Significance of adjusting salt intake by body weight in the evaluation of dietary salt and blood pressure

Journal of the American Society of Hypertension

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(2016) 1–9

Research Article

Significance of adjusting salt intake by body weight in the evaluation of dietary salt and blood pressure Tomomi Hashimoto, MDa, Hiroyuki Takase, MDa, Tateo Okado, MDa, Tomonori Sugiura, MDb,*, Sumiyo Yamashita, MDb, Genjiro Kimura, MDc, Nobuyuki Ohte, MDb, and Yasuaki Dohi, MDb a Department of Internal Medicine, Enshu Hospital, Hamamatsu, Japan; Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and c Asahi Rosai Hospital, Owariasahi, Japan Manuscript received April 4, 2016 and accepted June 10, 2016

b

Abstract The close association between dietary salt and hypertension is well established. However, previous studies generally assessed salt intake without adjustment for body weight. Herein, we investigated the significance of body weight–adjusted salt intake in the general population. The present cross-sectional study included 7629 participants from our yearly physical checkup program, and their salt intake was assessed using a spot urine test to estimate 24-hour urinary salt excretion. Total salt intake increased with increasing body weight. Body weight–adjusted salt intake was greater in participants with hypertension than in those without hypertension. Systolic blood pressure, estimated glomerular filtration rate, and urinary albumin were independently correlated with body weight–adjusted salt intake after adjustment for possible cardiovascular risk factors. Excessive body weight–adjusted salt intake could be related to an increase in blood pressure and hypertensive organ damage. Adjustment for body weight might therefore provide clinically important information when assessing individual salt intake. J Am Soc Hypertens 2016;-(-):1–9. Ó 2016 American Society of Hypertension. All rights reserved. Keywords: Glomerular filtration rate; organ damage; sodium; urinary albumin.

Introduction Hypertension is a major risk factor for cardiovascular, cerebrovascular, and kidney diseases that constitute major causes of morbidity and mortality,1–4 and reducing blood pressure (BP) in individuals with hypertension reduces the increased risk of disease.5–7 The etiology of hypertension is believed to encompass various genetic, environmental, and behavioral factors.4 Given the wide prevalence of hypertension worldwide, dietary interventions aimed at reducing the risk of hypertension in

Funding: None. Supplemental Material can be found at www.ashjournal.com. *Corresponding author: Tomonori Sugiura, MD, Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan. Tel: þ81-52-853-8221; Fax: þ81-52-852-3796. E-mail: [email protected]

individuals without hypertension as well as reducing BP in individuals with hypertension are important public health strategy.4,8–10 Indeed, dietary salt restriction was followed by successful BP reduction in several large-scale trials.11–13 Mechanisms underlying the association between excess dietary salt and an increase in BP are not completely understood. Classically, sodium retention, which is caused by an impaired ability to excrete sodium at the nephron (impaired pressure natriuresis of the kidney) and accompanied by water retention, is a major factor in the pathogenesis of saltinduced hypertension.14–16 Elevation of BP caused by excess dietary salt increases sodium excretion via pressure natriuresis to rebalance sodium intake and output. The total peripheral resistance gradually increases to compensate for the increasing tissue overperfusion caused by water retention. Thus, reduced number or impaired function of nephrons is a hallmark of salt-induced hypertension. These considerations lead to the concept that total salt intake per body is critical for the risk of hypertension. However,

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relatively small salt intakes in individuals with a relatively low body weight might also be critical in terms of the risk for developing hypertension. In line with the concept, recent clinical and experimental studies have proposed extrarenal mechanisms for salt-induced hypertension, such as endothelial dysfunction and activation of the reninangiotensin system, sympathetic nerve, and transcriptional of mineralocorticoid receptor-dependent genes.17–21 Furthermore, salt intake adjusted for body weight is a significant independent predictor of pulse wave velocity, one of the important indices of hypertensive arterial damage.22 Thus, both total and body weight–adjusted salt intakes are clinically significant in the association between salt and hypertension. Therefore, we studied the possible relationship of body weight–adjusted salt intake to BP and subclinical hypertensive organ damage in the general population.

Materials and Methods Study Design The present study tested the hypothesis that both body weight–adjusted and total salt intake are closely related to BP and subclinical hypertensive organ damage in the general population. Here, we cross-sectionally investigated the relationship of body weight–adjusted salt intake to BP and hypertensive organ damage in participants who visited

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our hospital for a yearly physical checkup from April 2010 to March 2011. We undertook the study in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Enshu Hospital. All patients gave written informed consent to participate before the start of the study.

