Increased Urine Osmolality Research Articles

6616 Copeptin Use To Reduce Hospital Stay In A Complicated DI Case

Abstract Disclosure: S.S. Kowsika: None. H. Moran: None. Introduction: While there is literature describing the use of copeptin for the diagnosis of polyuria-polydipsia syndrome, its utilization remains very limited in many hospitals. We present a case where the patient, initially misdiagnosed with central diabetes insipidus (DI), was appropriately diagnosed with partial nephrogenic DI through the use of copeptin. Case: A 48-year old female with a history of cardiac arrest, anoxic brain injury and diabetes insidious (DI) presented to the emergency department with hypernatremia (Na 154 mmol/L). The patient had been initiated on desmopresin (DDAVP) at an outside facility prior to her current admission. Despite receiving high doses of DDAVP, her sodium levels remained elevated, prompting further investigation. DDAVP administration was discontinued. A water deprivation test was subsequently performed, followed by IV administration of 2 mcg of DDAVP, which resulted in an increase in urine osmolality from 191 to 331 mosm/kg, which was less than the expected 50% increase observed in central DI. Additionally, a baseline copeptin level was obtained and noted to be 31 pmol/L, confirming the diagnosis of partial nephrogenic DI. The patient was started on Amiloride, leading to normalization of sodium levels. Discussion: Many patients with polyuria-polydipsia syndrome are frequently misdiagnosed and receive incorrect treatment, potentially worsening their clinical condition. Copeptin (Carboxy-Terminal-Pro-vasopressin) is the C-terminal peptide of pro-vasopressin, co-secreted with arginine vasopressin (AVP). It has been proposed as a direct test for diagnosing polyuria-polydipsia syndrome. Baseline Copeptin testing without stimulation can accurately diagnose nephrogenic DI if elevated (>21.4, pmol/L). To differentiate between central DI and chronic polyuria, prior thirsting with hypertonic saline or glucagon stimulation is necessary, with stimulated copeptin <4.9 pmol/L diagnosing central DI. Despite its diagnostic potential, Copeptin is underutilized in many settings. In this case, using Copeptin to accurately diagnose our patient led to appropriate treatment and the resolution of hypernatremia. Presentation: 6/1/2024

7227 Acute Hyponatremia Following Initiation of Antidepressant in Patient on Desmopressin Treatment for AVP Deficiency

Abstract Disclosure: M.E. Horowitz: None. Y. Gao: None. S.B. Abraham: None. P. Kishore: None. Introduction: Intranasal desmopressin (DDAVP) is indicated as antidiuretic replacement therapy in arginine vasopressin (AVP) deficiency. It increases water permeability in the distal nephron, reducing urine output, increasing urine osmolality, and decreasing serum osmolality. Treatment is titrated to normalize serum sodium and urine output (UOP). Initiation of medications affecting sodium balance or fluid status may lead to abnormalities in these markers. One of these is escitalopram, an antidepressant which can cause hyponatremia attributed to inappropriate AVP secretion. We report a case of acute hyponatremia in a patient with previously stable sodium on chronic DDAVP who was started on escitalopram. Clinical Case: A 44-year-old female with history of a craniopharyngioma resection in 2007 complicated by AVP deficiency on chronic DDAVP, bipolar disorder, and depression presented with nausea, vomiting, and dizziness for two days. Patient was found to be hyponatremic to 118 mEq/L (135-145 mEq/L). Sodium checked one month prior was 135 mEq/L, and historically was never less than 130 mEq/L since 2008. DDAVP was prescribed since resection with few dose changes, at this time four 10mcg sprays in each nostril three times daily since 2020. Escitalopram 5mg daily was initiated two months prior. Desmopressin was held in the setting of hyponatremia, which resolved appropriately to 135 mEq/L over the first five days. During this time, the patient complained of large volume diuresis at ∼three liters daily. On day six, sodium acutely increased to 146 mEq/L; subcutaneous (SC) DDAVP was given and sodium normalized. UOP decreased significantly over the next 24 hours, but large volume diuresis resumed thereafter. On day 10, DDAVP SC was given, again decreasing UOP for 24 hours. Psychiatry recommended continuing escitalopram given improvement in psychiatric symptoms since initiation. Upon discharge, the patient was prescribed DDAVP two 10mcg sprays in each nostril nightly, a significant reduction compared to her prior dose. Sodium rechecked one week later remained within normal limits. Clinical Lessons: This effect of combination DDAVP and escitalopram has not been reported previously. Prescribers should be aware of the potential for hyponatremia and the need to adjust DDAVP dose in combined use. To avoid these risks in patients on chronic DDAVP, the side effects of antidepressants and antipsychotics should be reviewed prior to initiation. Presentation: 6/2/2024

Abstract MP18: Evidence for An Important Physiological Role of Bradykinin B 2 Receptors in The Renomedullary Interstitial cells of The Kidney in Angiotensin II-induced Hypertension in Mice

