A total of 269 adolescents and young adults were included in the study. Subjects were diagnosed with hypertension and additionally evaluated for other cardiovascular risk factors. The diagnosis was made according to diagnostic guidelines and age dependent cut off values (21). The data for this study were analyzed retrospectively. We examined our PWV measurements and included all adolescents and young adults with hypertension for whom all necessary measurements and serum urate were available.

The study of PWV measurement was approved by the Institutional Ethics Committee as was their retrospective analysis with inclusion of other acquired data. Laboratory investigations were performed as part of routine follow-up. Subjects were additionally labeled as obese (with BMI above 95^th percentile according to International Obesity Task Force (IOTF) (22)) or non-obese; 155 subjects were normal- or overweight and 114 were obese. Moreover, subjects were divided to those with elevated (131 subjects) or those with normal urate (138 subjects) according to age and gender specific reference values (2), since urate also changes with age (2).

The following data were collected for each participant: age, height, weight, BMI, systolic blood pressure (SP), diastolic blood pressure (DP), PWV and serum urate.

PWV was measured using arterial applanation tonometry (SphygmoCor, SCOR-Vx, Australia). All measurements were performed according to the manufacturer's instructions by three trained investigators with good intra-observer reliability. Before the measurement, each subject's weight and height, blood pressure and the arterial path length between the two recording sites (e.g., radial and carotid artery) were measured. Next, a pressure tonometer was used to transcutaneously record the pressure pulse waveform at the recording site. An ECG signal provided a timing reference for the software to be able to calculate PWV (23, 24).

SPSS Statistics (IBM, version 22) was used for statistical analyses. The statistical tests used included multiple regression analysis and independent samples T test. Additionally, for the discussion, correlations with Pearson correlation coefficient between urate and variables were performed in only normal-weight participants, data are not shown. A value of p < 0.05 was considered statistically significant.

In adults, important sex difference between urate levels was observed already more than 40 years ago (25, 26), as in our study. The most obvious explanation is the hormonal difference between the men and women that becomes apparent after puberty starts, which is consistent with our findings. The same was the idea more than 40 years ago, and therefore the role of estradiol-17β was investigated, however, not confirmed (26). The architecture of the female kidney is likely distinct from that of the male kidney since being a woman seems to be protective from renal and cardiovascular disease with better outcomes (27). A recent study determined that females with chronic kidney disease have a slower decline in glomerular filtration rate and a lower risk of death compared to age-matched men with similar mild-to-moderate chronic kidney disease (28). Studies have shown that estrogen may play a role in the regulation of expression or activity of urate transporters, which is supported by the fact that females have different renal urate transporter expression, localization or activity. Estrogen could mediate either direct transcriptional regulation of the transporter genes, or activate transporter specific transcription factors (27). Consequently, the levels of estrogen were inversely correlated to the levels of urate in post-menopausal women, in transgender males (female to male) and even in urate level changes during ovulation, when estrogen is lowest. The urate was also lowered when estrogen was administered after menopause (27, 29–31).

Studies of the adult population cannot simply be transferred to the pediatric population. Pediatric studies in this field are lacking, however, an interesting study demonstrated that the increase in urate at the time of puberty might be also related to muscle mass. Girls with higher muscle mass, evaluated by multi-frequency bioelectrical impedance, had higher urate levels as did boys, where the effect of muscle mass was even higher. Therefore, the difference in urate between boys and girls might be partially a direct influence of muscle mass, affected by hormonal changes, specifically with testosterone in boys (32). Additionally, association between urate and testosterone was found among obese children, indicating an impact of androgens in the regulation of serum urate in obesity (33).

Hyperuricemia has been frequently associated with obesity, renal disease, hyperlipidaemia, atherosclerosis and hypertension (34). In our study, significantly higher urate levels were found in patients with obesity, confirming the previously published studies. The increase in serum urate has often been considered to be secondary, however, some recent findings suggested that it may have a contributory role, because elevated serum urate levels preceded obesity (35).

Similarly, obesity and urate levels were associated in children, both in boys and girls, where significant differences between urate levels were observed during puberty. Obese children had elevated urate levels already at the beginning of the puberty indicating that obesity may affect urate's metabolism with either renal retention of urate, different modulation of urate at the tubular level and at least in part due to the urate overproduction in obese individuals (36, 37). Obesity is commonly associated with increased risk of cardiovascular disease, however, approximately a third of obese individuals do not develop cardiovascular disease (they are so called “metabolically healthy obese”). Recently, serum urate was found to be a good predictor of “metabolically unhealthy obesity” with associated features of metabolic syndrome, suggesting increased cardiovascular risk in adolescents and adults and might be useful as a prognostic marker (3).