Study Subjects and Procedures The present study included men and women aged 20 years or more. The exclusion criteria applied for this study were a history of myocardial infarction, heart failure, or stroke. After screening of 7753 consecutive participants in our physical checkup program from April 2010 to March 2011, 7629 participants (male ¼ 4,798, mean age ¼ 56.3 years, range ¼ 21–91 years) were enrolled in the present study. Our physical checkup program included chest X-ray, electrocardiogram (ECG), and laboratory assessment of cardiovascular risk factors. Salt intake was assessed using a spot urine sample collected in the morning by estimating 24-hour urinary sodium excretion, calculated as previously reported.23 Urinary albumin concentrations were measured by a turbidimetric immunoassay (analytical range  1.1 mg/L) and are expressed as the ratio of concentrations of urinary albumin to urinary creatinine (UACR [mg/g Cr]). UACR was recorded as 0 mg/g Cr in participants with a urinary albumin concentration below the

Table 1 Characteristics of participants

Age (y) Body height (cm) Body weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Heart rate (bpm) Serum creatinine (mg/dL) Uric acid (mg/dL) Fasting plasma glucose (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) Hemoglobin (g/dL) Current smoking, n (%) Total salt intake (g/d) Body weight–adjusted salt intake (g/kg/d) ECG voltage (mV) eGFR (mL/min/1.73 m2) UACR (mg/g Cr)

Total (n ¼ 7629)

Female (n ¼ 2831)

Male (n ¼ 4798)

56.3  11.9 162.5  8.8 60.2  11.3 22.7  3.2 124.3  15.1 76.3  9.4 92.3  10.6 63.3  9.5 0.76  0.22 5.4  1.4 95.5  17.6 118.4  26.9 58.7  13.9 106.9  70.6 14.1  1.4 1550 (20.3%) 8.8  1.9 0.150  0.038 2.21  0.93 77.8  15.0 3.9 (2.2–6.9)

55.6  11.7 154.5  6.0 52.4  8.4 21.9  3.2 121.7  15.4 73.9  9.0 89.8  10.4 64.7  9.3 0.62  0.10 4.5  1.0 91.6  13.3 118.5  26.6 63.8  13.6 86.4  43.5 12.9  1.1 142 (5.0%) 8.5  1.9 0.165  0.039 2.00  0.82 79.1  15.0 3.9 (2.4–6.3)

56.7  12.1* 167.2  6.6* 64.8  10.2* 23.1  3.0* 125.8  14.7* 77.8  9.4* 93.8  10.4* 62.4  9.6* 0.84  0.23* 6.0  1.3* 97.8  19.4* 118.3  27.1 55.7  13.2* 119.1  80.0* 14.7  1.1* 1408 (29.3%)* 9.0  2.0* 0.141  0.034* 2.34  0.97* 77.0  14.9* 3.8 (2.1–7.3)

ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; UACR, urine albumin-to-creatinine ratio. Data were expressed as mean  standard deviation except for UACR (median [interquartile range]) and current smoking. * P < .001 vs. female by unpaired Student’s t test, Mann-Whitney U-test, or chi-square test.

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analytical limit. BP was measured using a standard mercury sphygmomanometer with the participant in the sitting position. Three consecutive BP measurements were taken at 2-minute intervals, and the mean of the second and third measurements was recorded as the BP. Hypertension was defined as systolic BP (SBP)  140 mm Hg, diastolic BP (DBP)  90 mm Hg, or the use of antihypertensive medications.4 Diabetes mellitus was defined as fasting plasma glucose 126 mg/dL or the use of antidiabetic medications, and dyslipidemia was defined as low-density lipoprotein (LDL) cholesterol  140 mg/dL, high-density lipoprotein (HDL) cholesterol < 40 mg/dL, triglycerides  150 mg/ dL, or the use of antidyslipidemic medications.24 The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.25 The relationships among body weight–adjusted salt intake, BP, ECG voltage (SV1 þ RV5), eGFR, UACR, and other cardiovascular risk factors were assessed.

