Sodium Loading Research Articles

PS-BPR01-4: A CASE OF ALDOSTERONE-PRODUCING ADENOMA DIAGNOSED BY ADRENAL ARTERIOGRAPHY AND BRANCH SELECTIVE ADRENAL VENOUS SAMPLING

Case report: A 43-year-old man had been followed up for hypertension and hypokalemia, but self-interrupted his hospital visits for the last four years. Based on the serum potassium level of 2.7 mEq/L, plasma aldosterone concentration of 202 pg/mL, and plasma renin activity of 1.1 ng/mL/hr, he was suspected of primary aldosteronism and was admitted to the previous hospital. A saline suppression test and a rapid ACTH stimulation test were both positive, and 24-hr urinary aldosterone level was 19 μg/day under sodium loading of 170 mEq/day, leading to the diagnosis of primary aldosteronism. Since contrast-enhanced CT showed an 8 mm-sized adenoma in the lower portion of the left adrenal gland, an aldosterone-producing adenoma was suspected and a non-segmental adrenal venous sampling (AVS) was performed. However, it yielded apparent bilateral aldosterone suppression in the main trunk of the bilateral adrenal veins, where the aldosterone-to-cortisol (A/C) ratio was lower than that in the inferior vena cava even after ACTH loading. The patient was referred to our hospital for a segmental AVS. Arteriography was first performed from the left inferior adrenal artery to confirm the outflow vessels from the adenoma. Strikingly, there was an aberrant vein which drained into the proximal segment of the left adrenal vein. CT imaging at the time of arteriography revealed, in addition to the known adenoma, a 6 mm-sized micronodule in the lateral region of the left adrenal gland, and the aberrant vein appeared to be the main outflow vessel from the micronodule. A segmental AVS was performed, and blood samples were taken from the bilateral adrenal veins including the aberrant vein and the main trunk of the left adrenal vein proximal to its confluence. The A/C ratio was highest in the aberrant vein, followed by in the main trunk of the proximal left adrenal vein, while it was markedly suppressed in other branches and the main trunk of the left adrenal vein distal to the confluence of the aberrant vein. Based on these results, the presence of aldosterone-producing adenoma in the left adrenal gland was suggested. Laparoscopic partial left adrenalectomy was performed without postoperative complications. Hypertension and hypokalemia were fully resolved afterwards. Conclusions: Adrenal arteriography and segmental AVS should be considered in such cases that apparent bilateral aldosterone suppression is noted in conventional AVS in patients with clinically suspected aldosterone-producing adenoma.

Abstract 13357: From Junctional Rhythm to Slow Vt: Flecainide Poisoning

Introduction: Flecainide is a class IC anti-arrhythmic used to treat atrial fibrillation. Toxicity can cause bradycardia, QRS prolongation, and ventricular tachyarrhythmia (VT) due to blockade of sodium channels. Although most metabolism occurs through the liver, up to 30% excretion is renal but not dialyzable. The case here represents two arrhythmogenic challenges associated with flecainide treated with alkalization and lipid emulsion. Case: A 75-year-old woman with atrial fibrillation initially presented with syncope and hematemesis. Initial ECG showed junctional bradycardia with narrow escape in HR 30s. Labs notable for creatinine 2.55 (nl <1.2 mg/dl) and potassium 4.8 (3.5-5.0 mmol/L). pH was 7.28 with bicarbonate 18 (22-31 mmol/L). She was treated with glucagon and atropine for suspected B-blocker toxicity but quickly went into shock. Rhythm then changed to a wide complex tachycardia (Fig) with wide QRS 280ms, VT rates in 100s. Due to development of this slow VT, flecainide toxicity was highly suspected, and a bicarbonate drip was started to maintain pH>7.50 in addition to intralipid infusion. In the span of 12 hours, she was able to wean off her vasopressor support. On hospital day 3, she started metoprolol and remained in sinus bradycardia at the time of discharge. Discussion: This case represented acute renal failure secondary to flecainide toxicity and gastrointestinal bleed. Toxicity led to QRS widening and slow VT, which diminished contractility. Serum alkalization and sodium load works to displace flecainide from its channel receptor; intralipid sequesters lipophilic toxin in a “lipid sink” mechanism. In extreme cases, ECMO and overdrive pacing are used. Conclusions: Early recognition of flecainide-related arrhythmias is key. The subsequent approach to flecainide toxicity includes reducing absorption (charcoal, lipid emulsion), antagonizing drug effect (alkalization), and proving hemodynamic support (phenylephrine, vasopressin).

