Effects of Within-Person Variability in Spot Urinary Sodium Measurements on Associations With Blood Pressure and Cardiovascular Disease

Randomized trials of salt restriction have consistently demonstrated that decreasing salt consumption lowers blood pressure, but results of observational studies of salt intake and cardiovascular disease have been conflicting. After excluding individuals with prevalent cardiovascular or kidney disease in the prospective UK Biobank study, we examined the within-person variability in spot urinary sodium excretion and its impact on associations with systolic blood pressure and risk of incident cardiovascular disease. Spearman correlation coefficients were used to assess within-person variability in spot urinary sodium, and associations between sodium and blood pressure were assessed using linear regression in participants with measurements at baseline (N=355 134) and after 9 years (N=33 915). Cox regression was used to assess associations with the risk of cardiovascular disease over the same follow-up period (N=5566 events). The within-person variability in urinary sodium was extreme, with a self-correlation coefficient of 0.35 over 4 years. Each 100 mmol/L higher usual urinary sodium was associated with 3.09 mm Hg higher systolic blood pressure (95% CI, 2.7–3.48) at baseline, but had no association at 9 years (0.97 [−0.44 to 2.37]). Likewise, there was no association between urinary sodium and risk of cardiovascular disease over the same follow-up period (hazard ratio, 1.05, [0.87–1.26]). While spot urinary sodium measurements were associated with immediate effects on blood pressure at baseline, the extreme within-person variability in urinary sodium precluded detection of associations with future blood pressure at resurvey or risk of cardiovascular disease. The limitations of observational studies, irrespective of study size, should be recognized when assessing public policy on salt restriction.

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Effects of within-person variability in spot urinary sodium measurements on the associations with blood pressure and risk of cardiovascular disease in 0.5 Million adults in UK Biobank

European Heart Journal ◽

10.1093/ehjci/ehaa946.2857 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Carter ◽

F Re ◽

I Hammami ◽

T Littlejohns ◽

M Arnold ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Sodium Excretion ◽

Cox Regression ◽

Sodium Intake ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

World Health ◽

Funding Source ◽

Uk Biobank

Abstract Background Randomised control trials have demonstrated direct positive and causal associations of 24-hr measurements of urinary sodium excretion on blood pressure. However, prospective studies, which often used spot (not 24-hr) measurements of urinary sodium, have reported J-shaped associations with higher risks of cardiovascular disease (CVD) at sodium intake <4 g/day. The reasons for the discrepant results are not fully understood, but have prompted some to question the World Health Organisation's recommendations to restrict sodium intake to <2.3g/day. Purpose We examined the effects of within-person variability in spot urinary sodium (UNa) measurements on immediate and delayed associations of UNa with blood pressure at baseline and at resurvey, and with incident cardiovascular disease in the UK Biobank (UKB). Methods Baseline spot urine samples were measured in 502,619 adults at baseline and in 20,346 participants who were resurveyed at 4 years after baseline. Linear regression was used to assess associations of baseline UNa measurements with systolic blood pressure (SBP; mmHg) at baseline and at resurvey. Cox regression was used estimate the associations between baseline measures of UNa with incident CVD events (recorded from linkage with hospital records). All analyses were adjusted for confounders and corrected for regression dilution bias. Results After excluding participants with prevalent diseases, the primary analyses involved 386,060 adults who were followed-up for a median of 7.8 years, during which ∼13,000 CVD events occurred. Estimated mean (SD) urinary sodium excretion was 77.4 mmol/L (SD 44.4, IQR = 42.8–103.7 mmol/L), and mean SBP/DBP were 137.5/82.3 (SD 18.5/10.1) mmHg, respectively. Within-person variability in UNa was high, with a self-correlation of 0.35 at 4 years between measurements. After adjustment for confounders and correction for regression dilution bias, a 100 mmol/L higher UNa was associated with an immediate 3.2 mmHg higher SBP (95% confidence interval [CI]: 2.8–3.6) in cross-sectional analyses (Figure 1). However, the corresponding associations of baseline UNa with SBP at resurvey was completely attenuated (p=0.20). The predicted risk of CVD was 1.06 (95% CI 1.06–1.07, p<0.001) for a 3.2 mmHg higher SBP, but the observed risk for a 100 mmol/L higher UNa was 0.95 (95% CI 0.82–1.10, p=0.47) (Figure 1). Conclusions While spot measurements of UNa were strongly associated with immediate effects on SBP, the magnitude of within-person variability in UNa precluded detection of associations with SBP several years after baseline or with risk of CVD. The extreme within-person variability in spot UNa may explain the discrepant results of the trials and observational studies of sodium and blood pressure. Figure 1. Spot UNa with SBP and CVD in UK Biobank Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Core funding from the Medical Research Council-Population Health Research Unit, British Heart Foundation

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Patients With Primary Aldosteronism Respond to Unilateral Adrenalectomy With Long-Term Reduction in Salt Intake

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz051 ◽

2019 ◽

Vol 105 (3) ◽

pp. e484-e493

Author(s):

Christian Adolf ◽

Daniel A Heinrich ◽

Finn Holler ◽

Benjamin Lechner ◽

Nina Nirschl ◽

...