Bradykinin is a potent vasoactive peptide of the kallikrein-kinin system and activates two different classes of G protein-coupled receptors, B 1 and B 2 , in the kidney. In the present study, we tested the hypothesis that deletion of B 2 receptors selectively in renomemdullary interstitial cells (RMICs) of the kidney medulla lowers basal blood pressure and attenuates angiotensin II (Ang II)-induced hypertension. To test the hypothesis, we generated a novel mouse model with deletion of B 2 receptors selectively in RMICs of the medulla (RMIC- Bdkrb2 -/- ) using inducible Tenascin-C-CreER2/Bdkrb2 fl/fl recombination approach. Mice with deletion of B 2 receptors selectively in RMICs developed and grew normally without structural abnormalities in the kidney medulla. Basal telemetry systolic (SBP), diastolic, and mean arterial blood pressure were significantly lower in RMIC- Bdkrb2 -/- than WT mice (WT: 123 ± 3 mmHg vs. RMIC- Bdkrb2 -/- : 106 ± 3 mmHg, P <0.01) (n=12-15). The hypotensive phenotype in RMIC- Bdkrb2 -/- mice was associated with significant decreases in 24 h urine output (WT: 1.86 ± 0.15 mL/24 h vs. RMIC- Bdkrb2 -/- : 1.09 ± 0.15 mL/24 h, P <0.05) and urine osmolality (WT: 1893 ± 441 mOsm/Kg H 2 O vs. RMIC- Bdkrb2 -/- : 1311 ± 78 mOsm/Kg H 2 O, P <0.01) (n=12=15). Deletion of Bdkrb2 receptors in RMICs significantly decreases COX-2, eNOS, ENaC, and AQP2 mRNA expression ( P <0.01 vs. WT), but not PGE 2 or prorenin receptor mRNA expression in the kidney medulla (n.s.) (n=6-10). In response to Ang II, SBP increased to 166 ± 6 mmHg in WT mice ( P <0.01 vs. Basal), but it increased only to 139 ± 5 mmHg in RMIC- Bdkrb2 -/- mice ( P <0.01 vs. WT+Ang II) (n=10-12). Ang II-induced hypertension was completely blocked by oral administration of AT 1 receptor blocker losartan (20 mg/kg/day, p.o.) in WT and RMIC- Bdkrb2 -/- mice (n=10). By comparison, infusion of DDAVP (1-deamino-8-D-arginine vasopressin, ~0.5 mg/kg/day, i.p., for 2 weeks) had no effect on blood pressure in WT and RMIC- Bdkrb2 -/- mice (n.s.) (n=8). Similarly, infusion of Ang II or DDAVP for 2 weeks significantly increased urine osmolality in WT mice ( P <0.01), and restored urine osmolality in RMIC- Bdkrb2 -/- mice to the WT basal level (1995 ± 315 mOsm/Kg H 2 O, P <0.01) (n=8-12). In conclusion, the present study demonstrates for the 1 st time that bradykinin B 2 receptors in RMICs of the kidney medulla plays an important role in maintaining basal blood pressure and urine osmolality homeostasis and the development of Ang II-induced hypertension.

Duloxetine-Induced Antidiuresis in Rats with Lithium-Induced Nephrogenic Diabetes Insipidus.

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia.

DELETION OF BRADYKININ TYPE 2 RECEPTORS SELECTIVELY IN THE RENOMEDULLARY INTERSTITIAL CELLS OF THE KIDNEY MEDULLA ATTENUATES ANGIOTENSIN II-INDUCED HYPERTENSION IN MICE

Objective: The present study tested the hypothesis that deletion of vasoactive peptide bradykinin B2 receptors selectively in the renomemdullary interstitial cells (RMICs) of the kidney medulla attenuates angiotensin II-induced hypertension in mice. Design and method: To test the hypothesis, we employed inducible Tenascin-C-CreER2 and bradykinin B2 receptor-floxed recombination approach to generate a novel mouse model with deletion of B2 receptors selectively in the RMICs of the kidney medulla (RMIC-B2R-/-). Basal blood pressure and urine osmolality and their responses to angiotensin II (Ang II, ∼500 μg/kg/day, i.p., for 2 weeks) were determined in adult male wildtype (WT) and RMIC-B2R-/- mice (n=10 per group), respectively. Results: Mice with deletion of B2 receptors selectively in RMICs of the kidney medulla developed normally without structural abnormalities in the kidney medulla. However, basal telemetry systolic, diastolic, and mean arterial blood pressure were significantly lower in RMIC-B2R-/- than WT mice (WT: 123 ± 3 mmHg vs. RMIC-B2R-/-: 106 ± 3 mmHg, P<0.01). The hypotensive phenotype in RMIC-B2R-/- mice was associated with significant decreases in 24 h urine output (WT: 1.86 ± 0.15 mL/24 h vs. RMIC-B2R-/-: 1.09 ± 0.15 mL/24 h, P<0.05) and urine osmolality (WT: 1893 ± 441 mOsm/Kg H2O vs. RMIC-B2R-/-: 1311 ± 78 mOsm/Kg H2O, P<0.01). In response to Ang II infusion (∼0.5 mg/kg/day, i.p., for 2 weeks), systolic blood pressure increased to 166 ± 6 mmHg in WT mice (P<0.01 vs. Basal), but it increased only to 139 ± 5 mmHg in RMIC-B2R-/- mice (P<0.01 vs. WT). By comparison, infusion of DDAVP (1-deamino-8-D-arginine vasopressin, ∼0.5 mg/kg/day, i.p., for 2 weeks) did not significantly alter blood pressure in WT and RMIC-B2R-/- mice (n.s.). However, infusion of Ang II for 2 weeks significantly increased urine osmolality in WT mice (P<0.01), and restored urine osmolality in RMIC-B2R-/- mice to the WT basal level (1995 ± 315 mOsm/Kg H2O, P<0.01). Conclusions: In conclusion, the present study demonstrates for the 1st time that bradykinin B2 receptors in the RMICs of the kidney medulla plays an important role in maintaining basal blood pressure and urine osmolality homeostasis and the development of Ang II-induced hypertension.

