2.1. UA Biology

UA is a weak acid, and in normal blood pH values it exists predominantly as urate anion. XOR catalyzes the generation of urate from hypoxanthine and xanthine, which are the last metabolites of endogenous and exogenous purine mononucleotide catabolism [40,42,60]. XOR has two forms: Xanthine dehydrogenase (XDH), the most prevalent, and xanthine oxidase (XO) [61]. Hyperuricemia is defined as SUA > 6 mg/dL in women, SUA > 7 mg/dL in men, and SUA > 5.5 mg/dL in the pediatric population, and its prevalence is increasing worldwide [42,62]. During the Miocene epoch, humans lost the capacity to metabolize UA into allantoin due to nonsense mutations in the gene codifying the enzyme uricase [63]. However, a minimal amount of UA can be indirectly metabolized through its reaction with oxidants, lipid radicals, nitric oxide, and peroxynitrite [41].

The most common cause of hyperuricemia is a decrease in UA excretion, e.g., during renal insufficiency, metabolic acidosis, hypothyroidism, or treatment with drugs such as beta blockers [42]. Increased purine degradation (e.g., during DNA, RNA, and ATP breakdown) also leads to a rise in SUA [40]. In addition, increased activity of aldose reductase and XO, as occurring during ischemia, heat stress, and dehydration, have been associated with a rise in intracellular UA and SUA.

Approximately two-thirds of urate elimination occurs in the kidney, while one-third occurs in the small intestine. In the kidney, UA is readily filtered, and up to 90% is reabsorbed by the proximal tubular cells by the apical transporters URAT1 and OAT4, and the basolateral GLUT9 [42]. In addition, UA can be secreted in variable amounts into the proximal tubular lumen by the apical transporters ABCG2, NPT1 and 4, SLC2A9b, and the basolateral OAT1 and 3 [42,43]. The intestinal elimination of UA is mediated by both bacterial uricolysis (mainly for orally administered purine-high aliments) and cellular excretion by the transporters P-Glycoprotein, MCT9, NPT4, NPT homolog (NPT5), OAT10, GLUT9, ABCG2, and MRP2 and 4 [64]. Recently, other UA transporters have been discovered with genome wide-association studies, increasing the UA-homeostatic system knowledge complexity [43,64].

The so-called UA remote sensing and signaling theory has hypothesized an interplay between gut microbiome, kidney urate transporters, and gut urate transporters in the regulation of SUA levels [43]. Interestingly, the composition of the gut microbiota has shown to play a role in UA metabolism in both human and animal models [65,66,67]. For example, higher prevalence of Escherichia coli has been associated with a greater extent of intestinal UA decomposition [65]. The transplant of fecal microbiota of hyperuricemic rats to healthy rats was able to induce an increase in SUA concentrations [66]. Additionally, in rat models, bariatric surgery has been shown to alter the composition of the gut microbiota, with a resulting reduction in SUA concentration [67].

2.2. Biology of the Association between UA and Hypertension

UA has demonstrated a crucial role in the pathogenesis of hypertension and kidney disease progression [41,42,68]. Possible pathophysiological mechanisms involve RAAS upregulation, kidney afferent arteriolopathy, endothelial dysfunction, oxidative stress, and systemic inflammation.

Experimental studies on human cell cultures and hyperuricemic animal models have shown that UA can upregulate the renin-angiotensin-aldosterone system (RAAS) [21,22,23,24,25,26]. In addition, RAAS can be indirectly activated by UA-mediated inflammatory status [23,69]. Some in vivo human studies showed a correlation between SUA and RAAS [70,71], while others did not [72,73]. A possible explanation for these inconsistent results is that most studies analyzed systemic RAAS activity and not specifically intrarenal RAAS. In fact, intrarenal RAAS could be upregulated by UA without a concomitant increase in systemic RAAS activity. Supporting this hypothesis, a study on 249 adults has shown that SUA correlated with intrarenal RAAS activity, but not with plasma renin activity [74].

