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Introduction: Long-term sodium balance studies show that sodium can be temporarily stored and released in tissues, mediated by circaseptan rhythms of aldosterone and cortisol. This complicates the reliability of a single 24-h urine collection to estimate individual sodium intake. We investigated whether repeated timed urine collection with and without correction for plasma aldosterone is a more accurate alternative for estimating daily sodium intake., Methods: We conducted a post hoc analysis of a metabolic ward study in which 16 healthy male adults consumed a diet with a fixed sodium content (50 or 200 mmol/day) for 7 days. Each day, urine was collected in 4 intervals (7:00-13:00 h, 13:00-19:00 h, 19:00-23:00 h, and 23:00-07:00 h). Plasma aldosterone was measured at 6:30 h, 12:30 h, and 18:30 h. Sodium intakes were estimated by various formulas using 3 timed urines of day 5-7., Results: During a 200-mmol daily sodium intake, sodium intake estimates based on three repeated timed urine samples and the Toft equation differed 10 [IQR: 3-14], 8 [6-19], 36 [16-49], and 20 [10-43] mmol from the actual intake for intervals 7:00-13:00 h, 13:00-19:00 h, 19:00-23:00 h, 23:00-7:00 h, respectively. These measurements did not significantly differ from a single 24-h urine (20 [12-55] mmol). During a 50-mmol daily sodium intake, repeated timed urine collection performed worse than a single 24-h urine collection. On both diets, correction for plasma aldosterone increased accuracy and sodium intake estimates were significantly more accurate than a single 24-h urine., Conclusion: In a controlled environment, repeated timed urine collection corrected for plasma aldosterone is more accurate than a single 24-h urine collection., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Blood pressure (BP) responses to sodium intake show great variation, discriminating salt-sensitive (SS) from salt-resistant (SR) individuals. The pathophysiology behind salt sensitivity is still not fully elucidated. We aimed to investigate salt-induced effects on body fluid, vascular tone, and autonomic cardiac response with regard to BP change in healthy normotensive individuals. We performed a randomized crossover study in 51 normotensive individuals with normal body mass index and estimated glomerular filtration rate. Subjects followed both a low-Na + diet (LSD, <50 mmol/day) and a high-Na + diet (HSD, >200 mmol/day). Cardiac output, systemic vascular resistance (SVR), and cardiac autonomous activity, through heart rate variability and cross-correlation baroreflex sensitivity (xBRS), were assessed with noninvasive continuous finger BP measurements. In a subset, extracellular volume (ECV) was assessed by iohexol measurements. Subjects were characterized as SS if mean arterial pressure (MAP) increased ≥3 mmHg after HSD. After HSD, SS subjects (25%) showed a 6.1-mmHg (SD 1.9) increase in MAP. No differences between SS and SR in body weight, cardiac output, or ECV were found. SVR was positively correlated with Delta BP ( r = 0.31, P = 0.03). xBRS and heart rate variability were significantly higher in SS participants compared to SR participants after both HSD and LSD. Sodium loading did not alter heart rate variability within groups. Salt sensitivity in normotensive individuals is associated with an inability to decrease SVR upon high salt intake that is accompanied by alterations in autonomous cardiac regulation, as reflected by decreased xBRS and heart rate variability. No discriminatory changes upon high salt were observed among salt-sensitive individuals in body weight and ECV. NEW & NOTEWORTHY Extracellular fluid expansion in normotensive individuals after salt loading is present in both salt-sensitive and salt-resistant individuals and is not discriminatory to the blood pressure response to sodium loading in a steady-state measurement. In normotensive subjects, the ability to sufficiently vasodilate seems to play a pivotal role in salt sensitivity. In a normotensive cohort, differences in sympathovagal balance are also present in low-salt conditions rather than being affected by salt loading. Whereas treatment and prevention of salt-sensitive blood pressure increase are mostly focused on renal sodium handling and extracellular volume regulation, our study suggests that an inability to adequately vasodilate and altered autonomous cardiac functioning are additional key players in the pathophysiology of salt-sensitive blood pressure increase.