Activation of TGR5 Increases Urine Concentration by Inducing AQP2 and AQP3 Expression in Renal Medullary Collecting Ducts

Introduction: G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular signaling pathways after interacting with bile acids. TGR5 plays an important role in multiple physiological processes and is considered to be a potential target for the treatment of various metabolic diseases, including type 2 diabetes. Evidence has emerged that genetic deletion of TGR5 results in an increase in basal urine output, suggesting that it may play a critical role in renal water and salt reabsorption. The present study aims to elucidate the effect and mechanism of TGR5 activation on urine concentration. Methods: Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days. The 24-h urine of mice was collected and analyzed for urine biochemical parameters. The mRNA expressions were detected by real-time PCR, and the protein expressions were detected by western blot. Immunohistochemistry and immunofluorescence were performed to examine the cellular location of proteins. The cultured primary medullary collecting duct cells were pretreated with H89 (a PKA inhibitor) for 1 h, followed by 12-h treatment of LCA and INT-777. Luciferase reporter assays were used to detect the effect of CREB on the gene transcription of AQPs. Gel electrophoretic mobility shift assays were used to analyze DNA–protein interactions. Results: Treatment of mice with the TGR5 agonist LCA and INT-777 markedly reduced urine output and increased urine osmolality, accompanied by a marked increase in AQP2 and AQP3 protein expression and membrane translocation. In cultured primary medullary collecting duct cells, LCA and INT-777 dose-dependently upregulated AQP2 and AQP3 expression in a cAMP/PKA-dependent manner. Mechanistically, both AQP2 and AQP3 gene promoter contains a putative CREB-binding site, which can be bound and activated by CREB as assessed by both gene promoter-driven luciferase and gel shift assays. Conclusion: Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect.

SAT624 Neurosarcoidosis Presenting With Panhypopituitarism

Abstract Disclosure: E.M. Niedzialkowska: None. T. Blazin: None. K. Strubchevska: None. M. Kozyk: None. N. Saini: None. Introduction: Neurosarcoidosis is estimated to occur in approximately 5-15% patients with sarcoidosis. Pituitary involvement may be present in up to 5% of those cases and can manifest as hypothalamus, adenohypophysis dysfunction or arginine vasopressin deficiency (AVP-D) in isolated fashion or variedly combined. Clinical case: 32 year old male presented with chief complaint of worsening bilateral lower extremity weakness, urinary incontinence, polyuria and polydipsia. 9 months prior to admission the patient was diagnosed with neurosarcoidosis. At that time brain MRI showed diffuse leptomeningeal enhancement, chest CT showed hilar lymphadenopathy, lumbar puncture with CSF analysis showed protein 227 mg/dl (N<38), ACE 6 U/l (N <2.5), WBC 10 (N<5) with 88% lymphocytes. Hilar lymph node biopsy was consistent with non-caseating granuloma. The patient was diagnosed with neurosarcoidosis and started on prednisone and methotrexate. The patient was referred to our institution for further evaluation. On examination gait ataxia and gynecomastia were noted. Laboratory results showed urine specific gravity of 1.001, LH 0.4 mIU/ml (N 0.6-1.2), FSH 1.1 mIU/ml (N 1-12), ACTH <5 pg/ml (N 6-46), cortisol 2.1 ug/dl (N 2.9-19.4), prolactin 10.5 ng/ml (N 2-18), total testosterone 4 ng/dl (N 240-1080), free testosterone 0.1 ng/dl (N 4.8-19), TSH 0.58 uIU/ml (N 0.4-4.5), free ft3 1.5 pg/ml (N 1.7-3.7), free ft4 0.6 ng/dl (N 0.7-1.5), IGF-1 52 ng/ml (N 71-234), Copeptin proAVP of <2.8 pmol/l( N>13.2), urine osmolality of 72 mOsmol/kg, blood osmolality of 297 mOsmol/kg (N <295), vit D 25-OH 9 ng/ml (N 30-100), vit D 1,25-OH 57.3 pg/ml (N 19.9-79.3). MRI of the spine showed extensive nodular enhancement of the leptomeninges of the cervical, thoracic spine and lumbar cauda equina nerve roots. Brain MRI was positive for numerous small nodular enhancement involving leptomeninges and pituitary stalk. The patient was started on desmopressin with significant improvement of symptoms and increase in urine osmolality to 709 mOsmol/kg. Due to risk of hypercalcemia and normal vit D 1,25-OH vitamin D supplementation was not initiated. For neurosarcoidosis the patient was started on pulse dose methylprednisolone and infliximab infusion. Upon discharge he was transitioned to oral hydrocortisone and started on levothyroxine and testosterone replacement therapy. Conclusion: We present a case of pituitary neurosarcoidosis presenting with AVP-D, secondary hypothyroidism, secondary adrenal insufficiency, hypogonadism and growth hormone deficiency. Panhypopituitarism with complete anterior and posterior pituitary dysfunction is extremely rare and might be found in up to 13% cases of pituitary sarcoidosis. The diagnosis should be considered in patients with sarcoidosis and endocrine dysfunctions. Presentation: Saturday, June 17, 2023

Impact of Preparticipating Hypohydration on Cardiopulmonary Exercise Capacity in Ambitious Recreational Athletes.

