Salt-sensitive trait of normotensive individuals is associated with altered autonomous cardiac regulation: a randomized controlled intervention study.

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.

Distinct osmoregulatory responses to sodium loading in patients with altered glycosaminoglycan structure: a randomized cross-over trial.

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).

Clinical impact of tissue sodium storage.

In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations.

Effects of Water Loading on Observed and Predicted Plasma Sodium, and Fluid and Urine Cation Excretion in Healthy Individuals.

RATIONALE & OBJECTIVE: The discovery of sodium storage without concurrent water retention suggests the presence of an additional compartment for sodium distribution in the body. The osmoregulatory role of this compartment under hypotonic conditions is not known. STUDY DESIGN: Experimental interventional study. SETTING & PARTICIPANTS: Single-center study of 12 apparently healthy men. INTERVENTION: To investigate whether sodium can be released from its nonosmotic stores after a hypotonic fluid load, a water-loading test (20mL water/kg in 20 minutes) was performed. OUTCOMES: During a 240-minute follow-up, we compared the observed plasma sodium concentration ([Na+]) and fluid and urine cation excretion with values predicted by the Barsoum-Levine and Nguyen-Kurtz formulas. These formulas are used for guidance of fluid therapy during dysnatremia, but do not account for nonosmotic sodium stores. RESULTS: 30 minutes after water loading, mean plasma [Na+] decreased 3.2±1.6 (SD) mmol/L, after which plasma [Na+] increased gradually. 120 minutes after water loading, plasma [Na+] was significantly underestimated by the Barsoum-Levine (-1.3±1.4mmol/L; P=0.05) and Nguyen-Kurtz (-1.5±1.5mmol/L; P=0.03) formulas. In addition, the Barsoum-Levine and Nguyen-Kurtz formulas overestimated urine volume, while cation excretion was significantly underestimated, with a cation gap of 57±62 (P=0.009) and 63±63mmol (P=0.005), respectively. After 240 minutes, this gap was 28±59 (P=0.2) and 34±60mmol (P=0.08), respectively. LIMITATIONS: The compartment from which the mobilized sodium originated was not identified, and heterogeneity in responses to water loading was observed across participants. CONCLUSIONS: These data suggest that healthy individuals are able to mobilize osmotically inactivated sodium after an acute hypotonic fluid load. Further research is needed to expand knowledge about the compartment of osmotically inactivated sodium and its role in osmoregulation and therapy for dysnatremias. FUNDING: This investigator-initiated study was partly supported by a grant from Unilever Research and Development Vlaardingen, The Netherlands B.V. (MA-2014-01914).

Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk.

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/1.73m2, 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.

Microvascular Permeability after an Acute and Chronic Salt Load in Healthy Subjects: A Randomized Open-label Crossover Intervention Study.

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.

Quantification of nonosmotic sodium storage capacity following acute hypertonic saline infusion in healthy individuals.

The assumption that sodium accumulation in the human body is always accompanied by water retention has been challenged by data showing that sodium can be stored nonosmotically. Here we investigated the contribution of nonosmotic sodium storage to short-term sodium homeostasis after hypertonic saline infusion in healthy individuals on a low-sodium diet. During four hours after infusion, we compared the observed changes in plasma sodium concentration and urinary cation excretion with changes that were calculated with the Adrogue-Madias and Nguyen-Kurtz formula, formulations widely implemented to guide the treatment of dysnatremias. We included 12 healthy non-smoking male individuals with normal blood pressure, body mass index, and kidney function. Right after infusion, the average observed plasma sodium change from baseline (3.5 mmol/L) was similar to the predicted changes by the Adrogue-Madias (3.3 mmol/L) and Nguyen-Kurtz formula (3.1 mmol/L). However, the observed plasma sodium concentration change after four hours (-1.8 mmol/L) was very different from the changes as predicted by the Adrogue-Madias (0.4 mmol/L) and the Nguyen-Kurtz formula (-0.9 mmol/L). Moreover, only 47% and 55%, respectively, of the expected sodium and potassium excretion were retrieved in the urine. Thus, healthy individuals are able to osmotically inactivate significant amounts of sodium after hypertonic saline infusion. Further research is needed to uncover factors that determine nonosmotic sodium storage.

Blood pressure-lowering effects of sulodexide depend on albuminuria severity: post hoc analysis of the sulodexide microalbuminuria and macroalbuminuria studies.

