV growth at Month 12. However, for the same decrease in spot Uosm, the corresponding reduction in TKV growth was greater for tolvaptan (for example, a -250 mOsm/kg reduction in Uosm at Week 3 was associated with a -1% change in TKV at Month 12 for tolvaptan versus +4.5% for placebo). In short-term trials, similar reductions in spot or trough Uosm values were achievable with tolvaptan and high water intake, but cumulative 24-hour suppression was greater with tolvaptan. This analysis supports a relationship between effects on Uosm and inhibition of disease progression by tolvaptan and high water intake alone. The findings further suggest that 24-hour Uosm measurement is superior to spot Uosm for assessing suppression of vasopressin activity by tolvaptan.

Chemical meningitis and syndrome of inappropriate antidiuretic hormone release (SIADH): a rare presentation of pituitary adenoma apoplexy

Pituitary apoplexy is an uncommon condition typically resulting from a sudden haemorrhage within a pituitary adenoma. This bleed can present clinically with a wide array of signs and symptoms. This report documents the case of a 62-year-old male who presented to the Lebanese Hospital Geitaoui University Medical Center with signs and symptoms of meningeal irritation. He was initially thought to have meningitis, and was started on antibiotics; he was then found to have pituitary adenoma apoplexy that was complicated by syndrome of inappropriate antidiuretic hormone release (SIADH). The patient was successfully treated with antibiotics, and fluid restriction and hypertonic saline after ruling out other more common causes for his hyponatraemia, before undergoing a transsphenoidal resection of the pituitary adenoma. A three-month follow-up evaluation of the patient demonstrated the absence of hormonal imbalances and the absence of residual tumours on imaging.

Syndrome of Inappropriate Antidiuretic Hormone (Siadh) in Lung Cancer

Lung cancer is one of the deadliest cancers in both men and women. Lung cancer is generally divided into 2, categories: small-cell lung carcinoma and non-small-cell lung carcinoma. Small cell lung carcinoma (SCLC) represents approximately 15% of all lung cancers. Paraneoplastic syndromes occur in 10% of lung cancer cases and constitute a group of disorders associated with the secretion of functional polypeptides or hormones from tumor cells. The syndrome of inappropriate antidiuretic hormone is a paraneoplastic syndrome that is closely related to SCLC and is associated with worse survival. The key to understanding SIADH is that the hyponatremia that occurs in this syndrome is not caused by Na+ deficiency but rather by excess fluid. The syndrome of inappropriate antidiuretic hormone that occurs is a secondary event caused by the release of antidiuretic hormone due to tumor lysis or because the tumor releases ectopic ADH. Hyponatremia in SCLC is a negative prognostic factor in hospitalized patients and patients with advanced disease

Effect of controlled hypotensive hemorrhage on plasma sodium levels in anesthetized pigs: An exploratory study.

Perioperative hyponatremia, due to non-osmotic release of the antidiuretic hormone arginine vasopressin, is a serious electrolyte disorder observed in connection with many types of surgery. Since blood loss during surgery contributes to the pathogenesis of hyponatremia, we explored the effect of bleeding on plasma sodium using a controlled hypotensive hemorrhage pig model. After 30-min baseline period, hemorrhage was induced by aspiration of blood during 30 min at mean arterial pressure <50 mmHg. Thereafter, the animals were resuscitated with retransfused blood and a near-isotonic balanced crystalloid solution and monitored for 180 min. Electrolyte and water balances, cardiovascular response, renal hemodynamics, and markers of volume regulation and osmoregulation were investigated. All pigs (n = 10) developed hyponatremia. All animals retained hypotonic fluid, and none could excrete net-free water. Urinary excretion of aquaporin 2, a surrogate marker of collecting duct responsiveness to antidiuretic hormone, was significantly reduced at the end of the study, whereas lysine vasopressin, i.e., the pig antidiuretic hormone remained high. In this animal model, hyponatremia developed due to net positive fluid balance and generation of electrolyte-free water by the kidneys. A decreased urinary aquaporin 2 excretion may indicate an escape from antidiuresis.