Heat induces a thermoregulatory strain that impairs cardiopulmonary exercise capacity. The aim of the current study is to elucidate the effect of isolated dehydration on cardiopulmonary exercise capacity in a model of preparticipating hypohydration. Healthy recreational athletes underwent a standardised fluid deprivation test. Hypohydration was assessed by bioelectrical impedance analysis (BIA) and laboratory testing of electrolytes and retention parameters in the blood and urine. The participants underwent cardiopulmonary exercise testing (CPET) with a cycle ramp protocol. Each participant served as their own control undergoing CPET in a hypohydrated [HYH] and euhydrated [EUH] state. Fluid deprivation caused a mild (2%) but significant reduction of body water (38.6 [36.6; 40.7] vs. 39.4 [37.4; 41.5] %; p < 0.01) and an increase of urine osmolality (767 [694; 839] vs. 537 [445; 629] mosm/kg; p < 0.01). Hypohydration was without alterations of electrolytes, serum osmolality or hematocrit. The oxygen uptake was significantly lower after hypohydration (-4.8%; p = 0.02 at ventilatory threshold1; -2.0%; p < 0.01 at maximum power), with a corresponding decrease of minute ventilation (-4% at ventilatory threshold1; p = 0.01, -3.3% at maximum power; p < 0.01). The power output was lower in hypohydration (-6.8%; p < 0.01 at ventilatory threshold1; -2.2%; p = 0.01 at maximum power). Isolated hypohydration causes impairment of workload as well as peak oxygen uptake in recreational athletes. Our findings might indicate an important role of hypohydration in the heat-induced reduction of exercise capacity.

#5852 EFFECT OF DIET ON THE COLLECTOR DUCT BEHAVIOUR: RELEVANCE IN PRECLINICAL DRUG DEVELOPMENT

Abstract Background and Aims Drug induced syndrome of inadequate antidiuretic hormone secretion (SIADH) is a common problem in clinical practice. Early detection of this side effect at a preclinical level would improve safety and efficiency. We investigate the role of different diets in preclinical detection of SIADH. Method Animals were divided into two groups (n = 4 each), one receiving standard pellet based diet, and the other one a diluted hyposodic gelified liquid diet. After one week, both groups were administered daily intraperitoneal (i.p.) injections of desmopressin acetate (ddAVP; 0.4 μg/kg) and a volume of distilled water equivalent to 2.5% of body weight for 7 days. Animals were placed in metabolic cages for 24h at the end of each period to collect and analyse the urine, and a blood sample from the tail vein was obtained. Weight, water and food intake were measured on a daily basis. Results Differences in water and electrolyte balance are shown in Table 1. Pellet fed animals presented an increased water intake and produced a more concentrated urine compared to those on a hyposodic diet. When analysed in detail, urinary osmolality was mainly driven by ionic osmoles in pellet fed animals (42,25 ± 4,72 vs 266,30 ± 17,32 mOsm/kg, p&amp;lt;0,005). Of note, there seems to be an occult osmole, especially prominent in the pellet group (osmol gap 20,40 ± 3,18 vs 99,89 ± 9,81 mOsm/kg, p = 0,017). All of the above suggest there is a net retention of water, sodium and potassium in those animals fed with a conventional pellet diet. Daily administration of ddAVP/water induced a mild transient hyponatremia that was recovered 24h later in both groups; this situation was repeated over a 7 day period. Pellet fed animals did not modify water intake, diuresis, free water clearance or urinary osmolality after ddAVP/water treatment, suggesting that hyperosmolar diets significantly increase urinary osmolality fixating urinary water losses and impairing further urinary concentration. On the contrary, animals on a hyposodic diet did present antiaquaresis, as shown by an increase in water intake, a decrease in diuresis and free water clearance and an increase in urinary osmolality. Animals fed with hyposodic diet progressively lost weight, while pellet fed animals did not. However, this trend was reversed after 4 days of treatment with ddAVP/water, again suggesting a degree of water retention. It is remarkable that we have found signs of water retention despite the fact that the induced hyponatremia is mild and transient. Conclusion The antiaquaretic effect of ddAVP is overridden by the amount of urinary osmoles excreted when on a pellet diet, which seem to fixate the amount of water in the urine. Therefore, the use of hyposodic diets in preclinical drug development is essential when SIADH is likely to be expected, as its effects will be unnoticed if a standard diet is used.

Shortening of primary cilia length is associated with urine concentration in the kidneys.