Other than triggering RAAS, UA has been shown to induce hypertension through a crystal and pressure-independent kidney afferent arteriolopathy [27,28,29]. Afferent arteriolopathy can indeed lead to impaired renal blood flow, ischemia, and consequent renovascular hypertension [75,76]. However, the exact mechanism whereby UA can induce arteriolopathy remains partially unsolved. UA-induced oxidative stress and inflammation may play a role, being responsible for the pathogenesis of endothelial dysfunction [24,25,26,32,33]. Another possible cause of afferent arteriolopathy is the UA-mediated vascular smooth muscle cell proliferation [25,31,77,78]. UA-mediated hypertension may also be caused by the up-regulation of thromboxane and endothelin-1. In fact, both these vasoconstrictor molecules can be over-expressed in the presence of high UA concentrations, inducing the development of hypertension [65,79]. UA can also mediate the development of hypertension through a crystal-dependent pathway [80,81]. In fact, monosodium urate deposits have been found in the kidney medulla, cardiac valves, arteries, and within the atherosclerotic plaque [80,81]. These deposits could lead to kidney injury and arterial stiffness, increasing the risk for hypertension [80,81].

Biological variables that could influence the association between UA and hypertension are sex and women’s menopausal state [82,83]. Indeed, it has been demonstrated that postmenopausal women had a stronger association between high SUA and hypertension, compared to premenopausal women [82]. Additionally, Nishio and colleagues have shown that women had a stronger association between high SUA and hypertension compared to men, after multivariate adjustment [83]. Further studies are warranted to fully elucidate the role of sex and menopausal state in the association between SUA and hypertension.

2.3. Genetic Studies on the Association between UA and Hypertension

In the last decades, an increasing number of genome wide association studies and Mendelian randomization studies have attempted to validate the epidemiological association observed between SUA and hypertension [84,85]. Genome wide association studies in European, African American, and East Asian populations have shown that genes encoding urate transporters (e.g., GLUT9, URAT1, ABCG2) were the main cause for SUA levels, and that the heritability of SUA in Europeans was estimated ~27–41% [84]. Different studies demonstrated that polymorphisms of the SLC2A9 gene associate with the risk of hypertension [85]. Additionally, aldehyde dehydrogenase II (ALDH-2) polymorphisms have been associated with SUA levels and hypertension in genome wide association studies [86]. Other genetic polymorphisms that regulate SUA levels and associate with hypertension are XOR gene variants [85,87,88]. Of note, XOR is not only associated with increased SUA levels, but also with increased oxidative stress, which in turn may lead to the development of hypertension [87,88]. In contrast with the aforementioned studies, the genetic risk score developed using 30 gene variants responsible for SUA levels has been associated with lower BP values [84]. Additionally, Mendelian randomization studies failed to demonstrate a causal relationship between SUA and the development of hypertension [41,84].

Possible explanations for these contrasting results include the role of intracellular UA, the use of diuretics, and the dietary sodium intake [41]. Intracellular UA concentrations are not always associated with SUA levels and are responsible for the biological effects of UA [41]. It is still unknown how urate transporters regulate intracellular UA levels. Indeed, different polymorphisms of SCL2A9 gene have been shown different effects ranging from hyperuricemia without hypertension (liver specific knockout) to hyperuricemia and hypertension (intestinal knockout) or hypouricemia (systemic knockout) [41]. In animal models, high salt diet has shown to induce intracellular hepatic urate generation and to increase BP values without a parallel increase in SUA concentration [89]. In addition, randomized controlled clinical trials have shown that high dietary sodium intake (200–250 mmol/day) was associated with lower SUA levels and higher BP values [90].

Finally, as suggested by Kei and colleagues, the association of the genetic risk score for hyperuricemia with lower BP values might be explained by the possible confounding effect of the treatment with diuretics [85]. In fact, people with a high risk score have a higher probability to develop hypertension and thus to be under diuretic treatment. In addition, treatment with diuretics is known to induce an increase in SUA concentrations [41,85].

2.4. Prognostic Role of UA in Hypertension

One of the main challenges in determining the association between UA and hypertension has been the coexistence of hyperuricemia with other cardiovascular (CV) risk factors. For example, SUA levels are usually increased in people with metabolic syndrome, which is a known risk factor for hypertension [91]. To determine if UA was an independent risk factor for hypertension, most epidemiologic studies have used multivariate analyses and adjustments.

Several cross-sectional studies have shown that hyperuricemia is present in 25–60% of individuals with untreated essential hypertension, and SUA levels are associated with prehypertension [92,93,94]. Longitudinal studies have confirmed the prognostic value of UA in hypertension, demonstrating that higher SUA levels were associated with an increased relative risk for hypertension [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20] (Table 1).