Statistical Analysis All analyses were performed using the software package IBM SPSS statistics 18 (Chicago, IL, USA). Data in the text and the tables are expressed as mean  standard deviation except for UACR, which is expressed as the median value and interquartile range. Because the distribution of UACR was skewed rightward, log-transformed values (UACR þ 0.5) were used for statistical analysis. Differences between two means that had a normal distribution were compared by unpaired Student’s t test. The significance of any difference in medians was assessed by the Mann-Whitney U-test. Yates’ corrected chi-squared (c2) test was used for comparisons between categorical data. The association between total salt intake or body weight– adjusted salt intake and age categories (or BP categories) was adjusted for SBP, heart rate, fasting plasma glucose, LDL cholesterol, HDL cholesterol, uric acid, smoking status, eGFR, and body weight (or heart rate, fasting plasma glucose, LDL cholesterol, HDL cholesterol, uric acid, smoking status, eGFR, and body weight) using analysis of covariance followed by the Bonferroni post hoc test for multiple comparisons (age categories, BP categories, or gender). Body weight was included only in the analysis of total salt intake associations. Age was divided into six categories (20–29, 30–39, 40–49, 50–59, 60–69, and 70 years). SBP was divided into four categories according to the Japanese Society of Hypertension Guidelines (JSH2014)4: optimal BP; SBP < 120 mm Hg and DBP < 80 mm Hg, normal BP; 120  SBP < 130 mm Hg and/or 80  DBP < 85 mm Hg, high normal BP; 130  SBP < 140 mm Hg and/or 85  DBP < 90 mm Hg, hypertension; SBP > 140 mm Hg and/or DBP > 90 mm Hg. Hypertension was further divided into with and without antihypertensive drugs.

Figure 1. Bar graphs show effects of aging on total (A) and body weight–adjusted salt intakes (B). Subjects were divided into six groups according to their ages. Both total and body weight–adjusted salt intake increased with increasing age after adjustment for heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, smoking status, estimated glomerular filtration rate, and body weight (body weight was included only in the analysis for total salt intake), (ANCOVA, P < .0001 for trend). *P < .05 vs. female, xP < .05 vs. 20–29 years, #P < .05 vs. 30–39 years, $P < .05 vs. 40–49 years, yP < .05 vs. 50– 59 years, zP < .05 vs. 60–69 years (Bonferroni methods). ANCOVA, analysis of covariance.

Linear regression analysis was used to study explanatory factors for total salt intake, body weight–adjusted salt intake, eGFR, ECG voltage, or log UACR. Multivariate linear regression analysis with forced entry was performed to explore the independent associations between dependent factors and independent factors. The adjustment factors included are presented in each table. To avoid the multicollinearity problem, DBP, triglyceride, age, gender, and creatinine were excluded from the multivariate model as necessary (DBP was related to SBP; triglyceride was related to HDL cholesterol; and eGFR was calculated using age, gender, and creatinine). The variance inflation factor was calculated to assess potential multicollinearity in

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Figure 2. Bar graphs show (A) total salt intake and (B) body weight–adjusted salt intake in different blood pressure categories. Subjects were divided into four categories according to Japanese Society of Hypertension Guidelines (JSH2014): optimal blood pressure (BP); systolic BP (SBP) < 120 mm Hg and diastolic BP (DBP) < 80 mm Hg, normal BP; 120  SBP < 130 mm Hg and/or 80  DBP < 85 mm Hg, high normal BP; 130  SBP < 140 mm Hg and/or 85  DBP < 90 mm Hg, hypertension (HT); SBP > 140 mm Hg and/or DBP > 90 mm Hg. Hypertension (HT) was further divided into with and without antihypertensive drugs. After adjustment for heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, smoking status, estimated glomerular filtration rate, and body weight (body weight was included only in the analysis for total salt intake), both total and body weight–adjusted salt intake showed a significant association with BP categories (ANCOVA, P < .0001 for trend). The numbers in the figure indicate adjusted means. *P < .05 vs. optimal BP, #P < .05 vs. normal BP, $P < .05 vs. high normal BP, yP < .05 vs. HT with drugs (Bonferroni methods). ANCOVA, analysis of covariance.

multivariate models. We confirmed that all variance inflation factors were <2.5. A P value of less than 0.05 was considered statistically significant.

Results Table 1 details the characteristics of study participants. Participants with hypertension, diabetes mellitus, or dyslipidemia constituted 31.6% (n ¼ 2411; with 66.3% under medication), 7.1% (n ¼ 545; 70.3% under medication), or 42.6% (n ¼ 3250; 27.9% under medication), respectively. A total of 427 participants (5.6%) showed chronic kidney disease (eGFR < 60 mL/min per 1.73 m2 [1.0%] or urinary albumin 30 mg/g Cr [5.0%]). Both total and body weight–adjusted salt intakes were increased with age (Figure 1) and with the progression of BP categories (Figure 2), although the impact was somewhat weak in analysis using body weight–adjusted values as salt intake. Dietary salt was greater in subjects with hypertension than in those without hypertension (both P < .001), but body weight–adjusted salt intake was not different between hypertensive subjects taking and not taking antihypertensive medication (Figure 2).