Objectives: To evaluate the relationship among dysnatraemia at hospital presentation and duration of admission, risk of intensive care unit (ICU) admission and all-cause mortality and to assess the underlying pathophysiological mechanism of hyponatraemia in patients with COVID-19. Our hypothesis is that both hyponatraemia and hypernatraemia at presentation are associated with adverse outcomes., Design: Observational study., Setting: Secondary care; 11 Dutch hospitals (2 university and 9 general hospitals)., Participants: An analysis was performed within the retrospective multicentre cohort study COVIDPredict. 7811 patients were included (60% men, 40% women) between 24 February 2020 and 9 August 2022. Patients who were ≥18 years with PCR-confirmed COVID-19 or CT with COVID-19 reporting and data system score≥4 and alternative diagnosis were included. Patients were excluded when serum sodium levels at presentation were not registered in the database or when they had been transferred from another participating hospital., Outcome Measures: We studied demographics, medical history, symptoms and outcomes. Patients were stratified according to serum sodium concentration and urinary sodium excretion., Results: Hyponatraemia was present in 2677 (34.2%) patients and hypernatraemia in 126 (1.6%) patients. Patients with hyponatraemia presented more frequently with diarrhoea, lower blood pressure and tachycardia. Hyponatraemia was, despite a higher risk for ICU admission (OR 1.27 (1.11-1.46; p<0.001)), not associated with mortality or the risk for intubation. Patients with hypernatraemia had higher mortality rates (OR 2.25 (1.49-3.41; p<0.001)) and were at risk for ICU admission (OR 2.89 (1.83-4.58)) and intubation (OR 2.95 (1.83-4.74))., Conclusions: Hypernatraemia at presentation was associated with adverse outcomes in patients with COVID-19. Hypovolaemic hyponatraemia was found to be the most common aetiology of hyponatraemia. Hyponatraemia of unknown aetiology was associated with a higher risk for ICU admission and intubation and longer duration of admission., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although we have sent humans into space for more than 50 years crucial questions regarding kidney physiology, volume regulation and osmoregulation remain unanswered. The complex interactions between the renin-angiotensin-aldosterone system, the sympathetic nervous system, osmoregulatory responses, glomerular function, tubular function, and environmental factors such as sodium and water intake, motion sickness and ambient temperature make it difficult to establish the exact effect of microgravity and the subsequent fluid shifts and muscle mass loss on these parameters. Unfortunately, not all responses to actual microgravity can be reproduced with head-down tilt bed rest studies, which complicates research on Earth. Better understanding of the effects of microgravity on kidney function, volume regulation and osmoregulation are needed with the advent of long-term deep space missions and planetary surface explorations during which orthostatic intolerance complaints or kidney stone formation can be life-threatening for astronauts. Galactic cosmic radiation may be a new threat to kidney function. In this review, we summarise and highlight the current understandings of the effects of microgravity on kidney function, volume regulation and osmoregulation and discuss knowledge gaps that future studies should address., (© 2023. The Author(s).)

Background: Hereditary Multiple Exostoses (HME) is a rare autosomal disorder characterized by the presence of multiple exostoses (osteochondromas) caused by a heterozygous loss of function mutation in EXT1 or EXT2 ; genes involved in heparan sulfate (HS) chain elongation. Considering that HS and other glycosaminoglycans play an important role in sodium and water homeostasis, we hypothesized that HME patients have perturbed whole body volume regulation and osmolality in response to high sodium conditions., Methods: We performed a randomized cross-over study in 7 male HME patients and 12 healthy controls, matched for age, BMI, blood pressure and renal function. All subjects followed both an 8-day low sodium diet (LSD, <50 mmol/d) and high sodium diet (HSD, >200 mmol/d) in randomized order. After each diet, blood and urine samples were collected. Body fluid compartment measurements were performed by using the distribution curve of iohexol and 125 I-albumin., Results: In HME patients, HSD resulted in significant increase of intracellular fluid volume (ICFV) (1.2 L, p  = 0.01). In this group, solute-mediated water clearance was significantly lower after HSD, and no changes in interstitial fluid volume (IFV), plasma sodium, and effective osmolality were observed. In healthy controls, HSD did not influence ICFV, but expanded IFV (1.8 L, p  = 0.058) and increased plasma sodium and effective osmolality., Conclusion: HME patients show altered body fluid distribution and osmoregulation after HSD compared to controls. Our results might indicate reduced interstitial sodium accumulation capacity in HME, leading to ICFV increase. Therefore, this study provides additional support that HS is crucial for maintaining constancy of the internal environment., Competing Interests: All authors have read the journals policy on disclosure of potential conflicts of interest. There are no conflicts of interest to declare., (© 2021 The Authors.)

