Current updates and future perspectives in uric acid research, 2024

Abstract

Uric acid, the final product of purine metabolism, plays a significant role in hypertension Research on uric acid has advanced significantly, particularly regarding its links to hypertension and cardiovascular disease (CVD). Our 2023 review covered the relationship between uric acid, hypertension; and CVD, however, numerous new studies have emerged since then. This paper provides an update, summarizing recent findings over the past two years on hyperuricemia and its association with hypertension, preeclampsia, arteriosclerosis, kidney disease, sleep-disordered breathing, CVD, and so on. Hyperuricemia, often driven by reduced uric acid excretion or increased production, is influenced by genetic factors and lifestyle habits, including high-purine foods, alcohol, and fructose intake. While hyperuricemia has been proposed to contribute to hypertension and CVD through mechanisms like inflammasome activation and oxidative stress, its causal role remains debated. Further clinical and basic science studies on hyperuricemia and purine metabolism are necessary to clarify its impact on CVD and guide therapeutic approaches.

Background

The progress in research on the uric acid area has been remarkable. We published an updated review article on the role of uric acid in hypertension and cardiovascular diseases in 2023 [1]. However, numerous novel studies on uric acid have been reported since then. In this paper, we provide a summary of recent developments in uric acid research, particularly focusing on research from the last two years.

Hyperuricemia, caused by either reduced uric acid excretion or overproduction, is influenced by genetic factors and lifestyle, such as the consumption of purine-rich food, alcohol, fructose, exercise, and so on [2]. Hyperuricemia is linked to increased risks of metabolic syndrome, hypertension, chronic kidney disease (CKD), stroke, and cardiovascular disease (CVD). Proposed mechanisms of damage from hyperuricemia include inflammasome activation, decreased nitric oxide bioavailability, and oxidative stress induced by uric acid, urate crystals, and xanthine oxidoreductase (XOR)-mediated reactive oxygen species (ROS) [1]. Nevertheless, the causal relationship between hyperuricemia and arteriosclerosis or CVD remains debated as uric acid is affected by various environmental factors [3]. To clarify the role of hyperuricemia in these diseases, high-quality, detailed clinical and basic science studies investigating hyperuricemia and purine metabolism are needed [4].

Hypertension

Waki, et al. analyzed a Japanese nationwide claims database in 2014, and found that around 27 million people had hypertension, with approximately 90% receiving treatment [5]. The age-adjusted prevalence of hypertension was similar between men and women but varied by region. About 59% of hypertensive patients sought care at smaller clinics (0–19 beds) [5]. Salim, et al. conducted a cohort study to explore the 5-year risk of developing hypertension based on uric acid levels in men and women without cardiometabolic diseases, using two blood pressure (BP) cutoffs [6]. The results showed that men with serum uric acid levels of ≧6.5 mg/dL were associated with hypertension regardless of the BP definition used, while in women serum uric acid levels of >6 mg/dL were strongly associated with moderate hypertension defined as ≧130/80 mmHg [6]. “These findings suggest that the relationship between uric acid and hypertension is influenced by both sex and BP, consistent with previous studies [7–9].”

Dong, et al. conducted a cohort study from Beijing to investigate the association between elevated serum uric acid and hypertension by using data from 7482 non-hypertensive individuals in 2015 who were followed until 2019 [10]. The results indicated that higher serum uric acid levels were associated with an increased risk of hypertension, with triglycerides, white blood cell count, and alanine aminotransferase playing significant mediating roles in this association [10]. Kochi, et al. investigated the impact of hyperuricemia on the relationship between systolic BP (SBP) and the prevalence of proteinuria and low estimated glomerular filtration rate (eGFR) in 24,728 Japanese adults [11]. The study revealed that higher SBP was associated with an increased odds ratio of proteinuria, particularly in those with hyperuricemia. Additionally, elevated SBP was linked to an increased risk of low eGFR with proteinuria but a decreased risk without it, with these patterns more prominent in individuals with hyperuricemia [11]. Sasaki, et al. also showed that higher serum uric acid levels were associated with increased BP and a greater risk of developing hypertension over 6.5 years [12]. Specifically, normotensive and normoglycemic individuals with serum uric acid levels ≥5 mg/dL had a higher incidence of hypertension, suggesting the management of serum uric acid may help to prevent the onset of hypertension in such individuals [12]. The results are consistent with previous research indicating that the optimal serum uric acid range associated with the lowest development of cardiometabolic diseases, including hypertension, is less than 5 mg/dL for men and between 2 and 4 mg/dL for women [13]. Previously, two large meta-analyses showed a significant effect of uric acid-lowering treatment on BP [14, 15], further reinforcing the robust relationship between high serum uric acid and BP regulation.