Participants were divided into several groups according to their salt intake (Table 2). A significant positive association between estimated salt intake and SBP was observed for both total salt intake and body weight–adjusted salt intake after adjustment for heart rate, fasting plasma glucose, LDL cholesterol, HDL cholesterol, and eGFR (Table 2). Similarly, eGFR decreased and UACR increased with increasing total salt intake or body weight–adjusted salt intake (Supplementary Tables A, B), while ECG voltage showed no significant association with salt intake (Supplementary Table C). Total salt intake was positively correlated with body weight (Table 3). Also by univariate analysis, SBP, eGFR, and UACR correlated with both body weight–adjusted and total salt intakes, but ECG voltage (SV1 þ RV5) correlated with only total salt intake. Multivariable regression analysis demonstrated that body weight–adjusted salt intake was independently correlated with SBP, eGFR, ECG voltage, and UACR after adjustment for factors listed in Table 3, while ECG voltage did not correlate with total salt intake. Similar results were obtained in subanalyses performed using normotensive subjects, subjects without antihypertensive medications, and subjects without any medications (Supplementary Table

T. Hashimoto et al. / Journal of the American Society of Hypertension Table 2 Relationship between total or body weight–adjusted salt intake and systolic blood pressure Total Salt Intake

Body Weight– Adjusted Salt Intake

n

n

Blood Pressure

Division of participants Quartiles (P < .0001 for trend) Q1 1907 121.6  0.3 Q2 1908 123.7  0.3 Q3 1909 124.7  0.3 Q4 1905 127.2  0.3 Quintiles (P < .0001 for trend) Q1 1530 121.3  0.4 Q2 1525 123.3  0.4 Q3 1525 123.8  0.4 Q4 1520 125.6  0.4 Q5 1529 127.4  0.4 7 Groups* (P < .0001 for trend) G1 415 119.9  0.7 G2 928 121.7  0.5 G3 1474 123.1  0.4 G4 1586 123.8  0.3 G5 1355 125.2  0.4 G6 893 126.1  0.5 G7 978 128.2  0.5

Blood Pressure

(P < .0001 for trend) 1922 123.0  0.3 1895 124.3  0.3 1881 124.1  0.3 1931 125.7  0.3 (P < .0001 for trend) 1552 123.1  0.4 1505 124.0  0.4 1533 124.0  0.4 1528 124.4  0.4 1511 125.9  0.4 (P < .0001 for trend) 530 122.4  0.6 1966 123.6  0.3 2491 124.2  0.3 1573 124.7  0.4 730 125.1  0.5 250 128.4  0.9 89 126.4  1.5

SD, standard deviation. Data are presented as adjusted mean  SD (mm Hg). Subjects were divided into quartiles, quintiles, or seven groups according to estimated salt intake (total or body weight–adjusted salt intake). The associations between estimated salt intake and systolic blood pressure were then evaluated after adjustment for heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, estimated glomerular filtration rate, current smoking status, and body weight (when body weight–adjusted salt intake was adopted as an independent variable, body weight was excluded). * Participants were divided into the following seven groups according to salt intake: <6 g, 6–7 g, 7–8 g, 8–9 g, 9–10 g, 10–11 g, >11g (for total salt intake); <0.100 g, 0.100–0.130 g, 0.130– 0.160 g, 0.160–0.190 g, 0.190–0.220 g, 0.220–0.250 g, >0.250 g (for body weight–adjusted salt intake).

D). To investigate the impact of salt intake on hypertensive target organ damage, multivariate analyses were performed including eGFR, ECG voltage, or UACR as a dependent variable and salt intake as an independent variable (Table 4). Although UACR and eGFR were independently correlated with both total and body weight–adjusted salt intakes, ECG voltage was correlated only with body weight– adjusted salt intake.

Discussion The present study demonstrates that dietary salt adjusted for body weight has significant correlations with hypertensive damage to target organs as well as BP in the general

