Effect of chronic kidney disease on the association between hyperuricemia and new‐onset hypertension in the general Japanese population: ISSA‐CKD study

Abstract We aimed to investigate the association between serum uric acid (SUA) level and development of hypertension as well as the interaction effect of chronic kidney disease (CKD) on this relationship in the general Japanese population. We included 7895 participants aged ≥30 years from the ISSA‐CKD study, a population‐based retrospective cohort study that used annual health check‐up data of residents from Iki Island, Japan. After the exclusion of 1881 with l < 1‐year follow‐up, 2812 with hypertension at baseline, and 165 with missing information on SUA, a total of 3037 participants were enrolled in this analysis. Participants were divided into four groups according to the quartiles of SUA level at baseline, and multivariable‐adjusted hazard ratios for new‐onset hypertension were calculated. Stratified analyses were performed for each subgroup (defined by sex, age, alcohol intake, and CKD) to assess the interaction effects. During a mean follow‐up period of 4.4 years, 943 participants developed hypertension. The first quartile group was set as the reference group, and the multivariable‐adjusted hazard ratios (95% confidence interval) for new‐onset hypertension were 1.11 (0.90–1.36) in the second quartile, 1.25 (1.02–1.54) in the third quartile, and 1.35 (1.07–1.70) in the fourth quartile compared with those in the reference group (p = .007 for trend). The stratified analyses showed that the association between SUA and hypertension was significantly stronger in participants with CKD than in those without CKD (p = .035 for interaction). SUA level is an independent risk factor for new‐onset hypertension. This tendency was significantly stronger in participants with CKD.


INTRODUCTION
Cardiovascular disease (CVD) is one of the leading causes of death in high-income countries, including Japan, and low-to middle-income countries. 1 Hypertension is a major independent risk factor for CVD 2 ; therefore, the prevention of hypertension is imperative in the field of public health to reduce the burden of CVD.
Uric acid is an end-product of purine metabolism in humans. 3 A number of observational studies have reported that hyperuricemia is an independent risk factor for hypertension; however, other observational studies and Mendelian randomization studies have reported no clear associations. 45 Previous studies have explored the association between serum uric acid (SUA) levels and the incidence of hypertension in subgroups defined by the presence of chronic kidney disease (CKD), which is highly correlated with SUA levels [6][7][8] and is therefore a strong predictor of hypertension. 9 In the present study, we aimed to determine whether hyperuricemia is an independent risk factor for the future development of hypertension in the general Japanese population. We also investigated the effects of hyperuricemia on hypertension stratified by the presence of CKD.

Study design and participants
This study was a population-based retrospective cohort study of the residents of Iki City, Nagasaki Prefecture, Japan, and used data from the Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD) study, which has been described in detail previously. 10

Data collection
The annual health check-ups included medical history, physical examinations, blood tests, and dipstick urine test. SUA level was determined using the enzymatic method, and hyperuricemia was defined as SUA ≥ 7.0 mg/dL (416 µmol/L). 16 We performed two sets of analyses. In the first set, we catego- We also acquired clinical information of the participants, including medical history and habitual information on current smoking, daily exercise, and alcohol intake, using a standard questionnaire. Current smoking was defined as smoking ≥100 cigarettes or regular smoking habits for more than 6 months. Daily exercise was defined as exercise for more than 30 minutes per day, two times or more per week.
Daily alcohol intake was defined as regular alcohol consumption.

Blood pressure measurement and definition of incident hypertension
In accordance with standardized guidelines, 21

Statistical analysis
All data were presented as the mean ± standard deviation or as n (%

DISCUSSION
In this large-scale retrospective cohort study of the general Japanese population, hyperuricemia was found to be an independent risk fac- The present longitudinal study of the general Japanese population confirmed the findings of the previous studies and clearly demonstrated significant linear associations between SUA and the incidence of hypertension, independent of other risk factors, including CKD.
We also demonstrated that increasing blood pressure was significantly associated with hyperuricemia even after adjusted for daily alcohol intake and the interaction for hypertension between hyperuricemia and alcohol were not significant. These results were almost accordance with recent previous study that was conducted in Japanese community-based population (p for interaction between hyperuricemia and alcohol drinking: .668 in male and .811 in female). 28 These findings suggest that the association between hyperuricemia and development of hypertension is dependent of alcohol drinking status.
In recent years, accumulating experimental studies have reported that hyperuricemia leads to vascular endothelial dysfunction, which causes BP elevation in several nonhuman animal models. 29 It is assumed that the mechanisms underlying vascular endothelial dysfunction involve (1) sodium urate crystals, which are deposited when there is a rapid increase in SUA level, (2) oxidative stress due to nitric oxide promotion through the process of metabolism of hypoxanthine to uric acid, and (3) increased urate reabsorption via urate transporter 1, resulting in the activation of the renin-angiotensin system and vascular proliferation. [29][30][31] The mechanism of interaction between hyperuricemia and CKD is not fully understood; however, Uedono and associates reported that hyperuricemia may lead to increased resistance of the renal artery and decreased glomerular filtration among participants with normal BP and renal function. 32 Therefore, hyperuricemia that accompanies CKD could result in more severe damage to an afferent arteriole and the development of hypertension.
To the best of our knowledge, this study is the first to clarify the role of CKD in the association between hyperuricemia and the incidence of hypertension in large community-based participants. We acknowledge there are some limitations in this study. First, the findings may have been affected by selection bias because the participants who attended the annual health check-ups were likely to be aware of healthy behaviors. Second, we were unable to obtain information regarding the use of antihyperuricemic agents and dietary habits, which can influence the level of SUA.

CONCLUSION
Hyperuricemia is an independent risk factor for the new development of hypertension. The effects of hyperuricemia on the incidence of hypertension were larger in participants with CKD than in those without CKD, and this interaction will be needed to be verified in future research.