Coastal Groundwater Quality Evaluation and Hydrogeochemical Characterization Using Chemometric Techniques

The physicochemical parameters and heavy metals concentration in the groundwater of the coastal region of Lasbela, Baluchistan were investigated. Cations and anions were determined through ion chromatography. The concentration levels of eight heavy metals (Cr, Cd, Pb, Zn, Fe, Cu, and Mn) in the groundwater were analyzed through the analytical procedures of atomic absorption spectrophotometry. The cations were present in the descending order of magnesium > sodium > calcium > potassium and anions as bicarbonate > sulfate > chloride. Two parameters (bicarbonate and total dissolved solids) were above and other physicochemical indices of groundwater were below the threshold limits of the WHO. Positive correlations of pH and electrical conductivity were observed with cations and anions. The significant positive correlation between sodium and bicarbonate (0.427) indicated the dissolution of carbonate rocks. The concentration of heavy metals (Cu, Cd, Mn, Cr, Pb, Fe, Zn, and Ni) ranged from 0.1 to 0.4, 0.02 to 0.09, 0.04 to 0.9, 0.03 to 0.5, 0.01 to 0.91, 0.05 to 1.30, 0.01 to 0.60, and 0.02 to 0.90 mg/L. The highest concentration of Pb (0.21 mg/L) and Cd (0.16 mg/L) were approximately 20 and 50 times higher than the permissible limits of the WHO. Hierarchical cluster analysis classified the twelve physicochemical parameters into four clusters and the eight heavy metals into seven clusters. Principal component analysis extracted eight latent components for physicochemical properties and heavy metals with eigenvalues greater than 1.0 that had positive loads of fluoride, iron, electrical conductivity, sodium, cadmium, and sulfate. Major pollutants in the groundwater were accounted for by PC 1, and the main factors that affected the water quality were Pb, Cr, and Cu. Fe had a modest impact on the water quality in this region. From the findings, it can be concluded that the coastal groundwater of the region has a higher concentration of heavy metals, which makes it unfit for drinking purposes.

PSUN61 Primary Aldosteronism Presenting as Chronic Hypokalemia in a Normotensive Patient

Abstract Introduction Conn first described the hallmark features of primary aldosteronism (PA) as a state of aldosterone excess in the setting of hypertension and hypokalemia. Recent work has shed light on a wide spectrum of disease that likely includes normotensive patients with elevated aldosterone and suppressed renin. Mineralocorticoid excess appears to be the main driver of disease progression; however, it is not known whether individual differences in intra-arterial plasticity and effective sodium potassium exchange alter the overt clinical presentation. Here, we describe a patient with chronic hypokalemia and normal blood pressure with the diagnosis of a unilateral aldosterone-producing adenoma. Clinical Case A 47-year-old woman with no significant medical history was referred to endocrinology for evaluation of isolated hypokalemia since 2012. Her potassium was 2.8mEq/L at its lowest a month prior to her visit and had numerous other values less than 3.5mEq/L over the past 10 years. She did not carry a diagnosis of hypertension nor was she hypertensive at the time of her initial and subsequent evaluations. Results on initial endocrinology evaluation demonstrated a potassium of 3.2mEq/L (3.5-5.0mEq/L), Plasma Aldosterone Concentration (PAC) of 29ng/dL (≤21ng/dL), Plasma Renin Activity (PRA) of 0.42ng/mL/h (0.25-5.82ng/mL/h), and Aldosterone Renin Ratio (ARR) of 69. PA was suspected based on hypokalemia with an ARR >30 and PAC >20ng/dL. Further work-up was pursued to confirm the diagnosis as the patient did not have hypertension. She underwent 3-day oral sodium loading. 24-hour urine collection at the conclusion revealed adequate sodium loading with a urine sodium content of 208mEq/24hr (>200mEq/24hr) and aldosterone secretion of 41.3mcg/24hr (<12mcg/24hr). She subsequently underwent a CT abdomen demonstrating a 1.3×0.8 cm right adrenal nodule. Adrenal venous sampling was performed (continuous cosyntropin infusion with simultaneous adrenal venous sampling) which revealed a cortisol-corrected aldosterone lateralization ratio (right to left) of 406 at -5 minutes, 368 at 0 minutes, 33 at 10 minutes and 85 at 15 minutes. Results were consistent with strong lateralization to the right with contralateral suppression. Diagnosis of a right-sided aldosterone-producing adenoma was confirmed and she was referred to surgery for right adrenalectomy. Conclusion This case highlights one of the many presentations of PA. The persistent hypokalemia for a decade suggests a history of longstanding untreated PA prior to eventual diagnosis, yet the patient has remained normotensive. Though normotensive PA is a recognized entity, most patients develop hypertension within 5 years. The ability to remain normotensive despite intravascular volume expansion may highlight the patient's highly compliant vasculature and kidneys that have likely adapted to excrete high sodium loads in the setting of sodium excess. This case emphasizes that isolated hypokalemia in patients without hypertension should prompt consideration of PA and that patients with PA may maintain normotension for multiple years. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

OR20-3 Characterization of the Pathophysiologic Spectrum of Subclinical Primary Aldosteronism in Normotension