The primary cilium, a microtubule-based cellular organelle present in certain kidney cells, functions as a mechano-sensor to monitor fluid flow in addition to various other biological functions. In kidneys, the primary cilia protrude into the tubular lumen and are directly exposed to pro-urine flow and components. However, their effects on urine concentration remain to be defined. Here, we investigated the association between primary cilia and urine concentration. Mice either had free access to water (normal water intake, NWI) or were not allowed access to water (water deprivation, WD). Some mice received tubastatin, an inhibitor of histone deacetylase 6 (HDAC6), which regulates the acetylation of α-tubulin, a core protein of microtubules. WD decreased urine output and increased urine osmolality, concomitant with apical plasma membrane localization of aquaporin 2 (AQP2) in the kidney. After WD, compared with after NWI, the lengths of primary cilia in renal tubular epithelial cells were shortened and HDAC6 activity increased. WD induced deacetylation of α-tubulin without altering α-tubulin levels in the kidney. Tubastatin prevented the shortening of cilia through increasing HDAC6 activity and consequently increasing acetylated α-tubulin expression. Furthermore, tubastatin prevented the WD-induced reduction of urine output, urine osmolality increase, and apical plasma membrane localization of AQP2. WD shortens primary cilia length through HDAC6 activation and α-tubulin deacetylation, while HDAC6 inhibition blocks the WD-induced changes in cilia length and urine output. This suggests that cilia length alterations are involved, at least in part, in the regulation of body water balance and urine concentration.

Insulin-regulated aminopeptidase (IRAP) is required for appropriate dilution of urine after an acute water load

Study Objective: Understand the response to acute water load in mice lacking the insulin-regulated aminopeptidase (IRAP). Hypothesis: IRAP degrades vasopressin in vivo, therefore, mice lacking IRAP would have impaired ability to dilute urine and to excrete water. Methods: Age matched 8–10-week-old IRAP WT and KO male mice were used for all experiments. Immunofluorescence and immunoblotting were performed on kidneys at baseline and after 1-hr acute water load (2ml sterile water/IP). Urine/serum electrolytes and urine osmolality were measured before and after water load. Urine was collected from IRAP WT and KO mice before and after 1-hr administration of OPC 31260 (10mg/kg/IP) and furosemide (2.5mg/ml/IP) for urine osmolality and electrolyte measurements. Results: IRAP is expressed in the glomerulus, thick ascending loop of Henle, distal tubule, connecting and collecting ducts. At baseline, IRAP WT and KO mice have similar systolic blood pressure (122 ± 6.6 vs 128 ± 1.9 mmHg), glomerular filtration rate (251 ± 20 vs 254 ± 16 uL/min), and serum Na + levels (142 ± 1.9 vs 143 ± 2.6 mmol/L), but KO mice have reduced proteinuria (3.3 ± 0.57 vs 4.5 ± 1.6 mg/mg). At baseline, IRAP KO have elevated serum copeptin levels (111 ± 43 vs 53 ± 31 pg/mL) and urine osmolality compared to respective IRAP WT (2506 ± 310 vs 1007 ± 212 mOsm/L). Urine osmolality decreased in IRAP KO after administration of vasopressin type 2 receptor antagonist, OPC 31260 (473 ± 341 vs 2479 ± 215 mOsm/L) and loop diuretic, furosemide (517 ± 96 vs 2750 ± 414 mOsm/L). After an acute water load, IRAP KO have lower serum Na + levels (127 ± 3.8 vs 134 ±3.1 mmol/L) and increased urine osmolality compared to IRAP WT (2741 ± 400 vs 577 ± 274 mOsm/L). Additionally, after an acute water load, IRAP KO mice also have higher protein abundance of the Na + /K + /2Cl - (NKCC2) co-transporter (0.36 ± 0.04 vs 0.20 ± 0.03 AU) and phosphorylation of water channel, AQP2 (0.032 ± 0.005 vs 0.025 ± 0.003 AU). Conclusions: IRAP is required to dilute urine and to increase water excretion in response to an acute water load due to persistent activation of NKCC2 and AQP2. Funding Sources: Harold Amos Medical Faculty Development Award - Robert Wood Johnson Foundation; Vanderbilt Center for Kidney Disease 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.

«Pressure diuresis» phenomenon: mechanisms and physiological significance in diving medical support practice: prospective cohort study