Background: By binding to negatively charged polysaccharides called glycosaminoglycans, sodium can be stored in the body-particularly in the skin-without concurrent water retention. Concordantly, individuals with changed glycosaminoglycan structure (e.g. type 1 diabetes (DM1) and hereditary multiple exostosis (HME) patients) may have altered sodium and water homeostasis., Methods: We investigated responses to acute (30-min infusion) and chronic (1-week diet) sodium loading in 8 DM1 patients and 7 HME patients in comparison to 12 healthy controls. Blood samples, urine samples, and skin biopsies were taken to investigate glycosaminoglycan sulfation patterns and both systemic and cellular osmoregulatory responses., Results: Hypertonic sodium infusion increased plasma sodium in all groups, but more in DM1 patients than in controls. High sodium diet increased expression of nuclear factor of activated t-cells 5 (NFAT5)-a transcription factor responsive to changes in osmolarity-and moderately sulfated heparan sulfate in skin of healthy controls. In HME patients, skin dermatan sulfate, rather than heparan sulfate, increased in response to high sodium diet, while in DM1 patients, no changes were observed., Conclusion: DM1 and HME patients show distinct osmoregulatory responses to sodium loading when comparing to controls with indications for reduced sodium storage capacity in DM1 patients, suggesting that intact glycosaminoglycan biosynthesis is important in sodium and water homeostasis. Trial registration These trials were registered with the Netherlands trial register with registration numbers: NTR4095 ( https://www.trialregister.nl/trial/3933 at 2013-07-29) and NTR4788 ( https://www.trialregister.nl/trial/4645 at 2014-09-12).

Lowering blood pressure (BP) can lead to an initial decline in estimated glomerular filtration rate (eGFR). However, there is debate how much eGFR decline is acceptable. We performed a post hoc analysis of ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial), which randomized patients to intensive or standard systolic BP-targets. We determined the relation between initial decline in mean arterial pressure and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR decline after 1 year. A total of 13 266 patients with 41 126 eGFR measurements were analyzed. Up to 10 mm Hg of BP-lowering, eGFR did not change. Hereafter, there was a linear decrease of 3.4% eGFR (95% CI, 2.9%-3.9%) per 10 mm Hg mean arterial pressure decrease. The observed eGFR decline based on 95% of the subjects varied from 26% after 0 mm Hg to 46% with a 40 mm Hg mean arterial pressure decrease. There was no difference in eGFR slope ( P =0.37) according to initial eGFR decline and BP-target, with a decrease of 1.24 (95% CI, 1.09-1.39), 1.20 (95% CI, 0.97-1.43), and 1.14 (95% CI, 0.77-1.50) in the 5%, 5% to 20%, and >20% stratum during intensive and 0.95 (95% CI, 0.81-1.09), 1.23 (95% CI, 0.97-1.49), and 1.17 (95% CI, 0.65-1.69) mL/minute per 1.73 m 2 per year during standard treatment. In patients at high cardiovascular risk with and without diabetes mellitus, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. Our results support that an eGFR decrease up to 20% after BP lowering can be accepted and suggest that the limit can be extended up to 46% depending on the achieved BP reduction. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000620, NCT01206062.