Abstract Context Accumulating evidence suggests that primary aldosteronism can manifest across a broad phenotypic spectrum and that its origins can at times be detected among normotensive individuals. Herein, we conducted deep-phenotyping studies to interrogate the pathophysiologic continuum of the primary aldosteronism phenotype among normotensive participants. Methods Normotensive participants with obesity, metabolic syndrome, and/or high-normal untreated blood pressure underwent dietary sodium loading and restriction protocols (to maximally suppress and stimulate angiotensin II-mediated aldosterone production), dexamethasone suppression and cosyntropin stimulation protocols (to maximally suppress and stimulate ACTH-mediated aldosterone production), and 24h ambulatory blood pressure monitoring. Measurement of aldosterone and 18-hybrid steroids via LC-MS/MS was conducted to quantify the degree of dysregulated CYP11B2 expression. Urinary extracellular vesicles (uEV) were isolated to measure renal tubular protein content associated with mineralocorticoid receptor activation. In order to characterize parameters across the severity spectrum of non-suppressible and renin-independent aldosterone production, participants with suppressed renin activity were categorized by tertile of 24h urinary aldosterone production following oral sodium suppression testing. Repeated measures linear mixed models were used to analyze trends for each parameter across tertiles of autonomous aldosterone production; for ease of presentation, the mean [SD] of the first vs. third tertile are presented for selected parameters. Results Following oral sodium loading, greater non-suppressible renin-independent aldosterone production was associated with greater kaliuresis, higher daytime ambulatory systolic blood pressure within the normal range, and a progressive impairment in the ability to suppress production of serum aldosterone (P-trend=0.009), 18-hydroxycorticosterone (9.3 [5.0] vs. 19.6 [6.5] ng/dL, P-trend=0.004), 18-hydroxycortisol (45.0 [25.4] vs. 70.9 [29.9] ng/dL, P-trend=0.03), and 18-oxocortisol (1.2 [0.03] vs. 3.4 [7.2], P-trend=0.01). Similarly, following dexamethasone suppression testing, there was a progressive inability to suppress 18-hydroxycorticosterone (8.3 [5.0] vs. 15.4 [8.2] ng/dL, P-trend=0.004), 18-hydroxycortisol (6.6 [3.8] vs. 10.2 [3.6] ng/dL, P-trend=0.03), and 18-oxocortisol (1.2 [0.01] vs. 1.4 [0.6] ng/dL, P-trend=0.01) in parallel with greater renin-independent aldosterone production. In contrast, following stimulation with cosyntropin, greater non-suppressible and renin-independent aldosterone production was associated with progressively enhanced production of 18-hydroxycorticosterone (77.6 [25.4] vs. 121.1 [31.1] ng/dL, P-trend=0.004), 18-hydroxycortisol (68.5 [28.4] vs. 86.2 [26.3] ng/dL, P-trend=0.03), and 18-oxocortisol (3.2 [2.8] vs. 7.3 [3.5] ng/dL, P-trend=0.01). Excretion of uEV's of pendrin (P=0.002) and aquaporin 2 (P=0.002) all increased with greater non-suppressible aldosterone production. Conclusions Dynamic phenotyping studies in normotensive individuals demonstrate a continuum of non-suppressible and renin-independent aldosterone production that parallels higher blood pressure, greater kaliuresis, increased 18-hybrid steroid production indicative of dysregulated CYP11B2 expression, and increased uEV excretion indicative of renal mineralocorticoid receptor activation. This pathophysiologic continuum of normotensive primary aldosteronism provides phenotypic support for histopathology studies showing ectopic CYP11B2 expression within adrenal glands of normotensive humans, and for epidemiologic studies demonstrating renin-independent aldosterone production in normotensive populations increases risk for developing hypertension. Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.

Abstract 122: Effect Of Tie2-cre Endothelial Caveolin-1 Deficiency Mice On Murine Cardiovascular And Metabolic Phenotypes

In humans, caveolin-1 (cav-1) gene polymorphisms confer a metabolic syndrome (MetS) phenotype and higher aldosterone (Aldo) levels. Further, global cav-1 knock out (KO) mice recapitulate the MetS phenotype, with both cardiovascular (CV) and metabolic dysfunction. We have shown that vascular dysfunction in the cav-1 KO is dissociated from the metabolic phenotype and is mediated by an endothelial crosstalk between cav-1 and the Aldo-mineralocorticoid receptor (MR) signaling pathway. Hence, we hypothesized endothelial cav-1 deficiency in mice is a major contributor to CV (but not metabolic) dysfunction.To assess this hypothesis, we generated Tie-2 mediated endothelium-specific cav-1 KO (ECKO) and appropriate genetic wild type (WT) control mice and studied their metabolic and CV traits in response to 1) changes in dietary salt intake (0.03% (LS) vs. 1.6% Na + (HS)) and 2) 3-weeks of Aldo infusion (200μg/kg/day) during sodium loading. Our results showed no difference in glucose, lipids and HOMA-IR in ECKO vs. WT mice, irrespective of the dietary intervention. However, on a HS (but not a LS) diet, ECKO vs. WT mice displayed similar CV dysfunction as previously shown in the full cav-1 KO: increased Aldo levels (73.7±11.1 vs 47.8±4.7ng/dl, p<0.05) and systolic BP (116.4±1.5 vs111±1.4 mmHg, p<0.015). Further, ECKO vs. WT mice had increased cardiac MR, eNOS, PAI-1 and CD68 expression (p<0.05 for each) as well as left ventricular hypertrophy (echocardiogram, p<0.05). In addition, 3-week HS diet led to higher albuminuria (p<0.05) and kidney/body weight ratios in ECKO vs. WT (7.2±0.2 vs 6.3±0.1). Surprisingly, as compared to placebo, Aldo infusion induced significant CV and renal damage only in the WT, but not in the ECKO. However, as compared to WT, Aldo infused ECKO had increased cardiac hypertrophy (5.9±0.2 vs 5.2±0.1) and molecular markers noted above (p<0.05 for each).In conclusion, lack of endothelial cav-1 in the mouse segregated the metabolic and CV phenotypes, and the associated CV phenotype resembles that described for the global cav-1 KO. Further, the CV and renal damage in the ECKO at baseline cannot be further enhanced by Aldo infusion. These data confirm our hypothesis that endothelial cav-1 is a major player in CV but not metabolic homeostasis.

