Introduction

Hypertension contributes to the burden of heart disease, stroke, and kidney failure, and it is one of the leading causes of morbidity and mortality. Prehypertension, a state between normotension and hypertension, is a strong predictor of hypertension1. According to the Seventh Report of the Joint National Committee (JNC-7) guideline, prehypertension is characterized by a systolic blood pressure (SBP) ranging from 120 mm Hg to 139 mm Hg and/or a diastolic blood pressure (DBP) ranging from 80 mm Hg to 90 mm Hg1. The prevalence of prehypertension is rapidly increasing worldwide. In the InterASIA study, the prevalence of prehypertension is 21.9% among Chinese adults (25.7% in males and 18.0% in females)2, and prehypertension is emerging as an independent risk factor for cardiometabolic disorders, including metabolic syndrome, diabetes, chronic kidney disease, stroke, and cardiovascular diseases3,4.

Excessive dietary salt intake plays an important role in the onset and maintenance of hypertension, whereas restricted salt intake lowers blood pressure (BP)5. Dietary salt intake by itself, even without causing hypertension or volume overload, might be deleterious, resulting in cardiac remodeling, renal fibrosis, and left ventricular hypertrophy6,7,8. Several mechanisms, including endothelial dysfunction, oxidative stress, inflammation, insulin resistance, and neurogenically mediated increase in peripheral resistance, contribute to the harmful effects of dietary salt9,10. Recent studies have shown that increased salt intake may be associated with the pathogenesis of prehypertension11,12,13. However, data on the association between dietary salt intake and prehypertension are lacking.

Uric acid (UA) is the metabolic end product of purine degradation in humans; xanthine oxidase is the enzyme responsible for UA production and free radical damage14. Epidemiological studies have identified serum UA is an important risk factor for cardiovascular disease and hypertension15,16,17. For example, Puddu et al.16,17 found that serum UA could predict not only short-term but also long-term incidence of cardiovascular events as well as cardiovascular death and all-cause mortality. Recent studies have shown that increased sodium intake significantly lowers serum UA18,19. However, no research has focused on the relationship between dietary salt intake and UA levels, especially urinary UA excretion, in prehypertensive participants. Furthermore, the relationship between UA and prehypertension and the synergistic effects of UA and dietary salt intake on the risk of prehypertension remain unclear to date.

In the present study, we used our previously established cohort that has been followed up for 30 years to examine the possible associations between urinary sodium excretion, which was used as surrogate for salt intake, and serum and urinary UA levels in prehypertensive participants. We particularly sought to investigate the interactions between urinary sodium excretion and serum UA on the risk of prehypertension in Chinese young adults.

Methods

Cohort of study

In March and April 1987, we established the cohort of Hanzhong Adolescent Hypertension Study based on a baseline survey of 4623 adolescents aged 6–15 years in over 20 schools of three towns (Qili, Laojun, and Shayan) in Hanzhong, Shaanxi, China20,21. To explore the BP trajectory and its risk factors from children to adults, we made the long-term follow-ups of this cohort in 1989, 1992, 1995, 2005, 2013, and 2017 (Supplementary Figure S1).

In this study, we followed up this cohort from April to July 2017, and a total of 2780 were followed up this time. The total rate of this follow-up was 60.3%, which was very rare for such a long-term follow-up. The participant selection process is described in Fig. 1. Of the 2780 participants, 911 were excluded from the current analysis for the following reasons: hypertension defined as a SBP ≥140 mm Hg or DBP ≥90 mm Hg or current use of antihypertensive medications (n = 584), missing important data (BP, n = 29; height and weight, n = 1; blood biochemistry, n = 207; urinary biochemistry, n = 87; urinary creatinine, n = 1), and self-identified history of stroke (n = 2). The remaining 1869 individuals were included in the analysis. Data including social demographic survey (age, gender, education, occupation, medical conditions, and prescription and nonprescription medication use), physical activity, physical examination with anthropometric measurements, and laboratory testing were collected by trained physicians or medical students.

Figure 1
figure 1

Flow diagram showing the selection of the study population.

Full size image

The present study complied with the Declaration of Helsinki, and the research protocol was approved by the Ethics Committee of the First Affiliated Hospital of ** hypertension. Circulation 125, 3108–3116 (2012)." href="/article/10.1038/s41598-018-26148-3#ref-CR32" id="ref-link-section-d222118526e3216">32. Another trial performed in 27 men showed that increasing sodium intake from 20 mEq/day to 200 mEq/day decreased UA levels by 1 mg/dL33. In addition, a randomized crossover trial of 103 adults with prehypertension or stage I hypertension showed that 30 days of low versus high sodium intake (60 versus 180 mmol/day) significantly decreased serum UA18,19. In this study, we showed that the serum UA levels were similar between each quartile of estimated sodium excretion in prehypertensive subjects. Furthermore, sodium excretion was not correlated with serum UA and hyperuricemia in the unadjusted and adjusted analyses. The discrepant results of these studies may be attributed to their different study populations, designs, sample sizes, and racial differences.