FRI165 BIUXX

Abstract Disclosure: A. Haider: None. M. Sadiq: None. J. Shakesprere: None. G.K. Sidhu: None. Background: Syndrome of inappropriate anti-diuretic hormone (ADH) secretion (SIADH) is characterized by inappropriate ADH secretion causing hyponatremia due to free water retention. Plasma volume expansion leads to renin inhibition by the renal juxtaglomerular complex, resulting in decreased aldosterone secretion with inappropriate natriuresis. However, when autonomous renin-independent aldosterone production is present, natriuresis can be suppressed, causing normal sodium levels despite inappropriately high ADH. Case: 58-year-old male with history of resistant hypertension &amp; bipolar disorder on Oxcarbazepine presented with dizziness, lightheadedness, and severe hypokalemia (2.7 mmol/L, n 3.5-5.0 mmol/L). CT Adrenals revealed an incidental 1.2 cm left-sided adrenal adenoma [HU 6, 40% washout]. Serum aldosterone and plasma renin activity (PRA) were obtained in the supine position via LC/MS/MS assay; concurrent serum K+ was 3.4 mmol/L. Spironolactone was started and titrated to 50 mg BID for blood pressure control due to high suspicion of hyperaldosteronism. The patient was continued on Oxcarbazepine 900 mg BID. A 3 mg Dexamethasone suppression test showed suppressed morning cortisol (1.0 μg/dL, n &amp;lt;1.8 μg/dL). Urine catecholamines and metanephrines were obtained and normal. 3-4 days after starting Spironolactone, the patient developed severe subacute hyponatremia (119 mmol/L, n 135-145 mmol/L) from an admission level of 137 mmol/L. No active renal or GI losses, diuretic use, or untreated hypothyroidism were documented. Serum osmolality was low (262 mOsm/kg, n 275-295 mOsm/kg) with urine osmolality of 357 mOsm/kg (n 50-1200 mOsm/kg) and urine sodium of 92 mEq/L (n &amp;gt;20 mEq/L). Serum aldosterone and PRA levels returned with normal aldosterone (7 ng/dL, n 2-9 ng/dL) but suppressed PRA (0.07 ng/mL/hr, n 0.7-3.3 ng/mL/hr) and elevated aldosterone-renin ratio (100 ng/dL per ng/mL/hr, n ≤ 30 ng/dL per ng/mL/hr). As renin was very low despite mild hypokalemia and active Losartan use at the time of testing, these findings were suggestive of primary aldosteronism. In-hospital 24-hour urine aldosterone collection showed urine aldosterone of 29.3 mcg/24 h (n 5-19 mcg/24 h) with urine sodium of 93 mmol/ 24 h (n 40-220 mmol/24 h). Oxcarbazepine was subsequently tapered off; Spironolactone was intermittently held until complete discontinuation. Fluid restriction and oral salt repletion were started and the patient’s sodium ultimately normalized. Outpatient saline suppression testing and adrenal vein sampling were scheduled. Conclusion: Oxcarbazepine was likely causing high ADH release but co-occurring untreated hyperaldosteronism inhibited natriuresis. Use of Spironolactone unmasked natriuresis by blocking aldosterone activity on the intercalated cells of the renal nephron. Stopping Oxcarbazepine ultimately resulted in hyponatremia resolution. Presentation Date: Friday, June 16, 2023

FRI357 A Rare Case Of Paraneoplastic Syndrome Of Inappropriate Secretion Of Antidiuretic Hormone In Oropharyngeal Squamous Cell Carcinoma