Sudden Infant Death Syndrome, Pulmonary Edema, and Sodium Toxicity: A Grounded Theory.

Sudden Infant Death Syndrome (SIDS) occurs unexpectedly in an otherwise healthy infant with no identifiable cause of death following a thorough investigation. A general hypervolemic state has been identified in SIDS, and fluid in the lungs suggests the involvement of pulmonary edema and hypoxia as the cause of death. The present perspective paper reviews pathophysiological, epidemiological, and dietary evidence in SIDS. A grounded theory is presented that proposes an association of SIDS with sodium toxicity from excessive sodium chloride intake, mediated by noncardiogenic pulmonary edema, hypoxia, and alveolar damage. The peak of SIDS cases occurs in infants 2–4 months of age, who are less efficient in excreting excessive dietary sodium load. Evidence implicating sodium toxicity in SIDS includes increased levels of sodium associated with fever and with inflammatory/immune responses in the lungs. Conditions in near-miss SIDS cases are linked to dysregulated sodium, and increased sodium dietary intake suggests that sodium toxicity from a high-salt diet potentially mediates the association of seasonality and socioeconomic status with SIDS incidence. In addition, exposure to sodium toxicity meets three main criteria of the triple risk model of SIDS. The proposed pathophysiological effects of pulmonary edema related to sodium toxicity in SIDS merit further investigations.

Salt, Not Always a Cardiovascular Enemy? A Mini-Review and Modern Perspective.

Dietary salt intake is a long-debated issue. Increased sodium intake is associated with high blood pressure, leading to salt-sensitive hypertension. Excessive salt intake leads to arterial stiffness in susceptible individuals via impaired nitric oxide action and increased endothelin-1 expression, overactivity of the renal sympathetic nervous system and also via aldosterone-independent activation of the mineralocorticoid receptor. Salt restriction in such individuals reduces blood pressure (BP) values. The optimal level of salt restriction that leads to improved cardiovascular outcomes is still under debate. Current BP and dietary guidelines recommend low sodium intake for the general population. However, a specific category of patients does not develop arterial hypertension in response to sodium loading. In addition, recent research demonstrates the deleterious effects of aggressive sodium restriction, even in heart failure patients. This mini review discusses current literature data regarding the advantages and disadvantages of salt restriction and how it impacts the overall health status.

Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness

In septic mice, 3-hydroxybutyrate-sodium-salt has shown to partially prevent sepsis-induced muscle weakness. Although effective, the excessive sodium load was toxic. We here investigated whether ketone ester 3-hydroxybutyl-3-hydroxybutanoate (3HHB) was a safer alternative. In a mouse model of abdominal sepsis, the effects of increasing bolus doses of 3HHB enantiomers on mortality, morbidity and muscle force were investigated (n = 376). Next, plasma 3HB- clearance after bolus d-3HHB was investigated (n = 27). Subsequently, in septic mice, the effect on mortality and muscle force of a continuous d,l-3HHB infusion was investigated (n = 72). In septic mice, as compared with placebo, muscle force was increased at 20 mmol/kg/day l-3HHB and at 40 mmol/kg/day d- and d,l-3HHB. However, severity of illness and mortality was increased by doubling the effective bolus doses. Bolus 3HHB caused a higher 3HB− plasma peak and slower clearance with sepsis. Unlike bolus injections, continuous infusion of d,l-3HHB did not increase severity of illness or mortality, while remaining effective in improving muscle force. Treatment of septic mice with the ketone ester 3HHB partly prevented muscle weakness. Toxicity of 3HHB administered as bolus was completely avoided by continuous infusion of the same dose. Whether continuous infusion of ketone esters represents a promising intervention to also prevent ICU-acquired weakness in human patients should be investigated.

Glucocorticoids Promote Na+ Excretion in the Renal Epithelia of Heart Failure Rats by Suppressing Transporter Proteins Involved in Acute Sodium Loading.