Preeclampsia

Preeclampsia, a hypertensive disorder in pregnancy, is believed to arise from abnormal placentation, though its exact causes remain unclear. Yue, et al. conducted a retrospective cohort study of 4725 pregnant women to reveal that higher uric acid levels (≥240 μmol/L [4.0 mg/dL]) before 20 weeks gestation were associated with increased risk of preeclampsia, particularly during the first 8–12 weeks [16]. The study also indicated that women with elevated uric acid levels delivered earlier, suggesting that early pregnancy uric acid elevation may contribute to preeclampsia development.

Ma, et al. examined risk factors for preeclampsia in 524 pregnant women with chronic kidney disease (CKD) at Peking University Third Hospital from 2012 to 2022 [17]. The results identified hypertension, proteinuria, fibrinogen >4 g/L, serum albumin ≤30 g/L, and uric acid >260 μmol/L (4.37 mg/dL) as independent risk factors for preeclampsia in CKD patients. The subgroup analysis revealed variations between referred and registered patients, though hypertension and elevated uric acid were consistently associated with preeclampsia risk across all groups. A predictive model developed from the registered group revealed good efficiency [17]. Nakagawa, et al. hypothesized that fructose might be a clue to the origin of hyperuricemia and preeclampsia [18]. Preeclampsia may involve excess fructose production, which supports fetal growth under hypoxia but contributes to oxidative stress and endothelial dysfunction when overproduced [18]. Moreover, uric acid-related endothelial dysfunction disrupts arterial development, worsening placental hypoxia. However, serum uric acid has long been linked to preeclampsia, though its exact role remains unclear due to inconsistent data. This variability may stem from changes in uric acid levels during pregnancy, which drop early on due to increased blood volume and uricosuric effects of estrogen, but rise later as fetal uric acid production and maternal filtration decline [19]. When conducting research on uric acid in women including pregnant, it is important to consider that serum uric acid levels are influenced by hormones due to age [20], and further studies are needed to clarify these mechanisms and their implications for preeclampsia..

Arteriosclerosis

Nardi, et al. examined the presence of uric acid in carotid atherosclerotic plaques and its link to cerebrovascular events [21]. In patients undergoing carotid endarterectomy, uric acid was found more frequently in symptomatic plaques (86.9%) compared to asymptomatic plaques (22.2%) when assessed by Gomori methenamine silver staining. Immunohistochemical analysis further revealed a higher detection rate in symptomatic plaques (69.5%) versus asymptomatic plaques (11.1%). Furthermore, uric acid concentrations were significantly higher in symptomatic plaques (25.1 μg/g) than in asymptomatic ones (17.9 μg/g). Additionally, symptomatic patients had higher preoperative serum uric acid levels (5.9 mg/dL) compared to asymptomatic patients (5.2 mg/dL) [21]. These results suggest that uric acid may contribute to carotid plaque instability and serve as a potential biomarker for ischemic cerebrovascular events. An, et al., conducted a prospective cohort study to examine the link between serum uric acid and arterial stiffness in 7444 Chinese adults with hypertension over 10 years [3]. A linear relationship between higher baseline serum uric acid levels and increased arterial stiffness was found. After an average follow-up of 4.6 years, participants with high serum uric acid had a significantly higher risk of arterial stiffness (HR = 1.33, 95% CI 1.17–1.52, p < 0.001), particularly notable in males, those under 65, individuals not on antihypertensive medication, and those not meeting BP targets [3]. These results suggested high serum uric acid as a risk factor for arterial stiffness in this population. Moreover, Tomiyama, et al. analyzed the impact of cardiovascular risk factors on arterial stiffness progression with the brachial-ankle pulse wave velocity measurements over 16 years in a middle-aged Japanese cohort [22]. The study found that smoking, heavy alcohol use, hypertension, diabetes, hypertriglyceridemia, and hyperuricemia were linked to accelerated progression of arterial stiffness. Conversely, lower uric acid levels within the normal range, as well as lower BP, HbA1c, and triglycerides, were associated with slower progression [22]. These findings highlight the importance of early intervention on cardiovascular risk factors, including uric acid, to slow the progression of arterial stiffness and reduce cardiovascular risks.