AIMS: It has been suggested that sulodexide is able to lower blood pressure (BP). This may be attributed to its ability to restore the endothelial surface layer (ESL). As ESL perturbation is known to be related to the degree of kidney damage, we investigated whether albuminuria, reflecting ESL status, modified the BP-lowering potential of sulodexide. METHODS: A post hoc analysis of the double-blind, randomized, placebo-controlled sulodexide microalbuminuria (Sun-MICRO) and macroalbuminuria (Sun-MACRO) studies, including 1056 microalbuminuric and 843 macroalbuminuric subjects with type 2 diabetes receiving maximal tolerated renin-angiotensin-aldosterone system inhibitor therapy, was carried out. We compared the effect of placebo and sulodexide on systolic BP (SBP) among albuminuria groups. RESULTS: Analysis of covariance, including data from both trials, showed that baseline urine albumin-to-creatinine ratio (UACR) was the only modifier of the SBP response (interaction with treatment P = 0.001). In subjects with an UACR >1000 mg g-1 , sulodexide lowered SBP by 4.6 mmHg [95% confidence interval (CI) 3.6, 5.6; P < 0.001] compared with placebo, whereas a 2.3 mmHg (95% CI 0.9,3.7; P = 0.001) reduction was seen in subjects with a UACR of 300-1000 mg g-1 . Sulodexide did not lower SBP in subjects with a UACR <300 mg g-1 (-0.2 mmHg, 95% CI -0.8, 0.5; P = 0.60). SBP-lowering effects were not accompanied by changes in body weight. CONCLUSION: The BP-reducing potency of sulodexide is modified by the degree of albuminuria in subjects with type 2 diabetes. As ESL status deteriorates with increasing albuminuria and nephropathy severity, this suggests that ESL restoration may represent a new target for BP treatment in subjects with diabetic nephropathy.

Role of the vascular wall in sodium homeostasis and salt sensitivity.

Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume.

The blood pressure lowering potential of sulodexide--a systematic review and meta-analysis.

AIMS: Sulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti-albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta-analysis, we therefore investigated the antihypertensive effects of sulodexide treatment. METHODS: We selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data. RESULTS: Eight studies, totalling 3019 subjects (mean follow-up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P < 0.001). Higher baseline systolic and diastolic BP were significantly associated with larger systolic (r(2)=0.83, P < 0.001) and diastolic BP (r(2)=0.41, P = 0.02) reductions after sulodexide treatment. In addition, systolic (r(2)=0.41, P = 0.03) and diastolic BP reductions (r(2)=0.60, P = 0.005) were significantly associated with albuminuria reduction. CONCLUSION: Our data suggest that sulodexide treatment results in a significant BP reduction, especially in hypertensive subjects. This indicates that endothelial glycosaminoglycans might be an independent therapy target in cardiovascular disease. Future studies should further address the BP lowering potential of sulodexide.

Microvascular glycocalyx dimension estimated by automated SDF imaging is not related to cardiovascular disease.

OBJECTIVE: The EG regulates vascular homeostasis and has anti-atherogenic properties. SDF imaging allows for noninvasive visualization of microvessels and automated estimation of EG dimensions. We aimed to assess whether microcirculatory EG dimension is related to cardiovascular disease. METHODS: Sublingual EG dimension was estimated by SDF imaging in healthy volunteers and in patients visiting an outpatient clinic for vascular medicine of a university hospital in Amsterdam, the Netherlands. EG dimension was compared among healthy volunteers, patients with CVD, and patients at low (<10%) or high risk (≥ 10%) of CVD according to the Framingham algorithm. RESULTS: In total 120 patients and 30 healthy volunteers were included. Patients had a mean age of 59 ± 14 years, 71 (59%) were men and 24 (20%) were black. Healthy volunteers were on average 28 ± 4 years and 19 (63%) were men. EG dimension was similar in healthy volunteers (2.04 ± 0.23 µm), low-risk patients (2.05 ± 0.24 µm, n = 39), high-risk patients (2.05 ± 0.23 µm, n = 30) and in patients with CVD (2.09 ± 0.21 µm, n = 51, p = 0.79). EG dimension was not correlated with cardiovascular risk factors. CONCLUSIONS: Microcirculatory EG dimension, as estimated by automated SDF imaging, is not associated with CVD, suggesting that this technique may not contribute to cardiovascular risk stratification.

Rapid and correct prediction of thrombocytopenia and hypofibrinogenemia with rotational thromboelastometry in cardiac surgery.