Glucocorticoid receptors are essential for normal development and stress responses. Their role in H 2 O and Na + metabolism, especially in chronic heart failure (CHF), is not well defined. In a previous study, we found that glucocorticoids potentiate urination in CHF and promote H 2 O excretion by inhibiting the vasopressin receptor 2 pathway. The present study examines the effect of glucocorticoids on renal Na + excretion and the underlying mechanisms in CHF rats with acute sodium loading. CHF was induced by left coronary artery ligation for 8 weeks. Rats were randomly assigned to 5 groups: control, CHF, dexamethasone (DEX)-administered CHF, DEX-administered CHF treated with RU486 (mifepristone, a glucocorticoid receptor antagonist), and RU486-treated CHF. An acute sodium loading test was performed 6 hours after DEX administration. Blood and urine samples were collected, and hemodynamics were measured. The expression and localization of Na + transporter proteins were determined by immunoblotting and immunohistochemistry. DEX increased the urine volume and urinary sodium and improved cardiac function and the estimated glomerular filtration rate in CHF rats. The upregulation of the epithelial sodium channel β and γ subunits, Na-K-2Cl cotransporter, serum glucocorticoid-regulated kinase 1 (SGK1), and Na + /K + -ATPase in the renal epithelium of CHF rats was downregulated by DEX. These beneficial effects were abolished by RU486. The expression of natriuretic peptide receptor A was opposite that of the above proteins. Glucocorticoids might induce profound natriuresis in CHF rats during acute sodium loading, which is associated with downregulating some Na + transporter proteins in the renal epithelium and improving intrarenal hemodynamics.

Sodium supply from administered blood products was associated with severe intraventricular haemorrhage in extremely preterm infants.

AimThe aim of this study was to investigate the associations between sodium supply, fluid volume, sodium imbalances and severe intraventricular haemorrhage (IVH) in extremely preterm (EPT) infants.MethodsWe used data from the EXtremely PREterm infants in Sweden Study (EXPRESS) cohort consisting of all infants born at 22 to 26 gestational weeks from 2004 to 2007 and conducted a nested case–control study. For every infant with severe IVH (grade 3 or peri‐ventricular haemorrhagic infarction), one IVH‐free control infant with the birthday closest to the case infant and matched for hospital, sex, gestational age and birth weight was selected (n = 70 case–control pairs).ResultsTotal sodium supply and fluid volume were higher in infants with severe IVH compared with controls [daily total sodium supply until postnatal Day 2: mean ± SD (mmol/kg/day): 5.49 ± 2.53 vs. 3.95 ± 1.91, p = 0.009]. These differences were accounted for by sodium and fluid from transfused blood products. High plasma sodium concentrations or large sodium fluctuations were not associated with severe IVH.ConclusionOur results suggest a relationship between sodium‐rich transfusions of blood products and severe IVH in EPT infants. It is unclear whether this is an effect of sodium load, volume load or some other transfusion‐related factor.

SALT-SENSITIVITY IN HEALTHY NORMOTENSIVE MEN IS ASSOCIATED WITH IMPAIRED BAROREFLEX SENSITIVITY

Objective: Blood pressure (BP) responses to Na+ intake show great variability, discriminating sodium sensitive (SS) from salt resistant (SR) individuals. The pathophysiology behind salt-sensitivity is still not fully elucidated. A pivotal role for the sympathetic nervous system to BP increase after sodium loading is suggested. Therefore, we aimed to investigate the effect of the sympathovagal balance on Na+-induced BP effects and if Na+-induced effects on sympathetic activation contribute to salt-sensitivity. Design and method: We performed a randomized cross-over study in 31 young healthy men with normal BMI and eGFR. Subjects followed both an 8-day low Na+ diet (LSD, < 50mmol/d) and high Na+ diet (HSD, > 200mmol/d), in 18 subjects the diets were extended to 14-days. SS was defined as an increase of three or more mmHg standardized measured office MAP after HSD. Cardiac-output (CO) and cross correlation baroreflex sensitivity (xBRS) were measured with continuous non-invasive finger photoplethysmography. Systemic vascular resistance (SVR) was calculated as the ratio of MAP by CO. Results: After HSD, SS men (19%) showed a mean 6.2 (±2.1 SD) mmHg increase in MAP. No absolute differences in Na+-induced effects on CO and SVR could be observed between groups. After HSD, xBRS was 34% lower in SS men compared to SR men (Fig1A). Sodium loading resulted in a mean xBRS decrease of 3.4 (±6.5 SD) ms/mmHg in SS men, whilst xBRS increased with 2.3 (±6.3 SD) ms/mmHg in SR men (p = 0.06). HSD xBRS values were significantly correlated with Na+-induced BP changes in the complete group when corrected for age and BMI (Fig1B). Conclusions: Salt-sensitivity of BP in young normotensive men seems to be predominantly driven by changes in sympathovagal balance. The significant correlation between xBRS and delta BP further suggests a continuous relation between sympathetovagal balance and salt exposure. Further studies are needed to unravel pathophysiological mechanisms underlying Na+-effects on sympathetic regulation.