Abstract Disclosure: N. Torres: None. H. Rios: None. G. Rios: None. Y. Medina: None. L. Valerio: None. S. Rosa: None. A. Ortiz: None. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by hyponatremia that results from water retention attributable to persistent arginine vasopressin release. SIADH is considered the most common cause of euvolemic hyponatremia. Head and neck cancers are linked with 1.5% of SIADH cases. Cases reported in the literature about this association with oropharyngeal squamous cell carcinoma (SCC) were few, and no incidence data is currently available. We present a rare case of a patient with SIADH secondary to well-differentiated oropharyngeal squamous cell carcinoma. A case of 63 y/o male with Oropharyngeal SCC, previous gastrostomy, and tracheostomy due to malignancy. The patient initially presented with general malaise and weakness. Maxillofacial and neck CT scans were remarkable for a mass at the left lateral floor of the mouth, measuring approximately 5.7 cm AP x 2.5 cm transverse x 3.7 cm CC. Physical examination was remarkable for cachexia, but normal skin turgor and moist oral mucosa. An incidental finding of severe hyponatremia of 114 mEq was found. Confirmation of hypotonic euvolemic hyponatremia was performed with a urine osmolality of &amp;gt;100 mOsm per kg and high urine sodium (&amp;gt;40 mEq). These findings presented a strong case for our differential diagnosis of SIADH. Other differential diagnoses were hypothyroidism or adrenal insufficiency. The patient’s thyroid stimulating hormone was within normal levels, and adrenal insufficiency workup was negative, making paraneoplastic SIADH the more likely diagnosis due to SCC. Initial treatment was started with a 3% hypertonic solution drip running at 15 ml/hr. The chemistry panel was monitored every six hours to achieve a 6 mEq change, at a slow rate to avoid osmotic demyelination syndrome, a goal of 122 mEq. Sodium was corrected in 24 hours; 3% saline solution drip was discontinued. Once this level was reached, we continued the fluid restriction (&amp;lt;1L daily), and salt packets with meals. After consultation, Nephrology and Endocrinology services agreed with our diagnosis of hypotonic euvolemic hyponatremia due to ectopic production of paraneoplastic SIADH due to the oropharyngeal SCC. The patient’s hypotonic euvolemic hyponatremia was corrected, symptoms improved, and he was discharged with close follow-up with Hematology/Oncology, Nephrology, and Endocrinology services. Paraneoplastic SIADH due to squamous cell carcinoma is rarely observed in the hospital setting. It is important to consider paraneoplastic SIADH from SCC in the differential diagnosis of hypotonic euvolemic hyponatremia since early diagnosis and treatment can decrease long-term complications. We could have also considered pharmacological therapy for SIADH including the use of demeclocycline, vaptans, and furosemide if the patient had not responded to our interventions. We followed guideline therapy with intravenous hypertonic saline at the start, then transitioned to only using oral salt tablets and fluid restrictions. The patient's hyponatremia steadily improved with our interventions and was able to be discharged with close outpatient follow-up. Presentation: Friday, June 16, 2023

Syndrome of Inappropriate Antidiuretic Hormone Release Secondary to Ectopic Olfactory Neuroblastoma: Case Report and Review of Literature.

Ectopic olfactory neuroblastoma (ONB) is a rare neuroendocrine sinonasal malignancy which arises from sinonasal regions where olfactory neuroepithelium does not exist. Presentation of syndrome of inappropriate antidiuretic hormone release (SIADH) in patients with ectopic ONB is extremely rare. We report a case of a 22-year-old patient with ectopic ONB and paraneoplastic SIADH that was managed at our center. The ONB was arising from the left lamina papyracea and extending into the maxillary and ethmoid sinuses and filling the nasal cavity. Correction of sodium levels occurred within 24 hours of endoscopic resection via a combined trans-nasal transorbital approach. To avoid negative sequela secondary to rapid sodium correction, the patient was managed by desmopressin to obtain gradual sodium correction, which was achieved on the fourth postoperative day. Ectopic presentation of ONB with paraneoplastic SIADH is extremely rare with only 7 cases reported in the literature to date. Management via surgical resection and/or radiotherapy for these patients requires the managing clinician to be vigilant of serum sodium levels. A multidisciplinary approach is essential for optimal outcomes.