Introduction: Patients with type 1 diabetes are susceptible to hypertension, possibly resulting from increased salt sensitivity and accompanied changes in body fluid composition. We examined the effect of a high-salt diet (HSD) in type 1 diabetes on hemodynamics, including blood pressure (BP) and body fluid composition., Research Design and Methods: We studied eight male patients with type 1 diabetes and 12 matched healthy controls with normal BP, body mass index, and renal function. All subjects adhered to a low-salt diet and HSD for eight days in randomized order. On day 8 of each diet, extracellular fluid volume (ECFV) and plasma volume were calculated with the use of iohexol and 125 I-albumin distribution. Hemodynamic measurements included BP, cardiac output (CO), and systemic vascular resistance., Results: After HSD, patients with type 1 diabetes showed a BP increase (mean arterial pressure: 85 (5) mm Hg vs 80 (3) mm Hg; p<0.05), while BP in controls did not rise (78 (5) mm Hg vs 78 (5) mm Hg). Plasma volume increased after HSD in patients with type 1 diabetes (p<0.05) and not in controls (p=0.23). There was no significant difference in ECFV between diets, while HSD significantly increased CO, heart rate (HR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in type 1 diabetes but not in controls. There were no significant differences in systemic vascular resistance, although there was a trend towards an HSD-induced decrease in controls (p=0.09)., Conclusions: In the present study, patients with type 1 diabetes show a salt-sensitive BP rise to HSD, which is accompanied by significant increases in plasma volume, CO, HR, and NT-proBNP. Underlying mechanisms for these responses need further research in order to unravel the increased susceptibility to hypertension and cardiovascular disease in diabetes., Trial Registration Numbers: NTR4095 and NTR4788., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Glycosaminoglycans in the skin interstitium and endothelial surface layer have been shown to be involved in local sodium accumulation without commensurate water retention. Dysfunction of heparan sulfate glycosaminoglycans may therefore disrupt sodium and water homeostasis. In this study, we investigated the effects of combined heterozygous loss of heparan sulfate polymerization genes (exostosin glycosyltransferase 1 and 2; Ext1+/-Ext2+/-) on sodium and water homeostasis. Sodium storage capacity was decreased in Ext1+/-Ext2+/- mice as reflected by a 77% reduction in endothelial surface layer thickness and a lower skin sodium-to-glycosaminoglycan ratio. Also, these mice were characterized by a higher heart rate, increased fluid intake, increased plasma osmolality and a decreased skin water and sodium content, suggesting volume depletion. Upon chronic high sodium intake, the initial volume depletion was restored but no blood pressure increase was observed. Acute hypertonic saline infusion resulted in a distinct blood pressure response: we observed a significant 15% decrease in control mice whereas blood pressure did not change in Ext1+/-Ext2+/- mice. This differential blood pressure response may be explained by the reduced capacity for sodium storage and/or the impaired vasodilation response, as measured by wire myography, which was observed in Ext1+/-Ext2+/- mice. Together, these data demonstrate that defective heparan sulfate glycosaminoglycan synthesis leads to abnormal sodium and water homeostasis and an abnormal response to sodium loading, most likely caused by inadequate capacity for local sodium storage., Competing Interests: The authors have declared that no competing interests exist.

Background: Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects., Methods: Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min., Results: Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P < 0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g · h; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of I-labeled albumin (-0.03 [-3.3 to 3.2] % cpm · g · h; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading., Conclusions: Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.

Background: A decrease in sodium intake has been shown to lower blood pressure, but data from cohort studies on the association with cardiovascular and renal outcomes are inconsistent. In these studies, sodium intake was often estimated with a single baseline measurement, which may be inaccurate considering day-to-day changes in sodium intake and sodium excretion. We compared the effects of single versus repetitive follow-up 24-hour urine samples on the relation between sodium intake and long-term cardiorenal outcomes., Methods: We selected adult subjects with an estimated glomerular filtration rate >60 mL/min/1.73m 2 , an outpatient 24-hour urine sample between 1998 and 1999, and at least 1 collection during a 17-year follow-up. Sodium intake was estimated with a single baseline collection and the average of samples collected during a 1-, 5-, and 15-year follow-up. We used Cox regression analysis and the landmark approach to investigate the relation between sodium intake and cardiovascular (cardiovascular events or mortality) and renal (end-stage renal disease: dialysis, transplantation, and/or >60% estimated glomerular filtration rate decline, or mortality) outcomes., Results: We included 574 subjects with 9776 twenty-four-hour urine samples. Average age was 47 years, and 46% were male. Median follow-up was 16.2 years. Average 24-hour sodium excretion, ranging from 3.8 to 3.9 g (165-170 mmol), was equal among all methods ( P =0.88). However, relative to a single baseline measurement, 50% of the subjects had a >0.8-g (>34-mmol) difference in sodium intake with long-term estimations. As a result, 45%, 49%, and 50% of all subjects switched between tertiles of sodium intake when the 1-, 5-, or 15-year average was used, respectively. Consequently, hazard ratios for cardiorenal outcome changed up to 85% with the use of sodium intake estimations from short-term (1-year) and long-term (5-year) follow-up instead of baseline estimations., Conclusions: Relative to a single baseline 24-hour sodium measurement, the use of subsequent 24-hour urine samples resulted in different estimations of an individual's sodium intake, whereas population averages remained similar. This finding had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcomes., (© 2017 American Heart Association, Inc.)