MO1059: A Case Series of 2 Patients with Perdialytic Dialysis Headache: Is There a Role for Isonatremic Dialysis?

Abstract BACKGROUND AND AIMS Per-dialytic headache (PDH) is a frequent complication of hemodialysis (HD) and often a challenge for nephrologists. Its pathophysiology has been though to involve sodium and/or osmotic variation during HD session. We assess here the effect of an Automatic Individualized Sodium Module Management (Na Mngt module) embedded into the dialysis machine on the PHD of two patients. Na Mngt module assesses pre-dialytic plasma sodium concentration and measures it through all the HD duration. Na Mngt module automatically controls the sodium concentration of the dialysate fluid and limits the diffusive sodium load during the HD session. METHOD 2 women aged of 87 and 76 years consistently reported unbearable PDH and nausea during several Online-Hemodiafiltration (HDF) sessions. They did not present other possible causes of PHD, including migraine, nervous depression, disequilibrium syndrome, and arterial hypertension. We suspected that the PDH was favored by dialysis-induced high plasma osmolarity (conductivity) in both patients (conductivity: 135–140 and 138 mmol/L) and decided to put them on Na Mngt module to align the sodium concentration of the dialysate fluid with their predialytic plasma sodium concentration. RESULTS After Na Mngt's activation, The PDH observed in both patients disappeared almost instantly. For both patients ‘1’ and ‘2’, the evolution of the main dialysis parameters before and after Na Mngt activation where respectively: Dry Weight (patient1: 42/41 Kg; patient2: 61/60.5 Kg); Pre-dialysis Sodium (patient1: 131/133 mmol/L; patient2: 143/138 mmol/L); Conductivity (patient1: 135–140/136+/-4 mmol/l; patient2: 140/139 mmol/L); IDWG (patient1: 2.5/2, patient2: 2/1.8 Kg); UF (patient1: 2/1.5 L/session; patient2: 2/1.6 L/session); Diffusive sodium balance (patient1: 10/2 g/session; patient2: 8/0 g/session). The Fig. 1 depicts the evolution of pre- and post-dialysis plasma sodium concentration before and after Na Mngt module activation for patient 1. The Fig. 2 shows for patient 2 the conductivity of the dialysate (in blue) throughout the session compared to the plasma conductivity (in red) with activation of Na Mngt module: the diffusive Na transfer remained around 0 g during ALL the session. For Patient 2, the predialytic plasma Na + was 139 mmol/L, and total Na removed was 18.8 g for the entire session. To obtain these results the dialysis machine module adjusted the dialysate Na within the range of 140–144 mmol/L. CONCLUSION This case report suggests that the Na Mngt module controls the diffusive sodium transfer during HD, reduces sodium load, osmotic fluctuations, and prevents PHD. Na Mngt activation allows isonatremic prescription of sodium with less variation between pre- and post- dialysis plasma sodium concentrations and decreases diffusive Na when isonatremic mode is selected. ‘Patient 2’ shows (Fig. 2) that the Na Mngt tool set a dialysate conductivity slightly higher than Na plasma to obtain an iso-natremic profile. Further controlled clinical study are needed to confirm the effect of the Na Mngt tool on intradialytic (PDH, hypotension) and interdialytic (thirst, IDWG) symptoms.

MO093: Dietary Sodium Restriction Reduces Nocturnal Blood Pressure in Treatment Resistant Hypertensive Patients