Other cardiovascular risk factors, such as blood pressure, lipid profile and insulin levels were associated with higher urate levels. Multiple regression analyses in the above-mentioned study showed BMI, triglycerides, cholesterol LDL and insulin to be significant predictors of increased urate (38), however, not blood pressure, which is frequently associated with hyperuricemia (12). In our cohort, all participants have been diagnosed with hypertension and many were taking antihypertensive medications at the time of the measurement and laboratory work-up. Therefore, their blood pressure was already influenced by external factors making them difficult to evaluate. We would expect higher values of both SP and DP among hyperuricemia patients, as in other studies (13), where urate-lowering therapy even resulted in significant reduction in blood pressure (14). Anyway, the association with diastolic blood pressure was confirmed with multiple regression analysis. According to studies, hyperuricemia in hypertensive adolescents and young adults might not be associated with only obesity-associated hypertension, but could be in some cases independent risk factor for hypertension development in normal-weight individuals (12).

Hyperuricemia in cardiovascular risk is commonly asymptomatic in contrast to acute hyperuricemia in gout. The question remains if hyperuricemia in this context should be treated or not. Several associations between urate and cardiovascular diseases have already been mentioned. In adults, urate was studied also as a prognostic tool where it was found a good marker of mortality in patients with stable coronary artery disease treated with percutaneous coronary interventions, patients with chronic obstructive pulmonary disease and terminally ill cancer patients (39).

In adolescents and young adults, the prognostic value of urate and the need to treat hyperuricemia is less clear. So far, we can associate its role in some cases of essential hypertension development and in obesity by delineating “metabolically unhealthy” adolescents and young adults with increased cardiovascular risk. Little is known how elevated urate affects atherosclerosis itself, the common denominator of cardiovascular diseases.

In our study, we aimed to assess the associations between urate and PWV, a marker of arterial stiffness, which was associated with most cardiovascular risk factors and established atherosclerosis in adults (40), as well as in children with hypertension, obesity, impaired lipid profile and glucose metabolism (19, 41–44). Elastic properties of arteries change over time due to the normal aging and due to the pathological processes, such as presence of cardiovascular risk factors that can accelerate atherosclerosis. Higher arterial stiffness is associated with higher cardiovascular mortality, chronic heart disease, and stroke in adults (45, 46). Some associations between urate and PWV in adults have been already studied, however, the results are not consistent. One study found correlation between urate levels with greater increase in PWV in men but not women, which was lost when men with hyperuricemia were not included (47). In a meta-analysis, a significant association between urate and carotid-femoral-PWV was found in the general population in both males and females while it was only significant for females regarding brachial-ankle-PWV. Additionally, in a few available studies no significant relationship was found between urate and both carotid-femoral- and brachial-ankle-PWV in hypertensive patients (48). On the contrary, a recent study demonstrated an association between urinary, not serum urate, and arterial stiffness in adult men (49).

Urate was associated with increased arterial stiffness in stroke survivors in adult population, independently of other risk factors (50). Decreasing urate with allopurinol did not seem to be effective in reducing stiffening, but febuxostat showed an effect in decreasing PWV (51). A therapeutic intervention trial of lowering of serum urate is required to see whether this will affect positively on mortality and morbidity in patients with high cardiovascular risk. In adults, xanthine oxidase blocking treatment can be considered to reduce the risk of all-cause mortality in patients with higher cardiovascular risk and hyperuricemia along with recommended lifestyle modifications (39).

The studies investigating associations between urate and arterial stiffness in the pediatric population are scarce, let alone the evaluation of its prognostic role in future cardiovascular events. In our study, we did not confirm any associations between urate and arterial stiffness in a cohort of hypertensive adolescents and young adults, who are at increased risk for subclinical atherosclerosis. Similarly, there were no associations between urate and arterial stiffness in a cohort of adolescents with type 1 diabetes (52).

However, in our study it might be challenging to separate the effect of urate on pulse wave velocity from those due to hypertension, obesity and age. Additionally, blood pressure modifications during measurement, such as antihypertensive modifications and stress, might influence PWV making our study deficient with larger sample of participants required to eliminate shortcomings.

To our knowledge, no other similar studies were conducted and further research is needed to evaluate the prognostic role of urate in adolescents and young adults at cardiovascular risk, especially in hypertension or obesity, where the role of urate seems to be more important.