INTRODUCTION: When staying in hyperbaric conditions there is an increase in diuresis, developing a negative water balance, loss of electrolytes and tissue dehydration after diving different in depth, duration, intensity and other parameters, which can be conditionally combined into specific physiological symptom complex – “pressure diuresis” phenomenon (or “diver diuresis”). OBJECTIVE: To investigate the mechanisms of “pressure diuresis” under the action of high gaseous medium pressure and determine the physiological nature of this phenomenon in divers. MATERIALS AND METHODS: 44 men aged 19–23 were examined. In the first study all the subjects had initial sustainability to hyperbaric adverse factors (decompression gas formation – DG, hypoxic hypoxia – HH, nitrogen toxic effect – NTE and oxygen toxic effect – OTE). Hormonal status and body’s osmotic homeostasis rates were defined in all the subjects. The second study evaluated changes of the subjects’ water-electrolyte metabolism, kidney function and osmotic homeostasis during the oral loading renal test with the water load in the baseline and conditions of hyperbaric adverse factor exposure on divers. Statistics: To perform statistical analysis, application packages of Statistica for Windows 10.0 were used. RESULTS: 17 (38,6 %), 29 (65,9 %), 20 (45,5 %) and 35 (79,6 %) subjects had medium and low resistance to DG, HH, OTE and NTE, respectively; 27 (61,4 %), 15 (34,1 %), 24 (54,5 %) and 9 (20,4 %) subjects had high resistance to DG, HH, OTE and NTE. Increase in the concentration of antidiuretic hormone was identified in the diving group with low and medium resistance to NTE, HH, and OTE (by 146,8, 141,1 and 93,2 %, respectively, compared to the results before hyperbaric adverse factor exposure). The highest concentration increase of aldosterone was found among the divers with low and medium resistance to OTE, DG and HH (by 41,5, 39,1 and 36,2 %, respectively). The increase in blood plasma osmolality was observed in the subjects with low and medium resistance to OTE (an increase by 6,6 % compared to the divers with high resistance). A significant reduction in blood plasma osmolality was recorded in the subject group with low and medium resistance to NTE and HH (reduction by 5,2 and 4,2 %, compared to the group with high resistance). The most significant decrease in urine osmolality was identified in the diving group with low and medium resistance to DG and OTE (reduction by 14,5 and 17,7 %, respectively). A significant increase in urine osmolality under the action of hyperbaric factors was defined in the diving group with low and medium resistance to NTE and HH (by 19,8 and 19,3 %). DISCUSSION: The data obtained indicate the emergence of a new body hydration status during person’s staying in hyperbaric conditions. Body hydration status will be connected with its individual resistance to hyperbaric adverse factor effect. Thus, with the development of marked DG iso-osmotic (isotonic) hyperhydration is formed, with OTE hyperosmotic (hypertonic) hyperhydration occurs, with NTE and HH hypo-osmolar (hypotonic) hyperhydration develops. CONCLUSION: The study showed a certain connection (correlation) between types of hyperhydration in the tissues of a diver’s body, mechanisms of occurrence, low and medium initial resistance to a particular hyperbaric factor. “Pressure diuresis” phenomenon (“diver diuresis”), that occurs in divers with high resistance to hyperbaric adverse factors, will be a normal body’s physiological response, aimed at eliminating hypervolemia and reduction in the volume of circulating plasma.

Intractable hyponatremia complicated by a reset osmostat: a case report

BackgroundHyponatremia associated with a low serum osmolality is a common and confounding electrolyte disorder. Correcting hyponatremia is also complicated, especially in the setting of chronic hyponatremia. Here, we provide a rational approach to accurately detecting and safely treating acute on chronic euvolemic hyponatremia in the setting of acute polydipsia with a chronic reset osmostat.Case presentationA 71-year-old hispanic gentleman with chronic hyponatremia presented with hiccups, polydipsia, and a serum sodium concentration of 120 mEq/L associated with diffuse weakness, inattentiveness, and suicidal ideation. Symptomatic euvolemic hyponatremia warranted hypertonic saline treatment in the acute phase and water restriction in the chronic phase. Both interventions resulted in improvement in symptoms and/or the serum sodium concentration, but to a serum sodium level that persistently remained below the normal range. Remarkably, the urine osmolality appropriately fell when the serum sodium concentration fell below 126 mEq/L. Also remarkable was the appropriate increase in urine osmolality when the serum sodium concentration exceeded 126 mEq/L. The preservation of both concentration and dilution, albeit at a lower-than-normal serum osmolality, shows that the osmostat regulating antidiuretic hormone release had been “reset.” Both physiologic and pharmacologic resetting of the osmostat are discussed.ConclusionsPreservation of urinary concentrating and diluting ability at a lower-than-normal serum sodium concentration, especially in the setting of chronic hyponatremia, is diagnostic of a reset osmostat. The presence of a reset osmostat often confounds the treatment of concomitant acute hyponatremia. Early recognition of a reset osmostat avoids the need to normalize serum sodium concentration, expedites hospital discharge, and limits potential harm from overcorrecting acute hyponatremia.

Transient diabetes insipidus in critically ill COVID19 patients

PurposeVasopressin has become an important vasopressor drug while treating a critically ill patient to maintain adequate mean arterial pressure. Diabetes insipidus (DI) is a rare syndrome characterized by the excretion of a large volume of diluted urine, inappropriate for water homeostasis. We noticed that several COVID19 patients developed excessive polyuria suggestive of DI, with a concomitant plasma sodium-level increase and/or low urine osmolality. We noticed a temporal relationship between vasopressin treatment cessation and polyuria periods. We reviewed those cases to better describe this phenomenon. MethodsWe retrospectively collected COVID19 ECMO patients' (from July 6, 2020, to November 30, 2021) data from the electronic medical records. By examining urine output, urine osmolality (if applicable), plasma sodium level, and plasma osmolality, we set DI diagnosis. We described the clinical course of DI episodes and compared baseline characteristics between patients who developed DI and those who did not. ResultsOut of 37 patients, 12 had 18 episodes of DI. These patients were 7 years younger and had lower severity scores (APACHE-II and SOFA). Mortality difference was not seen between groups. 17 episodes occurred after vasopressin discontinuation; 14 episodes were treated with vasopressin reinstitution. DI lasted for a median of 21 h, with a median increase of 14 mEq/L of sodium. ConclusionsTemporary DI prevalence after vasopressin discontinuation in COVID19 ECMO patients might be higher than previously described for vasopressin-treated patients.