Mild dehydration effects on the murine kidney single-nucleus transcriptome and chromatin accessibility.

Daily, we may experience mild dehydration with a rise in plasma osmolality that triggers the release of vasopressin. Although the effect of dehydration is well characterized in collecting duct principal cells (CDPCs), we hypothesized that mild dehydration (<12 h) results in many kidney cell-specific changes in transcriptomes and chromatin accessibility. Single-nucleus (sn) multiome (RNA-assay for transposase-accessible chromatin) sequencing and bulk RNA sequencing of kidneys from male and female mice that were mildly water deprived or not were compared. Water-deprived mice had a significant increase in plasma osmolality. sn-multiome-seq resulted in 19,837 nuclei that were annotated into 33 clusters. In CDPCs, aquaporin 2 (Aqp2) and aquaporin 3 (Apq3) were greater in dehydrated mice, but there were novel genes like gremlin 2 (Grem2; a cytokine) that were increased compared with ad libitum mice. The transcription factor cAMP-responsive element modulator (Crem) was greater in CDPCs of dehydrated mice, and the Crem DNA motif was more accessible. There were hundreds of sex- and dehydration-specific differentially expressed genes (DEGs) throughout the kidney, especially in the proximal tubules and thin limbs. In male mice, DEGs were enriched in pathways related to lipid metabolism, whereas female DEGs were enriched in organic acid metabolism. Many highly expressed genes had a positive correlation with increased chromatin accessibility, and mild dehydration exerted many transcriptional changes that we detected at the chromatin level. Even with a rise in plasma osmolality, male and female kidneys have distinct transcriptomes suggesting that there may be diverse mechanisms used to remain in fluid balance.NEW & NOTEWORTHY The kidney consists of >30 cell types that work collectively to maintain fluid-electrolyte balance. Kidney single-nucleus transcriptomes and chromatin accessibility profiles from male and female control (ad libitum water and food) or mildly dehydrated mice (ad libitum food, water deprivation) were determined. Mild dehydration caused hundreds of cell- and sex-specific transcriptomic changes, even though the kidney function to conserve water was the same.

Metabolic effects of vasopressin in pathophysiology of diabetic kidney disease.

The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.

Hyponatremia : Etiology, diagnosis and acute therapy

Hyponatremia is one of the most common electrolyte disorders in emergency departments and hospitalized patients. Serum sodium concentration is controlled by osmoregulation and volume regulation. Both pathways are regulated via the release of antidiuretic hormone (ADH). Syndrome of inappropriate release of ADH (SIADH) may be caused by neoplasms or pneumonia but may also be triggered by drug use or drug abuse. Excessive fluid intake may also result in adecrease in serum sodium concentration. Rapid alteration in serum sodium concentration leads to cell swelling or cell shrinkage, which primarily causes neurological symptoms. The dynamics of development of hyponatremia and its duration are crucial. In addition to blood testing, aclinical examination and urine analysis are essential in the differential diagnosis of hyponatremia.

Clinical importance of adenylate cyclase-activating polypeptide (PACAP)

The pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and characterized from sheep hypothalami. Its amino acid sequence, gene, receptors and receptor genes and its distribution in the mammalian organism were soon described. PACAP is a member of the secretin peptide family. Its closest relative is the vasoactive intestinal polypeptide (VIP). Its widespread occurrence suggests that it plays a significant role in physiological processes. With the aim of animal models, the role of PACAP was intensively investigated worldwide in a possible treatment of various diseases. The first part of this work contains the most important experimental data regarding the structure, genes and occurrence of the peptide and its receptors in mammalian body. In the second part, we overviewed the ever-increasing data on human material according to organ systems. The review contains the data where there is a chance to use PACAP for therapeutic purposes in the clinical practice. Determining the concentration of PACAP in the blood would help in establishing a clinical and differential diagnosis. In the future, there may be a possibility for non-invasive therapy of tumors expressing PACAP receptors. PACAP regulates the pituitary functions, stimulates vasopressin release, adrenalin secretion, insulin secretion. It is smooth muscle relaxant, immunosuppressant. PACAP is a neurotransmitter, it is neuroprotective in various diseases of the nervous system and cytoprotective in peripheral organs. PACAP inhibits apoptosis and the formation of pro-inflammatory factors and stimulates the anti-inflammatory factors and development of tumor cells. PACAP participates in regulating the daily rhythm of physiological functions. Orv Hetil. 2023; 164(33): 1300-1310.

