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.

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.

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)).

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.

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).

Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial.

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 125I-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.

Long-term potassium intake and associated renal and cardiovascular outcomes in the clinical setting.

BACKGROUND & AIMS: High potassium intake has been suggested to lower the risk for renal and cardiovascular outcome, but data are conflicting. This may be explained by the use of different methods for potassium intake assessment across studies. Also, most data are limited to the general population. We investigated the optimal potassium intake, as measured with multiple 24-h urine samples, in patients with a clinical indication for 24-h urine collection, for prevention of cardiorenal disease. METHODS: We performed a retrospective cohort study in 541 outpatient subjects with an estimated glomerular filtration rate >60 mL/min/1.73 m2 who had sampled a 24-h urine collection between 1998 and 1999, and had at least 1 additional collection during a 17-year follow-up. We assessed incidence of renal (i.e. renal replacement therapy, 60% decline in estimated glomerular filtration rate or death) and cardiovascular disease (i.e. cardiovascular event or death). RESULTS: Average age of subjects was 47 years. Estimated mean potassium intake was 74 mmol/day and remained similar during follow-up. The highest tertile of estimated potassium intake was associated with a significant 76% reduction in renal outcome, and 73% decrease of cerebrovascular events, while no effect for overall cardiovascular outcome was found. A 20-mmol increase in potassium intake during follow-up was associated with a 24% reduction in renal outcome. CONCLUSIONS: Our data demonstrate that high estimated potassium intake is associated with improved renal outcome and less cerebrovascular events in outpatient subjects with preserved kidney function.

Initial Estimated Glomerular Filtration Rate Decline and Long-Term Renal Function During Intensive Antihypertensive Therapy: A Post Hoc Analysis of the SPRINT and ACCORD-BP Randomized Controlled Trials.

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 m2 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.

[Morning or evening; What is the best time to take antihypertensive drugs?] / 's Ochtends of 's avonds?

Various studies suggest that evening dosing of antihypertensive drugs may be more effective. In line, a randomized open-label trial in 19,084 hypertensive patients recently demonstrated that evening dosing of at least one antihypertensive drug resulted in a 3.3 mmHg lower systolic night-time blood pressure and 1.3 mmHg lower systolic 48-hour blood pressure when compared to morning dosing. Cardiovascular outcomes were reduced by 45% in the evening dosing group, which is remarkable as previous meta-analyses have shown that a systolic blood pressure reduction of 3 mmHg is associated with a 7% reduction in cardiovascular outcome. Although this discrepancy may be partly explained by specific beneficial effects related to evening dosing, it is likely that the open-label trial design may have affected the study outcome in different ways. Also, the safety of evening dosing in elderly hypertensive patients and the consequences for therapy compliance in the clinical setting remain to be established.

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.

Abnormal sodium and water homeostasis in mice with defective heparan sulfate polymerization.

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.

[Hydrochlorothiazide and skin cancer]. / Hydrochloorthiazide en huidkanker.

Hydrochlorothiazide and skin cancer Hydrochlorothiazide is a frequently prescribed diuretic with known photosensitizing properties. Recently, a large case-control study in a Danish population found an association between the use of hydrochlorothiazide and an increased risk of developing non-melanoma skin cancer. These data suggest that it may be wise to limit the use of hydrochlorothiazide for the treatment of hypertension. We reviewed the current literature to examine whether a causal relationship between hydrochlorothiazide and non-melanoma skin cancer exists. We consider that the evidence for a causal relationship is limited and contradicting. Moreover, we found that other antihypertensive agents such as calcium blockers and angiotensin receptor blockers are also associated with basal cell carcinoma. Based on the current literature, there seems to be insufficient evidence to advice against the use of hydrochlorothiazide.

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).