UA is a product of the metabolic breakdown of purine nucleotides. Approximately 70% of UA is excreted into the urine but is easily filtered into the renal tubule, and about 90% of filtered UA is reabsorbed by the S1 segment of the proximal convoluted tubule32. Approximately 10% of filtered UA is excreted34. To the best of our knowledge, this present study is the first to demonstrate that urinary excretions of UA were significantly associated with sodium excretion in prehypertensive subjects. The mechanism by which sodium intake increases urinary excretion of UA remains unclear. It is possible that the relationship between sodium intake and urinary urate excretion results from effects of sodium intake on glomerular filtration rate and excretion or absorption of urate. Previous physiology studies have shown that reabsorption of sodium and urate accompanies one another at different sites in the nephron35,36. Thus, it is possible that decreased renal reabsorption of sodium from excess sodium intake contributes to a decrease in urate reabsorption. This hypothesis has been evidenced by our interventional study showing that urinary UA excretions were markedly increased during high-salt intake, which was further reinforced by the observation that urinary UA positively correlated with urinary sodium excretion37. Furthermore, a Spanish study also found a directly correlation between the clearance of UA and fractional excretion of sodium, indicating the potential interaction of sodium and UA excretion38. Finally, this relationship may reflect action of the renin-angiotensin system, as uric acid is inversely related to vascular resistance39 and renal blood flow40. Similarly, angiotensin II has been shown to decrease urate excretion after an acute infusion41,42. Determining the molecular mechanism and signaling molecules responsible for the effects of salt intake on urinary UA can be of great interest.

A limited number of studies have examined the relationship serum UA and prehypertension, and findings are conflicting. One US study found a positive association between serum UA and prehypertension with an OR of 1.96 for the top category of serum UA levels compared with the lowest43. Jiang et al.44 described that the OR for prehypertension is 1.36 in subjects with UA ≥365 μmol/L compared with those with UA <215.9 μmol/L after adjusting for many confounders. The other two cross-sectional studies demonstrated that serum UA was independently related to the prevalence of prehypertension in Chinese adults45,46. In contrast, Vucak et al.47 determined that no association existed between elevated serum UA level and prehypertension; this might be because of higher background rate of prehypertension with increasing age that would contribute to a reduction in the odd ratios for serum UA. Recently, a prospective cohort study demonstrates that serum UA is an independent predictor for develo** prehypertension48. In addition, Soletsky et al.49 reported that UA reduction rectifies prehypertension in obese adolescents. In the present study, we consistently showed that higher serum UA category was significantly associated with an increased OR for the presence of prehypertension, compared with the reference group. And the observed positive association between serum UA and prehypertension consistently occurred when serum UA was considered as a continuous variable.

Previously, ample evidence suggests that excess salt intake is positively associated with elevated blood pressure and it can be lowered with reductions in dietary salt5. However, clinical trials scarcely examined the relationship between salt intake and prehypertension. Moinuddin et al.11 showed that daily salt intake of prehypertensives (21.2 ± 1.2 g/day) was significantly greater than normotensive subjects (9.0 ± 0.5 g/day). This result is similar to our study, which found that compared with participants without prehypertension, those with prehypertension tended to have higher urinary sodium excretions (5.20 ± 1.38 vs. 4.86 ± 1.34; P < 0.001). We further observed that the risk of prehypertension was significantly increased with the increasing quartiles of sodium excretion. In addition, Forman et al.32 in a large, prospective, population-based cohort, found that a higher sodium intake is associated with an increased risk of develo** hypertension, particularly in those individuals who have higher levels of serum UA. Our results also showed that salt intake significantly interacted with serum UA. Taken both serum UA and sodium excretion into consideration to assess prehypertension, we found that the risk of prehypertension in the highest quartiles of serum UA and sodium excretion was 3.48 (95% CI, 3.32–5.86) times greater than in the lowest quartile. In other words, participants with higher serum UA levels and salt intake simultaneously were more likely to have a higher risk for prehypertension.

This study has limitations that deserve mention. Firstly, since the study population was included from our previously established cohort, all participants in the present work were middle aged and youth between the ages of 35 and 48 years during the follow-up at 2017. In addition, 24-h urinary sodium excretion was estimated using spot urine samples. Estimated sodium excretions may change according to the urine sampling time because urinary sodium excretion has a circadian rhythm and may also be influenced by the time at which food is consumed. Thus, a single measurement may be insufficient to assess the sodium excretion of individuals. However, spot urine samples are practical at general medical facilities, and the reliability of the findings obtained may be improved using a calculation formula incorporating the estimated 24-hour urinary creatinine excretion based on age, height, and body weight. The validation of the Kawasaki formula was conducted by Mente et al.27. Finally, the study was a single-center, cross-sectional study. A multi-center, prospective trial will be conducted to further understand and confirm the conclusions.

In conclusion, the present study showed that urinary sodium excretion was significantly associated with urinary UA excretions in prehypertensive individuals. However, we failed to find a significant relationship between sodium excretion and serum UA in this Chinese population. In addition, elevated serum UA and sodium excretions appeared to be associated with the development of prehypertension. Individuals with higher serum UA levels and sodium excretions simultaneously had a higher risk for prehypertension. Further clinical trials that include participants with hypertension to investigate evaluate the joint effects of salt intake and serum UA on hypertension and other cardiovascular diseases can be of significant interest. Our findings supported the need for the development of a salt reduction programme.