Nonatherosclerotic Renovascular Hypertension.

Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the renin-angiotensin-aldosterone system. Often, this occurs due to abnormally small, narrowed, or blocked blood vessels supplying one or both kidneys (ie: renal artery occlusive disease) and is correctable. Juxtaglomerular cells release renin in response to decreased pressure, which in turn catalyzes the cleavage of circulating angiotensinogen synthesized by the liver to the decapeptide angiotensin I. Angiotensin-converting enzyme then cleaves angiotensin I to form the octapeptide angiotensin II, a potent vasopressor and the primary effector of renin-induced hypertension. The effects of angiotensin II are mediated by signaling downstream of its receptors. Angiotensin receptor type 1 is a G-protein-coupled receptor that activates vasoconstrictor and mitogenic signaling pathways resulting in peripheral arteriolar vasoconstriction and increased renal tubular reabsorption of sodium and water which promotes intravascular volume expansion. Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion. Angiotensin II acts on glial cells and regions of the brain responsible for blood pressure regulation increasing renal sympathetic activation. Angiotensin II simulates the release of vasopressin from the pituitary which stimulates thirst and water reabsorption from the kidney to expand the intravascular volume and cause peripheral vasoconstriction (increased sympathetic tone). All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water.

Renal and hypothalamic inflammation in renovascular hypertension: role of afferent renal nerves.

Renal denervation (RDN) is a potential therapy for drug-resistant hypertension. However, whether its effects are mediated by ablation of efferent or afferent renal nerves is not clear. Previous studies have implicated that renal inflammation and the sympathetic nervous system are driven by the activation of afferent and efferent renal nerves. RDN attenuated the renal inflammation and sympathetic activity in some animal models of hypertension. In the 2 kidney,1 clip (2K1C) model of renovascular hypertension, RDN also decreased sympathetic activity; however, mechanisms underlying renal and central inflammation are still unclear. We tested the hypothesis that the mechanisms by which total RDN (TRDN; efferent + afferent) and afferent-specific RDN (ARDN) reduce arterial pressure in 2K1C rats are the same. Male Sprague-Dawley rats were instrumented with telemeters to measure mean arterial pressure (MAP), and after 7 days, a clip was placed on the left renal artery. Rats underwent TRDN, ARDN, or sham surgery of the clipped kidney and MAP was measured for 6 wk. Weekly measurements of water intake (WI), urine output (UO), and urinary copeptin were conducted, and urine was analyzed for cytokines/chemokines. Neurogenic pressor activity (NPA) was assessed at the end of the protocol calculated by the depressor response after intraperitoneal injection of hexamethonium. Rats were euthanized and the hypothalamus and kidneys removed for measurement of cytokine content. MAP, NPA, WI, and urinary copeptin were significantly increased in 2K1C-sham rats, and these responses were abolished by both TRDN and ARDN. 2K1C-sham rats presented with renal and hypothalamic inflammation and these responses were largely mitigated by TRDN and ARDN. We conclude that RDN attenuates 2K1C hypertension primarily by ablation of afferent renal nerves which disrupts bidirectional renal neural-immune pathways.NEW & NOTEWORTHY Hypertension resulting from reduced perfusion of the kidney is dependent on renal sensory nerves, which are linked to inflammation in the kidney and hypothalamus. Afferent renal nerves are required for chronic increases in both water intake and vasopressin release observed following renal artery stenosis. Findings from this study suggest an important role of renal sensory nerves that has previously been underestimated in the pathogenesis of 2K1C hypertension.