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population. Although of cross-sectional nature, this is the first study that implies causal association of body weight– adjusted salt intake with hypertension. In addition, salt intake adjusted for body weight as well as the total amount might have clinical significance in managing and preventing hypertension. Total salt intakes were greater in male than in female participants in our cohort, confirming a previous study.26 This may be attributable, at least in part, to the increased food intake, and thus increasing salt intake, that usually accompanies increasing body weight. It is notable and a matter of concern that dietary salt, whether adjusted for body weight or not, increases with age despite increasing salt-sensitivity with age. Furthermore, dietary salt was not dramatically decreased even after the diagnosis of hypertension or the start of antihypertensive medication. These findings suggested that neither public education as to the undesirable effects of excess dietary salt nor instructions from health care workers to reduce dietary salt is very successful. High BP is the second leading risk for death, accounting for 17.8% of premature death,27 and reduction in dietary salt leads to an improvement of population health.28 Importance of dietary salt reduction should be emphasized, and new strategies for such public and patient education should be developed. In the 7629 participants from our physical checkup program, we observed that dietary salt assessed as total amount per day correlated with BP, confirming the importance of ‘‘total daily dietary salt’’ in understanding the association between salt and hypertension. Furthermore, total salt intake correlated with a marker of hypertensive target organ damage, UACR, and eGFR, even after adjustment for BP. This may seem unexpected, but is compatible with previous findings that excessive salt intake is closely associated with an increase in arterial stiffness,22 incident stroke,29,30 and cardiovascular mortality,31–33 independently of its effects on BP. Salt may also induce target organ damage through a pathway independent of BP. The causal relationship between dietary salt and the development of hypertension remains unclear, with experimental and clinical studies proposing extrarenal (nephron independent) as well as renal (nephron dependent) mechanisms for salt-sensitive hypertension.14–21 Impairment of the kidneys to excrete sodium could be closely related with the number or function of nephrons and because the number of nephrons does not increase with increasing body weight,34 total dietary sodium, but not that adjusted for body weight, must be an important renal determinant of salt-sensitive hypertension. However, dietary salt adjusted for body weight might also be important in mechanisms that do not depend on pressure natriuresis at the nephron. Indeed, excess dietary salt impairs endothelial function17 and activates the sympathetic nerve system,18,20,21 renin-angiotensin system within the kidney,18,19 and the transcription of mineralocorticoid receptor-

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Table 3 Relationships of total and body weight–adjusted salt intakes with other variables Variable

Total Salt Intake (g/d)

Body Weight–Adjusted Salt Intake (g/kg/d)

Univariate Analysis

Multivariate Analysis (R2 ¼ 0.15)

b

b

t

P

VIF b

t

P

b

t

P

VIF

— — 0.317 0.134 — 0.023 0.052 0.023 0.024 — — 0.157 0.097 0.113 0.013 0.084

— — 24.3 11.3 — 2.1 4.7 2.1 2.1 — — 12.6 8.7 9.8 1.2 7.5

— — <.001 <.001 — .035 <.001 .035 .037 — — <.001 <.001 <.001 .243 <.001

— — 1.5 1.2 — 1.1 1.1 1.0 1.2 — — 1.4 1.1 1.2 1.1 1.1

33.7 28.6 — 4.9 5.2 3.1 1.4 6.4 19.0 11.7 19.7 28.9 19.0 10.2 0.2 9.4

<.001 <.001 — <.001 <.001 .002 .148 <.001 <.001 <.001 <.001 <.001 <.001 <.001 .877 <.001

— — — 0.045 — 0.020 0.022 0.034 0.146 — — 0.311 0.120 0.166 0.025 0.091

— — —

— — — <.001 — .060 .041 .001 <.001 — — <.001 <.001 <.001 .017 <.001

— — — 1.2 — 1.6 1.1 1.0 1.1 — — 1.2 1.1 1.2 1.0 1.1

t

P

Age 0.241 21.7 <.001 Gender (male) 0.115 10.1 <.001 Body weight 0.257 23.3 <.001 SBP 0.232 20.8 <.001 DBP 0.191 17.0 <.001 Heart rate 0.016 1.4 .168 FPG 0.154 13.6 <.001 LDL cholesterol 0.021 1.8 .066 HDL cholesterol 0.069 6.1 <.001 Triglyceride 0.108 9.5 <.001 Serum creatinine 0.012 1.0 .313 Uric acid 0.018 1.6 .119 Current smoking 0.091 7.9 <.001 eGFR 0.133 11.8 <.001 ECG voltage 0.045 4.0 <.001 Log UACR 0.140 12.3 <.001

Univariate Analysis

0.360 0.311 — 0.056 0.060 0.036 0.017 0.073 0.213 0.133 0.220 0.315 0.213 0.116 0.002 0.107

Multivariate Analysis (R2 ¼ 0.19)

4.0 — 1.9 2.0 3.3 13.6 — — 27.7 11.0 14.8 2.4 8.4

b, standardized regression coefficients; DBP, diastolic blood pressure; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic blood pressure; UACR, urine albumin-to-creatinine ratio; VIF, variance inflation factor. The multivariate analysis was adjusted for factors listed in the table.