PS-C18-7: EFFECT OF TOLVAPTAN IN PATIENTS WITH CHRONIC KIDNEY DISEASE STAGE G5 AND IMPACT OF CONCOMITANT USE OF THIAZIDE DIURETICS

Objective: Tolvaptan, a vasopressin V2 receptor antagonist, is used to treat congestive heart failure (CHF). Its diuretic effect in patients with severe renal dysfunction remains poorly characterized. Thiazide diuretics decrease urinary volume (UV) in patients with nephrogenic diabetes insipidus, in which V2 receptor function is absent. Likewise, thiazide diuretics may decrease UV in patients receiving tolvaptan. Design and method: This retrospective cohort study included inpatients with chronic kidney disease stage G5, in whom tolvaptan was administered for CHF. UVs at 24-h pre- and post-tolvaptan administration as well as 30-day dialysis initiation were compared between patients with and without thiazide diuretics. Results: Thiazide diuretics were used in 26 of 106 recruited patients (73.4 ± 13.0 years, estimated glomerular filtration rate: 8.07 ± 3.13 mL/min/1.73 m2). In contrast to those who received thiazide diuretics (1177.3 ± 686.5 vs. 1173.1 ± 629.1 mL/day, p = 0.93), patients without thiazide diuretics had significantly higher 24-h UV pre- and post-tolvaptan administration (1043.4 ± 645.6 vs. 1422.2 ± 774.0 mL/day, p &lt; 0.001). In a multivariate regression model, the use of thiazide diuretics was significantly associated with decreased 24-h UV (beta coefficient, -486.7 [95% confidence interval (CI), -674.5 to -298.8]) and increased urine osmolality (beta coefficient, 37.7 [95% CI, 17.1–58.4]), bodyweight (beta coefficient, 0.62 [95% CI, 0.31–0.92]) and 30-day dialysis initiation (odds ratio 3.40 [95% CI, 1.18–9.82]) after tolvaptan administration. Conclusions: Tolvaptan had significant diuretic effects on patients with CHF, even in those with severe renal dysfunction. Concomitant use of thiazide diuretics diminished these effects.

PMON82 SARS-CoV-2 Associated Hypophysitis and Central Diabetes Insipidus

Abstract Background The SARS-CoV-2 infection, known for severe respiratory complications, has also been found to cause multiple endocrinopathies. SARS-CoV-2 enters pneumocytes through the angiotensin-converting enzyme 2 receptor. The adrenal, thyroid, testes, ovaries, hypothalamic, and pituitary tissues express ACE2 receptors, making them putative targets.2,4 Hypothalamic and pituitary involvement was first reported in 2005 and cases continue to be reported during the newest pandemic.1,3 We present a case of central DI following positive RT-PCR testing for SARS-CoV-2. Clinical Case A 44-year-old man presented with headache, multiple neurologic symptoms, polyuria, and polydipsia approximately three weeks following a positive SARS-CoV-2 test. A pituitary MRI showed thickening of the infundibular stalk and inhomogeneity of the pituitary gland, suggestive of hypophysitis. A water deprivation study demonstrated undetectable ADH and inability to concentrate urine spontaneously, but increased urine osmolality in response to DDAVP consistent with central DI. He was started on oral DDAVP with improvement of polyuria and polydipsia. Additional hormone testing showed normal thyroid function and Cosyntropin stimulation, mild hypogonadotropic hypogonadism, and mild elevation in IGF-1. Pituitary hormone abnormalities were transient and DDAVP was discontinued three months later. However, neurologic symptoms persisted. Repeat pituitary MRI three months later was unchanged. Due to spontaneous resolution of pituitary hormone abnormalities, no biopsy of the hypothalamic pituitary area was performed. Conclusion We present a case of central DI following known SARS-CoV-2 infection. The patient presented with sudden onset polyuria and polydipsia prompting need for pituitary evaluation. Testing confirmed central DI which resolved within three months. Involvement of the HPA was first noted in 2005 by Leow et al. who reported SARS causing reversible hypophysitis.1 We found three similar cases of patients developing DI approximately four weeks following SARS-CoV-2 infection; however only one case with evidence of infundibular hypophysitis.2,5,6 Two contributing mechanisms of HPA dysfunction are thought to be the result of direct hypothalamic damage or reversible hypophysitis.4 The worldwide presence of SARS-CoV-2 and myriad of complications following infection prompts need for further research and follow-up to better determine clinical recovery for SARS-CoV-2. Reference: 1. Leow MK, et al. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf). 2005;63(2): 197-202. 2. Misgar RA, et al. Central diabetes insipidus (Infundibuloneuro hypophysitis): A late complication of COVID-19 infection. J Endocrinol Invest. 2021;44(12): 2855-2856. 3. Nonglait PL, et al. Hypophysitis after COVID-19 Infection. Indian J Endocrinol Metab. 2021;25(3): 255-256. 4. Pal R. COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications. Endocrine. 2020;68(2): 251-252. 5. Rajevac H, et al. DIABETES INSIPIDUS AS A SYMPTOM OF COVID-19 INFECTION: CASE REPORT. Chest. 2020;158(4): A2576. 6. Sheikh AB, et al. Diabetes Insipidus and Concomitant Myocarditis: A Late Sequelae of COVID-19 Infection. Journal of Investigative Medicine High Impact Case Reports. January 2021. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Effect of Tolvaptan in Patients with Chronic Kidney Disease Stage G5, and Impact of Concomitant Use of Thiazide Diuretics: A Retrospective Cohort Study.