Severe Hyponatremia During First Cycle of Cyclophosphamide/Doxorubicin Chemotherapy.

Syndrome of inappropriate anti-diuretic hormone release (SIDAH) is a condition characterized by an unregulated release of anti-diuretic hormone (ADH) resulting in increased water retention and decreased plasma osmolarity. Without regulation, ADH release will cause a significant decrease in plasma sodium concentration and can present with cramping, nausea, vomiting, and in severe cases, seizures, and potentially falling into a comatose state. The causes of SIADH are variable and range from infections, some malignancies to some medications. We report a rare case of SIADH resulting from a single cycle of doxorubicin and cyclophosphamide chemotherapy in a 66-year-old female with left and right, estrogen receptor positive breast cancer who experienced seizures resulting from a dramatic drop in sodium levels.

#3500 CENTRAL DIABETES INSIPIDUS ASSOCIATED WITH ACUTE MYELOID LEUKEMIA

Abstract Background and Aims Central Diabetes Insipidus (CDI) is a rare condition in which there is decreased release of antidiuretic hormone (ADH) from the posterior lobe of the pituitary gland resulting in polyuria. CDI is most commonly idiopathic with other known causes being primary or secondary tumors, cranial nervous system (CNS) infiltrative diseases, head trauma or neurosurgical procedures. Acute Myeloid Leukemia (AML) is rarely associated with CDI. We report a case of elderly male patient with recently diagnosed AML who developed polyuria due to CDI. Method Review of medical literature and hospital patient case workup based on reviewed medical literature. Results A 78-year-old male patient diagnosed with acute myeloid leukemia was started on treatment with Decitabine and Venetoclax 4–6 weeks prior to his hospitalization with chief complaints of back pain and oropharyngeal mucositis. The patient was also noted to have significant polyuria with hypernatremia during his hospitalization. His urine output ranged around 6–7 liters per day and his serum sodium levels were noted to be elevated to 162 mmol/L. 24-hour urine osmolality was calculated at around 1700 milliosmoles/day. Though patient's initial labs were suggestive of osmotic diuresis as a cause of his polyuria from ongoing hyperosmolar IV fluids input and significant increased oral dietary osmolar input, his polyuria persisted despite decreased total daily osmolar input. Further investigation with desmopressin suppression testing was notable for doubling of his urine osmolality with 10 mcg intranasal desmopressin administration with urine osmolality reaching to a peak of 447 mOsm/kg, indicating CDI as a reason for patient's ongoing polyuria. Patient's urine output as well as hypernatremia improved with initiating the patient on daily Desmopressin. MRI head with and without contrast ruled out any intracranial masses or infiltrative CNS diseases. Conclusion The pathogenic mechanism for association between CDI and AML is not completely clear, but it is thought to be secondary to infiltration of the central nervous system with leukemic cells, especially Sella Turcica, though this may not be evident on CNS imaging studies in all the cases, like in our patient. Polyuria can present in patients with AML either before or after the diagnosis of AML and sometimes it might be the only presentation in patients with AML which would lead to further workup and diagnosis of AML. Early identification of CDI in these patients lead to prompt management and avoidance of any significant electrolyte imbalances which could be sometimes attributed to patient's chemotherapeutic agents rather than to the patient's disease process itself.

WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release.

Maintaining internal osmolality constancy is essential for life. Release of arginine vasopressin (AVP) in response to hyperosmolality is critical. Current hypotheses for osmolality sensors in circumventricular organs (CVOs) of the brain focus on mechanosensitive membrane proteins. The present study demonstrated that intracellular protein kinase WNK1 was involved. Focusing on vascular-organ-of-lamina-terminalis (OVLT) nuclei, we showed that WNK1 kinase was activated by water restriction. Neuron-specific conditional KO (cKO) of Wnk1 caused polyuria with decreased urine osmolality that persisted in water restriction and blunted water restriction-induced AVP release. Wnk1 cKO also blunted mannitol-induced AVP release but had no effect on osmotic thirst response. The role of WNK1 in the osmosensory neurons in CVOs was supported by neuronal pathway tracing. Hyperosmolality-induced increases in action potential firing in OVLT neurons was blunted by Wnk1 deletion or pharmacological WNK inhibitors. Knockdown of Kv3.1 channel in OVLT by shRNA reproduced the phenotypes. Thus, WNK1 in osmosensory neurons in CVOs detects extracellular hypertonicity and mediates the increase in AVP release by activating Kv3.1 and increasing action potential firing from osmosensory neurons.