dependent genes.19 The present results at least partially support an involvement for these mechanisms in human salt-sensitive hypertension. Univariate analyses showed significant correlations of most factors studied with body weight–adjusted salt intake, and multivariate analysis identified that dietary salt adjusted for body weight was independently correlated with SBP. The present crosssectional study does not present a definite conclusion; however, the findings support our fundamental hypothesis that

dietary salt adjusted for body weight has clinical significance in the development of hypertension. Similar results were obtained from a subanalysis of participants without any medication, although with reduced statistical power. Thus, effects of medication on the present results might be minimal. Although meta-analyses of observational and interventional studies focused on the effects of sodium restriction on BP demonstrated beneficial effects of sodium restriction, results from each study provided various and

Table 4 Multivariate models including eGFR, ECG voltage, or UACR as a dependent variable and dietary salt as an independent variable Variable

Model 1 Total salt intake Model 2 Body weight–adjusted salt intake

eGFR (Adjustment Type 1)

ECG Voltage (Adjustment Type 2)

Log UACR (Adjustment Type 3)

b

P

b

t

P

b

t

P

t

0.109

9.8

<.001

0.014

1.2

.243

0.088

7.5

<.001

0.170

14.8

<.001

0.030

2.4

.017

0.101

8.4

<.001

b, standardized regression coefficients; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; UACR, urine albumin-tocreatinine ratio. Adjustment type 1: multivariate analyses were adjusted for variables (*) þ ECG voltage and log UACR. Adjustment type 2: multivariate analyses were adjusted for variables (*) þ eGFR and log UACR. Adjustment type 3: multivariate analyses were adjusted for variables (*) þ eGFR and ECG voltage. (*) The variables were systolic blood pressure, heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, current smoking, and body weight (body weight was excluded from the model 2).

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complicated information in detail.35 Lack of adjustment for body weight may have affected the complicated results from previous studies. The importance of adjustment for body weight in the evaluation of dietary salt was also emphasized by the finding that eGFR, ECG voltage, and UACR (dependent variables) were independently correlated with body weight–adjusted salt intake. The relationships were confirmed based on the analysis whereby participants were divided into several groups according to their salt intake. Accordingly, both total and body weight–adjusted salt intake were closely associated with SBP, eGFR, and UACR, but not ECG voltage. Notably, the present study demonstrated close relationships between salt intake (whether adjusted for body weight or not) and BP even in the normal range below the threshold defined for high BP. Taking into consideration of the fact that a half of BP-related disease occurs in individuals with higher levels of BP even within the normal range,28 the present study reinforces the concept that approaches aimed at strict reduction in dietary salt need to be globally strengthened.27,28,36 Interpretation of the present results is limited by several points. Due to the cross-sectional study design, our findings that support an association between dietary salt and BP, eGFR, or UACR do not yield any conclusions about causation. Only well-designed, powerful, and longitudinal studies could attempt to answer the crucial question of whether an increase in dietary salt adjusted for body weight causes hypertension and hypertensive target organ damage. In the present study, a spot urine sample was used to estimate dietary salt. However, this method does not take into consideration day-to-day or circadian variations of salt, meat (effecting creatinine excretion), and fluid intake that may affect the estimation. A wide range of correlations between spot and 24-hour urinary sodium (from 0.17 to 0.92) has been reported,37 and thus, multiple days of 24hour urinary sodium assessments are necessary to obtain reliable data on salt intake.37,38 Information about urinary potassium was lacking despite the demonstrated importance of the ratio of sodium to potassium intake has been demonstrated. The study subjects were participants in our health checkup program, thus potentially introducing a selection bias. Finally, the use of ratios in statistical analyses can create interpretive difficulties because ratios do not easily take into account the nonlinear effects between numerator and denominator and can introduce spurious correlations among the ratios and other variables.39,40 These points should be noted when interpreting the present data. In conclusion, adjustment for body weight may provide clinically important information when evaluating dietary salt. Excessive body weight–adjusted salt intake could affect the development of hypertension and hypertensive organ damage independently of its effects on BP in the general population. Salt intake adjusted for body weight thus provides useful information in the assessment, prevention,

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and management of hypertension and hypertensive organ damage in the general population.

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Table A Relationship between salt intake and estimated glomerular filtration rate Total Salt Intake n Division of participants Quartiles Q1 Q2 Q3 Q4 Quintiles Q1 Q2 Q3 Q4 Q5 7 Groups* G1 G2 G3 G4 G5 G6 G7

1907 1908 1909 1905 1530 1525 1525 1520 1529 415 928 1474 1586 1355 893 978

Body Weight–Adjusted Salt Intake eGFR

n

(P < .0001 for trend) 100.7  0.3 99.1  0.3 97.4  0.3 96.5  0.3 (P < .0001 for trend) 100.8  0.3 99.7  0.3 98.5  0.3 96.8  0.3 96.3  0.3 (P < .0001 for trend) 101.5  0.6 100.8  0.4 99.9  0.3 98.4  0.3 96.9  0.3 96.9  0.4 96.0  0.4