The diuretic effect of tolvaptan, a vasopressin V2 receptor antagonist, in patients with severe renal dysfunction remains poorly characterized. Thiazide diuretics reduce urinary volume (UV) in patients with nephrogenic diabetes insipidus, which lacks V2 receptor function. This retrospective study investigated the acute urinary effects of tolvaptan in patients with stage G5 chronic kidney disease and congestive heart failure (CHF), and the impact of thiazide diuretics on the urinary effects of tolvaptan. UVs 24h before and after tolvaptan administration and 30-day dialysis initiation rate were compared between patients with and without thiazide diuretic administration. Thiazide diuretics were used in 26 of the 106 recruited patients (age 73.4±13.0 years; estimated glomerular filtration rate 8.07±3.13 mL/min/1.73 m2). The pre- and post-tolvaptan 24-h UVs were significantly higher in patients not administered thiazide diuretics (1043.4±645.6 vs. 1422.2±774.0 mL/day; p<0.001) than in those administered thiazide diuretics (1177.3±686.5 vs. 1173.1±629.1 mL/day; p=0.93). In a multivariate regression model, thiazide diuretic use was significantly associated with decreased 24-h UV (β coefficient -486.7, 95% confidence interval [CI] -674.5 to -298.8); increased urine osmolality (β coefficient 37.7, 95% CI 17.1-58.4); increased body weight (β coefficient 0.62, 95% CI 0.31-0.92); and increased 30-day dialysis initiation rate (odds ratio 3.40, 95% CI 1.18-9.82) after tolvaptan administration. Tolvaptan exhibited significant diuretic effects in patients with CHF, including those with severe renal dysfunction, which were diminished with concomitant thiazide diuretic use.

Transient Diabetes Insipidus in a Preterm Neonate

Background: Diabetes insipidus (DI) is a disorder of water homeostasis due to insufficient production or inappropriate action of vasopressin. Central DI (CDI) develops due to intracranial causes such as hypoxic–ischemic encephalopathy, meningitis, and intraventricular hemorrhage. Manifestations such as polyuria, polydipsia, and irritability may not be obvious in preterm infants, resulting in delayed recognition and difficulty in establishing diagnosis. Clinical Description: A 1.4 kg preterm girl delivered by cesarean section for a significant nonstress test (but normal Apgar scores) was admitted for very low birth weight and preterm care. Initial clinical examination was normal, and the baby remained euglycemic. The neonate developed shock and fever on the 3rd day of life without any apparent cause. Management: DI was suspected on identification of hypernatremia (150 mEq/L) and polyuria (9 mL/kg/h). The urine osmolality was low (62.54 mOsmol/kg), despite high serum osmolality (312 mOsmol/kg) confirming the diagnosis. An increase in urine osmolality by &gt;50% following oral desmopressin (5 μg/kg/day) suggested CDI. This was continued until the baby became asymptomatic and urine/serum osmolality normalized. A trial of discontinuation of desmopressin did not lead to recurrence of symptoms. Magnetic resonance imaging brain showed features of subacute hypoxic insult and absent posterior pituitary bright spot. After 7 months of follow-up, she is asymptomatic without any treatment, and her growth and development are age appropriate. Conclusion: A high index of suspicion of CDI should be kept in neonates presenting with unexplained shock, fever, hypernatremia, and polyuria.

Aldosterone Regulates Vasopressin Escape through Changes in Water and Urea Transporters

Vasopressin escape is a process that prevents the continuous decrease in serum sodium even under conditions of sustained high vasopressin. Previous reports suggest that this process is regulated by aldosterone but the mechanism is not fully defined. In this study, aldosterone synthase (Cyp11b2) knockout and wild‐type mice were implanted with 14‐day osmotic mini‐pumps delivering 5 ng/h dDAVP (desmopressin, type 2 vasopressin receptor agonist) to promote distal nephron water reabsorption. Urine osmolality was measured before and then daily (24‐h urine collections) throughout the experiment. After 4 days of increased urine osmolality, mice were given a gel diet to force additional fluid consumption. Urine osmolality of the wild type mice was significantly lower (successful escape) than that of aldosterone synthase knockout mice. Protein analysis showed that both AQP2 and UT‐A1 protein abundances were higher in the aldosterone synthase knockout than wild‐type mice at the end of the escape period. To confirm the findings from the aldosterone synthase knockout mice, the mineralocorticoid receptor blocker spironolactone (20mg/kg/day, s.c.) or vehicle was given to rats that were receiving vasopressin by mini‐pump in a comparable vasopressin escape protocol to the mice. The spironolactone‐treated rats displayed a higher urine osmolality and lower serum sodium level versus untreated escaping rats. Phosphoserine 256‐AQP2 (PS256‐AQP2) was significantly increased in the spironolactone‐treated rats. Our results indicate that: vasopressin escape is prevented if aldosterone or its receptor are not available; and increased abundance of AQP2 or UT‐A1, or PS256‐AQP2, contributes to deficient vasopressin escape in the absence of aldosterone.

Apelin and Vasopressin: The Yin and Yang of Water Balance.

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect via its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring via the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin in vivo. In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (s.c.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.