OBJECTIVES: In the present study, the authors have investigated whether rotational thromboelastometry (ROTEM) could predict thrombocytopenia and hypofibrinogenemia in cardiac surgery using the clot amplitude after 5 minutes (A5). Another parameter, PLTEM, in which the contribution of fibrinogen is eliminated by subtracting a fibrin-specific ROTEM test (FIBTEM) from an extrinsically-activated ROTEM test (EXTEM), was investigated. Furthermore, the turnaround time of ROTEM was compared to conventional laboratory tests. DESIGN: Prospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: Ninety-seven patients undergoing cardiac surgery between July 2011 until August 2012. INTERVENTIONS: The correlations between EXTEM/FIBTEM A5, A10, and maximal clot formation (MCF), EXTEM/PLTEM (A5/A10, and MCF) and platelet count, and FIBTEM (A5/A10, and MCF) and fibrinogen were evaluated using the Pearson's correlation coefficient and receiver-operating characteristic curves. Turnaround times of ROTEM tests and conventional laboratory tests were assessed in the central laboratory. MEASUREMENTS AND MAIN RESULTS: EXTEM A5 and FIBTEM A5 showed an excellent correlation with A10 (R:0.99/1.00) and MCF (R:0.97/0.99). The correlation between EXTEM A5 and platelet count (R:0.74) was comparable with the correlation of A10 (R:0.73) and MCF (R:0.70) with platelet count. FIBTEM A5 predicted fibrinogen levels (R:0.87) as well as A10 (R:0.86) and MCF (R:0.87). PLTEM A5 (R:0.85) correlated better with platelet count than EXTEM A5 (R:0.74; p = 0.04) and showed significantly better area under the curve values than EXTEM for predicting thrombocytopenia (A5 p = 0.012, A10 p = 0.019). Turnaround time for ROTEM tests, 12 minutes, was comparable with emergency requests for platelet count, 13 minutes, and shorter than emergency requests for fibrinogen levels, 37 minutes. CONCLUSIONS: Implementation of PLTEM and FIBTEM A5 in ROTEM-guided transfusion protocols may improve transfusion management.

Hypomanic episode as a first presentation of a large B-cell lymphoma.

This case report describes a cachectic patient with a first hypomanic episode, hypercortisolism and a newly diagnosed large B-cell lymphoma. Hypercortisolism, causing the manic symptoms, may be explained due to low leptin levels as a result of cancer cachexia and fasting. Patients with cancer frequently have psychiatric complications, but manic symptoms are rare. To our knowledge, this is the first report of a patient with a lymphoma presenting with manic symptoms without any cerebral abnormalities.

The kidney, volume homeostasis and osmoregulation in space: current perspective and knowledge gaps.

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.

The use of specific antihypertensive medication and skin cancer risk: A systematic review of the literature and meta-analysis.

BACKGROUND: The use of hydrochlorothiazide has recently been linked to skin cancer in observational studies. This may be explained by its photosensitizing properties, but photosensitivity has also been reported for other antihypertensive drugs. We conducted a systematic review and meta-analysis to compare skin cancer risk among antihypertensive drug classes and individual blood pressure lowering drugs. METHODS: We searched Medline, Embase, Cochrane and the Web of Science and included studies that investigated the association between antihypertensive medication exposure and non-melanoma skin cancer (NMSC) or cutaneous malignant melanoma (CMM). We combined the extracted odds ratios (OR) using a random effects model. RESULTS: We included 42 studies with a total of 16,670,045 subjects. Diuretics, in particular hydrochlorothiazide, were examined most frequently. Only 2 studies provided information about antihypertensive co-medication. Exposure to diuretics (OR 1.27 [1.09-1.47]) and calcium channel blockers (OR 1.06 [1.04-1.09]) was associated with an increased risk for NMSC. The increased risk for NMSC was only observed in case control studies and studies that did not correct for sun exposure, skin phototype or smoking. Studies that did correct for covariates as well as cohort studies did not show a significantly increased risk for NMSC. Egger's test revealed a significant publication bias for the subgroup of diuretics, hydrochlorothiazide and case-control studies concerning NMSC (p < 0.001). CONCLUSION: The available studies investigating the potential skin cancer risk that is associated with antihypertensive medication have significant shortcomings. Also, a significant publication bias is present. We found no increased skin cancer risk when analyzing cohort studies or studies that corrected for important covariates. (PROSPERO (CRD42020138908)).

What is the aetiology of dysnatraemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, retrospective observational study in 11 Dutch hospitals.

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.

Reconsidering the Edelman equation: impact of plasma sodium concentration, edema and body weight.

BACKGROUND: Guidelines recommend treatment of dysnatremias to be guided by formulas based on the Edelman equation. This equation describes the relation between plasma sodium concentration and exchangeable cations. However, this formula does not take into account clinical parameters that have recently been associated with local tissue sodium accumulation, which occurs without concurrent water retention. We investigated to what extent such clinical factors affect the Edelman equation and dysnatremia treatment. METHODS: We performed a post-hoc analysis with original data of the Edelman study. Linear regression was used to examine the effect of age, sex, weight, edema, total body water (TBW) and heart and kidney failure on the Edelman equation. With attenuated correction, we corrected for measurement errors of both variables. Using piecewise regression, we analyzed whether the Edelman association differs for different plasma sodium concentrations. RESULTS: Data was available for 82 patients; 57 males and 25 females with a mean (SD) age of 57 (15) years. The slope of the Edelman equation was significantly affected by weight (p=0.01) and edema (p=0.03). Also, below and above plasma sodium levels of 133 mmol/L the slope of the Edelman equation was significantly different (1.25 x0025vs 0.58x0025, p<0.01). CONCLUSION: Edelman's equation's coefficients are significantly affected by weight, edema and plasma sodium, possibly reflecting differences in tissue sodium accumulation capacity. The performance of Edelman-based formulas in clinical settings may be improved by taking these clinical characteristics into account.

Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses.

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 125I-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.