The major findings in the present study enable us to identify the importance of age in the relation between serum UA and BP. Although serum UA and BP showed a significant relation in the overall population, when we evaluated it according to different age groups (<40, 40–59, ≥60), it was only significant in the non-elderly population under age 60 in both genders. There have been several studies suggesting that the strength of the relationship between serum UA and BP is more dominant in the younger age groups and decreases during the aging process as the duration of hypertension gets longer [1,6,12,21-23]. However, none of the previous studies have tried to investigate the effect of different age groups on the relation as a primary goal. To our knowledge, this is the first study to confirm the effect of different age groups on the relation between serum UA and BP in a single large cohort.

The prognostic significance of serum UA in different disease entities such as diabetes, chronic kidney disease, and cardiovascular diseases have been recognized in several previous studies [2,5,6,9,24,25]. Understanding the relationship between each diseases and serum UA has been important due to the potential benefit which could be achieved by applying it to new treatment strategies. Feig et al. [16] mentioned that early hypertension developed in children and adolescents with hyperuricemia could be reversed with urate reduction. Considering the practical implications in every day clinical practice, our results suggest the same could be applied beyond the adolescent to the non-elderly adults under age 60 with early hypertension and hyperuricemia.

There are several potential explanations for the attenuation of the relationship in the elderly. Previous studies implicating similar results have mentioned that the effect of a single estimate of serum UA in the young may decrease over time, and the higher background rate of hypertension incidence by other causes with increasing age may contribute to the reduction of the strength of the relationship between serum UA and BP [21]. Although most of the studies controlled possible confounding variables such as age, BMI, and serum cholesterol levels, many of them did not adjust for diabetes [6,25], antihypertensive therapy [24-26], or diuretic use [25-27] which led to controversial results regarding the relationship between serum UA and BP, especially in the elderly. However, our study initially was designed for complete control over the variables mentioned above and excluded patients taking medications possibly affecting serum UA levels and BP. Variables such as age, BMI, diabetes, dyslipidemia, and renal function, represented by eGFR, were all taken into account for adjustment in the final analysis. Even after the adjustments, the current study confirmed a significant correlation with serum UA and BP in the non-elderly patients under age 60. Hyperuricemia increased the risk of hypertension in both genders, but was only significant in men <60 and women <40 in the multiple logistic regression analysis. Particularly in women younger than 40 with hyperuricemia, our study demonstrated a 2.6-fold increase in the risk of hypertension. Stronger association of serum UA with BP and hypertension in women was seen, which is in line with previous studies [6,23,28,29]. Awareness and early interventional strategies in controlling hyperuricemia associated with BP reduction in this specific group may obtain maximal benefit.

Studies using animal models and cell cultures have revealed mechanisms by which UA could cause hypertension. In short, hypertension was developed by UA-mediated renal vasoconstriction resulting from a reduction in endothelial levels of nitric oxide, with activation of renin-angiotensin system [30,31]. Microvascular renal disease independently was caused by UA over time, inducing the development of hypertension [30].

Recent therapeutic trials with UA-lowering agents have demonstrated promising results for reducing BP. In one small study, the use of allopurinol, a xanthine oxidase (XO) inhibitor, resulted in reduction of BP in adolescents with newly diagnosed hypertension with hyperuricemia [16]. In another small study, UA-lowering therapy with either allopurinol or probenecid, a uricosuric agent, significantly reduced BP in prehypertensive, obese, adolescents with hyperuricemia irrespective of the UA-lowering mechanisms [32]. Allopurinol also showed significant additional BP reduction when it was combined with enalapril compared to enalapril alone in hyperuricemic hypertensive adolescents [33]. There was a report that a 6-month treatment of febuxostat, a more recently developed selective XO inhibitor, showed a significant BP reduction even in the elderly patients (mean age, 67 ± 10.3 years) with serum UA ≥ 8 mg/dL in contrast to allopurinol [34]. Febuxostat had a stronger UA-lowering effect and a renoprotective effect and was also superior to allopurinol at inhibiting oxidative stress atherogenesis, hypertension, and vascular endothelial damage. However, the study was performed with an intermediate size specific group who underwent cardiac surgery, and 90% of the patients were already being treated with antihypertensive therapy. Therefore, the effect of febuxostat on BP reduction may not be applicable to the general hyperuricemic population including the elderly, yet.

Our study has several limitations. First, its cross-sectional design could not reveal the causal role of serum UA in the development of hypertension. Increased UA levels at baseline are suggested to result in vascular dysfunction but after chronic exposure to high UA levels, the corresponding alterations in the vasculature diminish over time [35]. There may be an underlying genetic difference between genders but the results of this study demonstrating a stronger association between UA and hypertension in women than in men could have occurred due to the difference in the duration of exposure to elevated UA levels [36]. Second, in contrast with previous studies [37], the prevalence of hyperuricemia was highest in group <40. In previous studies, the increasing prevalence of hyperuricemia in the elderly was because of higher incidence of taking antihypertensive and/or diuretic agents [7,17]. The exclusion of these patients may have led to the results above. Third, the statistical insignificance in the elderly may have been due to the relatively smaller sample size compared to the other groups. Fourth, with the exclusion of subjects on antihypertensive medications, this may have generated a bias in which our study results only regard subjects with mild hypertension. However, our distinct study design compared to previous observational studies [24-27] in which we completely controlled medications affecting serum UA levels may provide a more accurate interpretation in the relationship between serum UA and BP. Finally, we cannot absolutely exclude the possibility that the study subjects were taking medications which could affect serum UA levels or BP from family or friends in secrecy because we only evaluated the medication history based on the legal prescriptions recorded by HIRA.