Keyword(s):

Blood Pressure ◽

Primary Aldosteronism ◽

Sodium Excretion ◽

Salt Intake ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Care Hospital ◽

Unilateral Adrenalectomy ◽

The Impact

Abstract Context High dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients. Patients and Methods A total of 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn’s Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment. Study design Observational longitudinal cohort study. Setting Tertiary care hospital. Results At baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs 178 mmol/d, P = 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid, and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (P = 0.012) 1 year after unilateral adrenalectomy and remained low at 3 years of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs 183 mmol/d). Conclusion PA patients consuming a high-salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment.

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Faculty Opinions recommendation of Urinary sodium excretion, blood pressure, cardiovascular disease, and mortality: a community-level prospective epidemiological cohort study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733790826.793552587 ◽

2018 ◽

Author(s):

Carmine Zoccali ◽

Davide Bolignano

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Cohort Study ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Community Level ◽

Epidemiological Cohort

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Urinary sodium excretion and the risk of cardiovascular disease: A community-based cohort study in Taiwan

British Journal Of Nutrition ◽

10.1017/s0007114521001768 ◽

2021 ◽

pp. 1-42

Author(s):

Yi-Jie Wang ◽

Kuo-Lioug Chien ◽

Hsiu-Ching Hsu ◽

Hung-Ju Lin ◽

Ta-Chen Su ◽

...

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Systolic Blood Pressure ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Salt Sensitivity ◽

Urinary Sodium ◽

Mediating Effect ◽

Cvd Risk ◽

Media Thickness

Abstract Urinary sodium excretion is a potential risk factor for cardiovascular diseases (CVD). However, the underlying biological mechanisms and effects of salt sensitivity are unclear. The purpose of this study was to characterize the relative contribution of biological factors to the sodium-CVD association. A total of 2112 participants were enrolled in this study. Structured questionnaires and blood and urine samples were obtained. Twenty-four-hour sodium excretion was estimated using a single overnight urine sample. Hypertension, metabolic syndrome, and overweight status were considered to indicate salt sensitivity. Cox proportional hazard models were used to investigate the effects of salt sensitivity on urinary sodium excretion and CVD risk. The traditional mediation approach was used to calculate the proportion of mediation. The mean age (standard deviation) of the 2112 participants was 54.5 (12.2) years, and they were followed up for a mean of 14.1 [8.1] years. Compared with those in the lowest quartile, the highest baseline urinary sodium excretion (>4.2g/24 hours) was associated with a 43% higher CVD risk (hazard ratio, 1.43; 95% confidence interval, 1.02-1.99). Participants with high urinary sodium excretion, hypertension, or metabolic syndrome had a significantly high risk of CVD. The carotid intima-media thickness had the largest mediating effect (accounting for 35% of the sodium-CVD association), followed by systolic blood pressure (33%), left ventricular mass (28%), and diastolic blood pressure (14%). Higher urinary sodium excretion increased the risk of CVD, which was explained largely by carotid media-thickness and systolic blood pressure.

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Abstract P142: The CKD273 Urinary Peptidomic Biomarker is Associated with Mortality in People at Early Stages of Diabetic Nephropathy Independent of Traditional Risk Factors

Hypertension ◽

10.1161/hyp.70.suppl_1.p142 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Gemma E Currie ◽

Sheon Mary ◽

Bernt J von Scholten ◽

Morten Lindhardt ◽

Harald Mischak ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Diabetic Nephropathy ◽

Cox Regression ◽

Outcome Data ◽

Diagnostic Purpose ◽

Urine Albumin ◽

Geometrical Mean ◽

Traditional Risk Factors

Background: Mortality in type 2 diabetes (T2D) is primarily driven by cardiovascular disease. This is amplified in diabetic nephropathy (DN), even in early ‘pre-clinical’ stages. A urinary peptidomic classifier (CKD273) has been found to predict DN development in advance of detectable microalbuminuria. Whether it is also a determinant of mortality and cardiovascular disease in patients with established albuminuria is unknown. Methods: We studied 155 subjects with T2D, albuminuria (geometrical mean [IQR]: 85 [34;194] mg/24hrs), controlled blood pressure (129±16/74±11 mmHg) and preserved renal function (eGFR 88±17 ml/min/1.73m 2 ). Blood and urine samples were collected for measurement of estimated glomerular filtration rate (eGFR), urine albumin excretion (UAE), N-terminal pro-brain natriuretic peptide (NT-proBNP; ELISA) and urinary proteomics (capillary electrophoresis coupled to mass spectrometry). Computed tomography imaging was performed to assess coronary artery calcium (CAC) score. Outcome data were collected through national disease registries over a 6 year follow up period. Results: CKD273 correlated with UAE (r=0.481, p=<0.001), age (r=0.238, p=0.003), CAC score (r=0.236, p=0.003), NT-proBNP (r=0.190, p=0.018) and eGFR (r=0.265, p=0.001). On multiple regression only UAE (β=0.402, p<0.001) and eGFR (β=-0.184, p=0.039) were statistically significant determinants. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p=0.004), and retained significance (p=0.050) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. Neither eGFR nor UAE were determinants of mortality in this cohort. Conclusions: A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the peptidomics-based classifier CKD273 is associated with mortality in albuminuric people with T2D in even when adjusted for other established cardiovascular and renal biomarkers.

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