(P < .0001 for trend) 1922 1895 1881 1931 (P < .0001 for trend) 1552 1505 1533 1528 1511 (P < .0001 for trend) 530 1966 2491 1573 730 250 89

eGFR

101.8 99.3 97.2 95.3

   

0.3 0.3 0.3 0.3

102.0 100.1 97.9 96.9 95.1

    

0.3 0.3 0.3 0.3 0.3

103.2 101.0 98.3 96.3 95.0 95.2 92.0

      

0.5 0.3 0.2 0.3 0.5 0.8 1.3

SD, standard deviation. Data are presented as adjusted mean  SD (mL/min per 1.73 m2). Subjects were divided into quartiles, quintiles, or seven groups according to estimated salt intake (total or body weight–adjusted salt intake). The associations between estimated salt intake and estimated glomerular filtration rate (eGFR) were then evaluated after adjustment for systolic blood pressure, heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, current smoking status, and body weight (when body weight–adjusted salt intake was adopted as an independent variable, body weight was excluded). * Participants were divided into the following seven groups according to salt intake: <6 g, 6–7 g, 7–8 g, 8–9 g, 9–10 g, 10–11 g, >11g (for total salt intake); <0.100 g, 0.100–0.130 g, 0.130–0.160 g, 0.160–0.190 g, 0.190–0.220 g, 0.220–0.250 g, >0.250 g (for body weight– adjusted salt intake).

T. Hashimoto et al. / Journal of the American Society of Hypertension Table B Relationship between salt intake and urinary albumin

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Table C Relationship between salt intake and electrocardiogram voltage

Total Salt Intake

Body Weight– Adjusted Salt Intake

Total Salt Intake

Body Weight– Adjusted Salt Intake

n

n

n

n

Log UACR

Division of participants Quartiles (P < .0001 for trend) Q1 1907 Q2 1908 Q3 1909 Q4 1905 Quintiles

0.65  0.01 0.62  0.01 0.62  0.01 0.74  0.01 (P < .0001 for trend)

Q1 1530 Q2 1525 Q3 1525 Q4 1520 Q5 1529 7 Groups*

0.66  0.01 0.62  0.01 0.62  0.01 0.63  0.01 0.76  0.01 (P < .0001 for trend)

G1 G2 G3 G4 G5 G6 G7

-(-)

415 928 1474 1586 1355 893 978

0.70 0.64 0.63 0.62 0.62 0.69 0.79

      

0.02 0.02 0.01 0.01 0.01 0.02 0.02

Log UACR

(P < .0001 for trend) 1922 0.63  1895 0.60  1881 0.66  1931 0.73  (P < .0001 for trend) 1552 0.65  1505 0.61  1533 0.61  1528 0.68  1511 0.75  (P < .0001 for trend) 530 0.68  1966 0.61  2491 0.62  1573 0.69  730 0.75  250 0.77  89 0.98 

0.01 0.01 0.01 0.01

0.01 0.01 0.01 0.01 0.01

0.02 0.01 0.01 0.01 0.02 0.03 0.05

SD, standard deviation. Data are presented as adjusted mean  SD (log UACR). Subjects were divided into quartiles, quintiles, or seven groups according to estimated salt intake (total or body weight–adjusted salt intake). The associations between estimated salt intake and urinary albumin (urinary albumin-to-creatinine ratio; UACR) were then evaluated after adjustment for systolic blood pressure, heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, estimated glomerular filtration rate, current smoking status, and body weight (when body weight–adjusted salt intake was adopted as an independent variable, body weight was excluded). * Participants were divided into the following seven groups according to salt intake: <6 g, 6–7 g, 7–8 g, 8–9 g, 9–10 g, 10–11 g, >11g (for total salt intake); <0.100 g, 0.100–0.130 g, 0.130– 0.160 g, 0.160–0.190 g, 0.190–0.220 g, 0.220–0.250 g, >0.250 g (for body weight–adjusted salt intake).