Sex-specific differences in the circadian pattern of action potential firing by rat suprachiasmatic nucleus vasopressin neurons.

The suprachiasmatic nucleus (SCN) of the hypothalamus serves as the master circadian clock in mammals. Most SCN neurons express the inhibitory neurotransmitter GABA (gamma amino butyric acid) along with a peptide cotransmitter. Notably, the neuropeptides vasopressin (VP) and vasoactive intestinal peptide (VIP) define two prominent clusters within the SCN: those located in the ventral core (VIP) and those forming the dorsomedial "shell" of the nucleus (VP). Axons emerging from VP neurons in the shell are thought to mediate much of the SCN's output to other brain regions as well as VP release into the cerebrospinal fluid (CSF). Previous work has shown that VP release by SCN neurons is activity dependent and SCN VP neurons fire action potentials at a higher rate during the light phase. Accordingly, CSF VP levels are higher during daytime. Interestingly, the amplitude of the CSF VP rhythm is greater in males than females, suggesting the existence of sex differences in the electrical activity of SCN VP neurons. Here we investigated this hypothesis by performing cell-attached recordings from 1070 SCN VP neurons across the entire circadian cycle in both sexes of transgenic rats that express green fluorescent protein (GFP) driven by the VP gene promoter. Using an immunocytochemical approach we confirmed that >60% of SCN VP neurons display visible GFP. Recordings in acute coronal slices revealed that VP neurons display a striking circadian pattern of action potential firing, but the characteristics of this activity cycle differ in males and females. Specifically, neurons in males reached a significantly higher peak firing frequency during subjective daytime compared to females and the acrophase occurred ~1 h earlier in females. Peak firing rates in females were not significantly different at various phases of the estrous cycle.

Input from afferent renal nerves is involved in progression of hypertensive heart failure through central vasopressin-mediated sympathoexcitation

Introduction: Paraventricular nucleus of hypothalamus (PVN), a control center of sympathetic outflow, receives the input from afferent renal nerves. Although acute stimulation of afferent renal nerves increases central sympathetic outflow, it remains unclear if the renal afferents contribute to progression of heart failure. Acute stimulation of afferent renal nerves was reported to increase plasma vasopressin concentration. In addition, central dendritic release of vasopressin by activation of vasopressin-expressing neurons located in the PVN may cause sympathoexcitation via stimulation of neighboring presympathetic neurons in the PVN. Therefore, we hypothesized that the chronic input from afferent renal nerves contributes to sympathoexcitation and hypertensive cardiac dysfunction along with activation of vasopressin-expressing neurons and presympathetic neurons in the PVN. Methods: Male Dahl salt-sensitive rats were fed low salt diet (LS) or 8% high salt diet from 6 weeks of age, and the high salt-fed rats were allocated to selective afferent renal denervation (HS-ARDN) or sham surgery (HS-Sham) at 9 weeks. The effect of ARDN on central sympathetic regulation was investigated at 12 weeks (pre-heart failure phase). In another cohort, its effect on cardiac phenotypes was evaluated at 16 weeks (heart failure phase). Results: At 12 weeks, plasma norepinephrine level was increased in HS-Sham compared to LS and was attenuated by ARDN (LS 188.7±16.5 pg/ml, HS-Sham 563.8±82.7 pg/ml, HS-ARDN 327.4±50.2 pg/ml; n=15, 12, 14; p&lt;0.05). The c-Fos expression, a marker of neuronal activity, in presympathetic neurons in the PVN was also increased in HS-Sham and attenuated in HS-ARDN, which was in parallel with the c-Fos expression in vasopressin-expressing neurons in the PVN. At 16 weeks, the decrease of left ventricular (LV) fractional shortening (HS-Sham 25.9±1.7 % vs LS 46.7±0.6 %, n=9, 9; p&lt;0.01) was improved in HS-ARDN (42.2±1.2 %, n=7; p&lt;0.01 vs HS-Sham). LV weight and lung weight were significantly increased in HS-Sham compared to LS (LV weight/body weight: 4.39±0.19 mg/g vs 2.53±0.03 mg/g; lung weight/body weight: 5.29±0.37 mg/g vs 3.55±0.05 mg/g; p&lt;0.05), and these changes were attenuated in HS-ARDN (LV weight/body weight: 3.73±0.14 mg/g; lung weight/body weight: 4.17±0.11 mg/g; p&lt;0.05 vs HS-Sham). Histological LV fibrosis and fibrosis marker expression, such as connective tissue growth factor, in LV were significantly attenuated in HS-ARDN compared to HS-Sham. ARDN did not significantly impact the high salt-induced blood pressure elevation in both cohorts. Conclusion: The input from afferent renal nerves contributes to cardiac dysfunction, probably via the central vasopressin-mediated sympathoexcitation even without blood pressure changes in hypertensive heart failure model. 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.