Abstract BACKGROUND AND AIMS High blood pressure (BP) is an essential contributor to the risk of cardiovascular disease (CVD) and death. Hence, diagnosing and treating patients with high BP is paramount if the number of cardiovascular related death should be reduced. High nocturnal BP and blunting of normal nocturnal BP decrease have stronger correlation to the risk of CVD than high day time BP. Lowering nocturnal BP is assumed to reduce the risk of CVD. Patients with treatment resistant hypertension (TRH) represent a subgroup of hypertensive patients characterized by lack of BP control despite antihypertensive treatment. These patients are at particular risk of CVD and target organ damage. Patients with TRH are more likely to experience BP increase as a response to sodium loading than other individuals. Lifestyle modification is an important treatment angle in hypertensive patients. It is, in particular, central to reduce sodium intake, as high sodium intake increases the risk of TRH. Thus, in this study we aimed to analyse if self-performed dietary sodium restriction could be implemented in patients with TRH. Moreover, we aimed to analyse the effect of this attempted restriction on nocturnal BP and 24 h BP, on plasma levels of BNP and nitric oxide, and on body water content. METHOD Patients with TRH from 20 to 70 years with normal renal function were invited for participation in this cross-over interventional study. Patients were screened with 24 h ambulatory BP monitoring initiated after observed intake of usual antihypertensive medication, and they were included if 24 h systolic BP/diastolic BP ≥ 130/80 mmHg. Study participation included two periods of 14 days; a standard period with usual diet and an interventional period with instructed dietary sodium restriction and handed-out sodium-reduced bread. For both periods, all antihypertensive medication was dosed and handed out and ingested in the morning. At the end of each period, patients were examined with 24 h BP monitoring, 24 h urine collection (sodium excretion), blood samples (nitric oxide and BNP) and bioimpedance measurement (body water content). RESULTS Baseline characteristics of the fifteen included patients are shown in Table 1. Eleven of the patients were male. Patients had been treated for hypertension for a mean of 12.5 (7) years and excreted a mean of 11.2 grams of salt at baseline [192 (86) mmol sodium]. All patients but one reduced sodium excretion at follow up. Table 2 shows the effect of sodium restriction on BP, nitric oxide, BNP and body water content. Sodium excretion was reduced to 91 mmol/24 h, which equals 5.3 g of salt. BP (24 h, day and nocturnal) decreased significantly as well as body water content and plasma levels of BNP. These changes were, however, not correlated. Plasma levels of nitric oxide increased, but it was not related to the changes in BP. Nocturnal fraction of 24 h sodium excretion increased after sodium restriction; however, this was not correlated to changes in nocturnal BP. Renal function and urinary potassium excretion both remained unchanged. Four patients experienced side effects; three reported newly onset dizziness at follow-up; two of them had 24 h BP reduction > 10 mmHg systolic. One patient had increased creatinine and potassium at follow-up. CONCLUSION In a population of 15 treatment resistant hypertensive patients, we demonstrated that self-performed dietary sodium restriction could be implemented. Urinary sodium excretion was reduced significantly to 5.3 g/24 h. Nocturnal BP was reduced significantly; dipping status was, however, unchanged. Increased plasma levels of nitric oxide may be evidence of improved endothelial function. Hence, by the local vasodilating effect, NO may be one of the involved mechanisms in BP decrease following a sodium restriction. Reduced extracellular water content and BNP may be other explainable effects of BP reduction after inducing sodium restriction.

Medullary overexpression of sphingosine‐1‐phosphate receptor 1 transgene attenuates sodium retention and hypertension in deoxycorticosterone acetate (DOCA) salt‐treated mice

Our previous studies have showed that sphingosine‐1‐phosphate (S1P) agonist stimulates urinary sodium excretion and the S1P type 1 receptor (S1PR1) knockout in the collecting duct led to increased sodium retention and enhanced salt‐sensitive hypertension under the treatment of deoxycorticosterone (DOCA) and high salt. We hypothesized that the increase in medullary S1PR1 would attenuate sodium retention by promoting sodium excretion in such model. Male C57BL/6J mice around 25g bodyweight received intramedullary transfection of S1PR1 plasmids to achieve renal medullary S1PR1 overexpression (OE). The mice were then implanted with the silastic DOCA sheet subcuntaneously and 1% NaCl drinking water to induce salt‐sensitive hypertension (SS‐HTN). Thereafter, the mice underwent either acute or chronic assessments on blood pressure and urinary sodium excretion. Under DOCA‐salt challenge, mice with S1PR1‐OE showed increased urine volume (UV) and urinary sodium excretion (UNAV) in responses to the acute sodium loading (IV of normal saline at 5% body weight in 30 min); the UV and UNAV were 12.51±2.31 vs. 28.50±4.23mL/min/gKW and 0.93±0.27 vs. 4.72±1.12mmole/min/gKW (p<0.05) in control and S1PR1‐OE mice, respectively. The mice with S1PR1‐OE also showed enhanced pressure natriuretic responses (UV, 18.73±7.57 vs. 40.61±6.43mL/min/gKW, p<0.05; UNAV, 3.58±1.77 vs. 9.52±1.38nmole/min/gKW, p<0.05). In the long‐term DOCA‐salt treatment, S1PR1‐OE mice showed less daily sodium balance with the greater sodium excretion (2.72±0.56 vs. 5.60±0.72mmole/day, p<0.05) and ameliorated sodium retention (3.05±0.39 vs. 1.65±0.39mmole/72hr, p<0.05), which was accompanied with the attenuation of SS‐HTN (SBP 134.2±6.79 vs. 109.8±3.54mmHg, p<0.05). The level of alpha subunit of epithelial sodium channel (αENaC) was not changed. However, the beta subunit (βENaC) was significantly decreased (55%, p<0.01). Although ENaCγ was significantly increased (350%) in the S1PR1‐OE group, immunostaining showed that the DOCA‐stimulated translocation of γENaC onto the apical membrane was inhibited. These results suggested that the overexpression of S1PR1 in the renal medulla attenuates sodium retention by the inhibition of ENaC function in the DOCA‐induced SS‐HTN.

Tissue Sodium Accumulation: Pathophysiology and Clinical Implications.

Excessive sodium intake has been well established as a risk factor for the development and progression of cardiovascular and renal diseases. Its adverse effects are achieved by renal sodium retention and related volume expansion and by inducing low-grade inflammation and oxidative stress (OS) in the target tissues. This review presents the recent concept of nonosmotic sodium storage in the skin interstitium, the subsequent dissociation of sodium and volume homeostasis, and the cellular response to the increased tissue sodium concentration. Furthermore, data are shown on the sodium barrier and buffering potential of the endothelial glycocalyx that may protect the functional integrity of the endothelium when it is challenged by an increased sodium load. Finally, examples will be given of the involvement of oxygen free radicals (OFR) in sodium-induced tissue damage, and some clinical entities will be mentioned that are causally associated with sodium/volume retention and OS.