ECG Voltage

Division of participants Quartiles (P ¼ .78 for trend) Q1 1907 2.21  0.02 Q2 1908 2.20  0.02 Q3 1909 2.22  0.02 Q4 1905 2.23  0.02 Quintiles (P ¼ .28 for trend) Q1 1530 2.21  0.02 Q2 1525 2.23  0.02 Q3 1525 2.17  0.02 Q4 1520 2.22  0.02 Q5 1529 2.23  0.02 7 Groups* (P ¼ .66 for trend) G1 415 2.21  0.05 G2 928 2.20  0.03 G3 1474 2.23  0.02 G4 1586 2.18  0.02 G5 1355 2.22  0.03 G6 893 2.21  0.03 G7 978 2.24  0.03

ECG Voltage

(P ¼ .20 for trend) 1922 2.19  0.02 1895 2.19  0.02 1881 2.24  0.02 1931 2.24  0.02 (P ¼ .058 for trend) 1552 2.16  0.02 1505 2.24  0.02 1533 2.21  0.02 1528 2.21  0.02 1511 2.25  0.02 (P ¼ .24 for trend) 530 2.17  0.04 1966 2.21  0.02 2491 2.21  0.02 1573 2.21  0.02 730 2.23  0.03 250 2.30  0.06 89 2.42  0.10

SD, standard deviation. Data are presented as adjusted mean  SD (mV). Subjects were divided into quartiles, quintiles, or seven groups according to estimated salt intake (total or body weight–adjusted salt intake). The associations between estimated salt intake and electrocardiogram (ECG) voltage (SV1 þ RV5) were then evaluated after adjustment for systolic blood pressure, heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, estimated glomerular filtration rate, current smoking status, and body weight (when body weight–adjusted salt intake was adopted as an independent variable, body weight was excluded). * Participants were divided into the following seven groups according to salt intake: <6 g, 6–7 g, 7–8 g, 8–9 g, 9–10 g, 10–11 g, >11g (for total salt intake); <0.100 g, 0.100–0.130 g, 0.130– 0.160 g, 0.160–0.190 g, 0.190–0.220 g, 0.220–0.250 g, >0.250 g (for body weight–adjusted salt intake).

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Table D Relationships of total and body weight–adjusted salt intakes with other variables in subgroups of participants: normotensive participants, participants without antihypertensive medication, and participants without any medication (subanalysis of Table 3) Variable

Total Salt Intake (g/d)

Body Weight–Adjusted Salt Intake (g/kg/d)

Univariate Analysis

Multivariate Analysis

b

b

t

P

t

Normotensive (n ¼ 5218) SBP 0.199 14.7 <.001 0.119 8.6 eGFR 0.147 10.7 <.001 0.150 10.8 ECG voltage 0.025 1.8 .068 0.007 0.6 Log UACR 0.056 4.1 <.001 0.034 2.6 (R2 ¼ 0.14) Without antihypertensive drugs (n ¼ 6030) SBP 0.234 18.7 <.001 0.142 10.8 eGFR 0.130 10.2 <.001 0.125 9.7 ECG voltage 0.039 3.0 .003 0.011 0.9 Log UACR 0.096 7.5 <.001 0.057 4.6 (R2 ¼ 0.15) Without any drugs (n ¼ 5440)* SBP 0.231 17.5 <.001 0.145 10.4 eGFR 0.124 9.2 <.001 0.121 8.8 ECG voltage 0.044 3.3 .001 0.015 1.2 Log UACR 0.085 6.3 <.001 0.051 3.9 (R2 ¼ 0.14)

Univariate Analysis

Multivariate Analysis

P

VIF b

<.001 <.001 .573 .010

1.2 1.2 1.0 1.1

0.019 1.380 .168 0.026 2.1 .044 1.1 0.131 9.576 <.001 0.194 14.7 <.001 1.1 0.026 1.896 .058 0.021 1.7 .092 1.0 0.071 5.162 <.001 0.060 4.8 <.001 1.0 (R2 ¼ 0.20)

<.001 <.001 .352 <.001

1.2 1.2 1.1 1.1

0.044 3.409 <.001 0.042 3.3 <.001 1.2 0.123 9.618 <.001 0.178 14.5 <.001 1.1 0.017 1.305 .192 0.024 2.2 .044 1.1 0.093 7.257 <.001 0.081 6.8 <.001 1.1 (R2 ¼ 0.20)

<.001 <.001 .233 <.001

1.2 1.2 1.1 1.1

0.039 2.901 .004 0.047 3.6 <.001 1.2 0.115 8.532 <.001 0.176 13.5 <.001 1.1 0.020 1.439 .150 0.027 2.2 .030 1.1 0.086 6.373 <.001 0.074 5.9 <.001 1.1 (R2 ¼ 0.20)

t

P

b

t

P

VIF

b, standardized regression coefficients; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; UACR, urine albumin-tocreatinine ratio; VIF, variance inflation factor. Multivariate analyses were adjusted for heart rate, fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid, current smoking status, and body weight (when body weight–adjusted salt intake was adopted as a dependent variable, body weight was excluded). * Any drugs: antihypertensive, antidiabetic, or antidyslipidemic drugs.