Relaxin mechanistic effects on renal hemodynamics and natriuresis: a mathematical modeling approach

Relaxin (RLX) is a hormone that stimulates renal vasodilation during early pregnancy. Recombinant RLX may have potential as a treatment for heart failure and chronic kidney disease, but its application has been limited in part due to uncertainties about its mechanism of action, and particularly its effect on glomerular capillary hydrostatic pressure (P gc ) and fluid status. The objective of this study was to couple mathematical modeling with experimental observations of the renal hemodynamic and natriuretic response to RLX, in order to quantitatively describe the mechanistic effects of relaxin on the kidney, and to predict its effect on clinically difficult-to-measure variables such as P gc . Utilizing a previously developed mathematical model of kidney function and hemodynamics, we began by hypothesizing a minimum set of RLX mechanisms (afferent/efferent vasodilation), fitting the available hemodynamic/natriuretic response in two previously published rat studies (GFR, renal plasma flow (RPF), mean arterial pressure (MAP), sodium and water excretion), and adding additional RLX mechanisms to the model only when the minimal set could not explain available data. We found that changes in renal vascular resistances alone were sufficient to reproduce observed changes in RPF, but insufficient to explain other data features. Experimental studies reported much larger increases in sodium excretion relative to water excretion with RLX, and this effect could only be reproduced if an effect of RLX on the osmotic setpoint for vasopressin release was included in the model – a mechanism that has previously been reported in ovariectomized rats treated with RLX. A small effect of RLX on heart rate was necessary to produce observed changes in MAP.In addition, the single experimental study in which P gc has been measured with RLX reported a rise in GFR but fall in P gc , and this difference could not be explained mathematically by relative afferent/efferent dilation or by downstream shifting of the filtration equilibrium with increased RPF; it could only be reproduced mathematically if RLX was assumed to large positive effect on glomerular membrane permeability. However, the magnitude of this effect is difficult to justify physiologically. Thus, while the model can be forced to fit this limited data, further study is needed to understand whether and how RLX might have such large permeability effects.The fitted model was then able to make predictions consistent with observed renal responses in human subjects, and these effects were better predicted when the RLX effect on permeability was excluded, further suggesting that this effect may not be real. In these simulations, RLX had no net effect on P gc . In conclusion, while some uncertainty remains, this analysis suggests that RLX acts primarily by dilating the afferent and efferent arterioles and shifting the osmotic setpoint for vasopressin release. AstraZeneca and Eli Lilly 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.