Endothelial Cullin3 Mutation Impairs Nitric Oxide-Mediated Vasodilation and Promotes Salt-Induced Hypertension.

Human hypertension caused by in-frame deletion of CULLIN3 exon-9 (Cul3∆9) is driven by renal and vascular mechanisms. We bred conditionally activatable Cul3∆9 transgenic mice with tamoxifen-inducible Tie2-CREERT2 mice to test the importance of endothelial Cul3. The resultant mice (E-Cul3∆9) trended towards elevated nighttime blood pressure (BP) correlated with increased nighttime activity, but displayed no difference in daytime BP or activity. Male and female E-Cul3∆9 mice together exhibited a decline in endothelial-dependent relaxation in carotid artery. Male but not female E-Cul3∆9 mice displayed severe endothelial dysfunction in cerebral basilar artery. There was no impairment in mesenteric artery and no difference in smooth muscle function, suggesting the effects of Cul3∆9 are arterial bed-specific and sex-dependent. Expression of Cul3∆9 in primary mouse aortic endothelial cells decreased endogenous Cul3 protein, phosphorylated (S1177) endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. Protein phosphatase (PP) 2A, a known Cul3 substrate, dephosphorylates eNOS. Cul3∆9-induced impairment of eNOS activity was rescued by a selective PP2A inhibitor okadaic acid, but not by a PP1 inhibitor tautomycetin. Because NO deficiency contributes to salt-induced hypertension, we tested the salt-sensitivity of E-Cul3∆9 mice. While both male and female E-Cul3∆9 mice developed salt-induced hypertension and renal injury, the pressor effect of salt was greater in female mutants. The increased salt-sensitivity in female E-Cul3∆9 mice was associated with decreased renovascular relaxation and impaired natriuresis in response to a sodium load. Thus, CUL3 mutations in the endothelium may contribute to human hypertension in part through decreased endothelial NO bioavailability, renovascular dysfunction, and increased salt-sensitivity of BP.

Re-Assessment of the Oral Salt Loading Test Using a New Chemiluminescent Enzyme Immunoassay Based on a Two-Step Sandwich Method to Measure 24-Hour Urine Aldosterone Excretion.

Since April 2021, the plasma aldosterone concentration has been measured by chemiluminescent enzyme immunoassay (CLEIA) in Japan. In the present study, we developed a new CLEIA using a two-step sandwich method to measure the 24-hour urine aldosterone level. We collected 115 urine samples and measured 24-hour urine aldosterone levels employing radioimmunoassay (RIA), CLEIA, and liquid chromatography–tandem mass spectrometry (LC-MS/MS). The results showed that the 24-hour urine aldosterone levels measured using CLEIA and LC-MS/MS were significantly correlated (ρ = 0.992, P < 0.0001). Based on the results of Passing–Bablok regression analysis, the slope was 0.992 and the intercept –19.3. The 24-hour urine aldosterone levels measured using CLEIA and RIA were also significantly correlated (ρ = 0.905, P < 0.0001). However, the aldosterone level measured by CLEIA was lower than that measured by RIA (slope, 0.729; intercept, 120.9). In Japan, a new guideline for primary aldosteronism has been announced, with changes in the aldosterone measurement method. The cutoff values for oral sodium loading test (OSLT) were changed, but clinical verification using real-world urine samples has not been performed. Therefore, we examined the cut-off value of the 24-hour urine aldosterone level after the OSLT. Receiver operating characteristic analysis revealed a cut-off value for primary aldosteronism of 3 μg/day.

Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach.

Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium–proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium–calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.

Reversal of Trimethoprim-Induced Antikaliuresis in an HIV Patient With Pneumocystis Pneumonia

Abstract High-dose trimethoprim-sulfamethaxazole is the drug of choice for treatment of severe Pneumocystis jiroveci pneumonia (PJP) with the caveat that at higher doses, serious adverse events occur more frequently. A lethal complication is hyperkalemia which often mandates premature discontinuation of therapy despite lower efficacy of second-line agents. We report a case of a patient with severe PJP causing respiratory failure treated with high-dose trimethoprim-sulfamethaxazole who experienced hyperkalemia, which was successfully managed with a combination of fludrocortisone and furosemide allowing completion of antibiotic course. Administration of fludrocortisone and furosemide may enable practitioners to effectively address trimethoprim-induced hyperkalemia in critically ill patients with PJP. We speculate that exogenous administration of fludrocortisone may promote transcription of ENaC-amiloride sensitive epithelial sodium channels, which is unaffected by circulating trimethoprim allowing for kaliuresis to be restored. The addition of furosemide increases sodium load, further promoting potassium excretion.