Kidney disease

Kohagura, et al. conducted the URIC CKD study to compare the effects of the xanthine oxidase inhibitor (XOI) febuxostat and the uricosuric drug benzbromarone on kidney function in patients with stage G3 CKD, hypertension, and hyperuricemia [23]. Over 52 weeks, there were no significant differences between the two drugs in slowing eGFR decline or in secondary outcomes, except febuxostat reduced xanthine oxidase activity. Subgroup analysis showed febuxostat had a slightly better effect on eGFR in CKD stage G3a but not G3b. Both treatments were welltolerated, with no specific adverse effects noted [23].

Sleep-disordered breathing

Shimizu, et al. investigated the link between sleep-disordered breathing (SDB) and oxidative stress in males with coronary artery disease (CAD). Serum uric acid, xanthine oxidoreductase (XOR) activity, and urinary oxidative stress marker 8-hydroxy-2’-deoxyguanosine (8-OHdG) were measured overnight in 32 CAD patients [24]. The study found significant overnight increases in serum uric acid, XOR activity, and 8-OHdG levels with SDB severity (measured by 3% oxygen desaturation index) correlated with changes in XOR activity and 8-OHdG [24]. These findings suggest that SDB may contribute to oxidative stress through increased uric acid production, potentially worsening CAD.

Transporters and inflammation

Notsu, et al. investigated whether inhibiting the ABCG2 transporter increases IL-1β production by allowing intracellular uric acid accumulation, particularly in hyperuricemic conditions, using J774.1 mouse macrophage cells [25]. Both genetic knockdown and pharmacological inhibition of ABCG2 raised pro-IL-1β, mature IL-1β, and caspase-1 protein levels. Febuxostat, an ABCG2 inhibitor, further enhanced IL-1β production in uric acid-pretreated cells, while dotinurad, a uric acid reabsorption inhibitor, did not induce the same effect [25]. These findings suggest that ABCG2 inhibition promotes IL-1β production by increasing intracellular uric acid levels, activating the NLRP3 inflammasome, and stimulating pro-IL-1β transcription.

Analyses of randomized controlled trials

The AMETHYST randomized clinical trial (RCT) of 159 patients with heart failure with preserved ejection fraction (HFpEF) and elevated serum uric acid levels, the combination of verinurad and allopurinol significantly reduced serum uric acid levels compared to allopurinol alone or placebo after 32 weeks [26]. However, this combination did not lead to meaningful improvements in exercise capacity, symptoms, or key echocardiographic parameters [26]. This suggests that while verinurad effectively lowers serum uric acid, it does not improve clinical outcomes in HFpEF patients.

Several results from post-hoc analysis of the RCTs have been released. The post hoc analysis of the Excited-UA study [27], which previously showed that topiroxostat did not induce significant benefits in patients with chronic heart failure and hyperuricemia compared with allopurinol, examined optimal uric acid targets for vascular endothelial function in chronic heart failure patients treated with xanthine oxidase inhibitors [28]. Among 133 patients grouped by uric acid levels after 24 weeks, those with moderate levels showed a greater improvement in reactive hyperemia index (RHI) compared to those with low or high levels [28]. This suggests that excessively low uric acid levels may not be as beneficial for enhancing microvascular endothelial function, which is consistent with previous research showing that the depletion of uric acid due to loss-of-function mutations in the uric acid transporter (SLC22A12/URAT1) is associated with endothelial dysfunction, as measured by flow-mediated dilation in hypouricemic patients [29].

In the sub-analysis of CANDLE trial [30], which found no significant change in NT-proBNP levels after 24 weeks of treatment with canagliflozin versus glimepiride, canagliflozin significantly lowered estimated plasma volume and serum uric acid levels over 24 weeks in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF), regardless of diuretic use [31]. This reduction in uric acid and estimated plasma volume occurred without worsening renal function or causing major electrolyte imbalances [31].

The sub-analysis of the PRIZE study [32] investigated the long-term effects of febuxostat on atherosclerosis and arterial stiffness. Among 100 participants, 48 received lifestyle modifications, and 52 received febuxostat [33]. Over 24 months, febuxostat significantly reduced arterial stiffness compared to controls (−5.099%, 95% CI−10.009% to −0.188%, p = 0.042), though no improvement in carotid atherosclerosis was observed [33]. Further long-term studies are needed to evaluate febuxostat’s impact on cardiovascular outcomes linked to arterial stiffness.

The post-hoc analysis of this FREED (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy) [34], which showed a 25% reduction in the rate of the cardio-renal composite outcome in the febuxostat group compared with the non-febuxostat group, was conducted using 1,070 asymptomatic hyperuricemic elderly patients were divided into febuxostat (n = 537) and non-febuxostat (n = 533) groups [35]. The febuxostat group had a 56% lower risk of developing or worsening macroalbuminuria (hazard ratio 0.44, P = 0.0098), while other outcomes showed no significant difference [35]. Thus, febuxostat appears to reduce the risk of macroalbuminuria progression in asymptomatic hyperuricemia without gout.

Uric acid as an indicator of cardiovascular risk

The Uric Acid Right for Heart Health (URRAH) study, a nationwide Italian study among 20 724 participants followed-up for 126 ± 64 months, identified a serum uric acid to creatinine (sCr) ratio cut-off of >5.35 as a predictor of cardiovascular events [36]. This threshold was consistent across both men and women. Participants with serum uric acid/sCr >5.35 had a higher hazard ratio for cardiovascular events, which increased significantly across higher quintiles. This finding suggests that serum uric acid/sCr >5.35 is a dynamic, independent indicator of cardiovascular risk [36]. Another study from the URRAH cohort explored the link between serum uric acid and mortality in older adults [37]. In individuals aged 65–74, higher serum uric acid levels were independently associated with increased all-cause and cardiovascular mortality, with a threshold of 4.8 mg/dL predicting mortality risk. In those aged 75 and older, a J-shaped relationship was observed, indicating increased risk at both high and low serum uric acid levels [37]. Although the exact reasons for this phenomenon remain unclear, some articles have proposed potential explanations. Low serum uric acid levels can sometimes serve as a marker of poor health status and malnutrition, including insufficient intake of protein, cholesterol, and calories [38]. It suggested that low-serum uric acid levels are associated with increased mortality in older adults especially those suffering from malnutrition [39]. Additionally, given the known antioxidant properties of uric acid, very low serum uric acid may reduce the ability to counteract oxidative stress and damage [40]. These findings suggest age-related differences in serum uric acid’s impact on mortality and highlight the need for further research on uric acid-lowering treatments in older adults.

Xanthine oxidase inhibitors withdrawal syndrome

A Japanese nationwide database study examined the effects of XOI on mortality in 1,648,891 cardiovascular patients using the J-ROAD registry [41]. Continuous use of XOI significantly reduced mortality (OR, 0.576; 95% CI, 0.567–0.587; P < 0.001), with allopurinol (OR, 0.578), febuxostat (OR, 0.610), and topiroxostat (HR, 0.545) showing lower mortality compared to no uric acid-lowering treatment. Conversely, XOI withdrawal was associated with a higher mortality rate (19.8% vs. 0.03% in continuous users; P < 0.001), highlighting the need for cautious XOI management [41]. These results were compatible with sub-analysis of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial [42], which showed that nearly 85% of deaths occurred while subjects were off of therapy [43] and increased major adverse cardiovascular events and cardiovascular death verse events were increased in the initial stage after discontinuation of febuxostat or allopurinol [44]. The article hypothesized that the main cause of death is from XOI withdrawal by removing beneficial effects of XOI, such as uric acid reduction, reduced ROS production, lower inflammation, and adenosine triphosphate (ATP) preservation [45, 46].

Conclusions and future research

This review highlights recent advancements in understanding the association between hyperuricemia and various health outcomes, particularly hypertension and CVD (Fig. 1). Although the association is supported by observational data, randomized controlled trials have yet to confirm a direct causal relationship. Future research should prioritize refining cardiovascular risk thresholds for uric acid, investigating the effects of uric acid fluctuations over time, and identifying markers of uric acid overproduction [47]. Such efforts will improve our understanding of hyperuricemia’s role in hypertension and help tailor interventions to optimize cardiovascular and renal health.

Fig. 1.

2024 Update and perspective in uric acid research