Large meta-analyses confirmed the same findings, however Mendelian Randomization studies failed to demonstrate a causal relationship between SUA and hypertension [95,96,97]. Interestingly, genetic population-based association analyses have shown that XOR genetic polymorphisms, but not major urate transporters ones, associated with hypertension [34,35,36,37,38,39]. Since XOR is involved in intracellular UA production, the results of those genetic studies may underlie a critical role of intracellular UA production, instead of SUA, in the development and progression of hypertension. Supporting this hypothesis, plasma XO activity has been associated with CV outcomes, independently of SUA levels [98,99]. In addition, Boban et al. showed that XOR was upregulated in subjects with essential hypertension [100].

2.5. UA Lowering-Therapies Effects on Blood Pressure

There are two main classes of hypouricemic agents: UA production inhibitors and UA excretion promoters [101,102]. So far, there have been only a few studies that have analyzed the effects of UA-lowering drugs in patients with hypertension [44,45,46,48,49,50,51,52,53,54,55,56,57,58,59,103] (Table 2). Allopurinol, febuxostat, probenecid, and pegloticase all demonstrated antihypertensive properties [50,51,52,53,54,55,56,57,58,59].

Children and adolescents with hyperuricemia and prehypertension or hypertension showed a greater decrease in BP values after allopurinol or probenecid initiation, compared to placebo [50,51,55]. In another controlled study, allopurinol treatment was able to decrease systolic BP values in adults with overweight and prehypertension [52]. Interestingly, allopurinol has also shown a long-term effect in decreasing central blood pressure in adults with recent ischemic stroke or transient ischemic attack [56]. UA lowering-drugs have demonstrated an antihypertensive effect in populations with hypertension and hyperuricemia [50,54,59]. Indeed, the population of the studies that showed no BP effects of hypouricemic drugs did not include subjects with both hypertension and hyperuricemia [44,45,46,48,49,103].

Most studies on subjects with chronic kidney disease (CKD) did not show any antihypertensive property of UA-lowering medications [44,45,49]. A possible explanation is that several factors other than UA drive BP in subjects with CKD. Furthermore, since people with CKD are commonly prescribed with RAAS inhibitors and RAAS activation could be one of the UA-mediated hypertension mechanisms, in this population, the antihypertensive effect of UA-lowering drugs could be masked [21,22,23,24,25,26,66].

Overall, the results of the available studies appear controversial. Possible explanations include the different study designs, the small and heterogeneous populations, the presence of confounding factors, the complex relationship between SUA and intracellular UA, and the short follow-up periods.

Several studies have shown a U-shaped association between SUA concentrations and different CV outcomes [104]. Additionally, a U-shaped association between SUA and microvascular remodeling indexes has been recently demonstrated [105]. The U-shaped relationship between SUA and different CV indexes may explain the heterogeneity of UA-lowering medications trials results.

Large clinical trials on the BP effects of UA-lowering drugs in specific study populations are warranted to further clarify the benefits of this class of drugs in the treatment of hypertension and its complications.

2.6. Antihypertensive Medications Effects on SUA

Most antihypertensive medications, such as RAAS inhibitors, alpha-1 blockers, beta blockers, and diuretics, have been shown to increase SUA levels, with an enhanced risk of incident gout [106,107].

On the other side, calcium channel blockers and the angiotensin II receptor blocker losartan have been shown to reduce SUA concentrations and the risk of gout [108,109,110]. In particular, losartan has been shown to reduce SUA levels when administered alone [106] or, to a greater extent, in combination with the calcium channel blocker amlodipine [108]. Interestingly, in The Losartan Intervention. For Endpoint reduction in hypertension (LIFE) study, the increased CV risk reduction obtained with losartan compared to atenolol was mainly attributable to the UA-lowering properties of losartan [104]. The mechanism of losartan reduction of SUA seems to involve the inhibition of UA reabsorption with a uricosuric effect [110].

Altogether these findings underlie the importance of the so-called personalized medicine. In other words, it appears mandatory to take into account the characteristics of the single patient in order to choose the appropriate antihypertensive drugs. This approach also leads to a holistic view of CV risk, with a potential improvement of preventive and therapeutic strategies to reduce CVD burden.

2.7. How to Choose the Right Hypouricemic Agent

A recent systematic review of clinical practice guidelines and consensus statements on the treatment of hyperuricemia and gout recommended long-term treatment of patients with gout or with comorbities and SUA > 6.0 mg/dL (or 360 μmol/L) [102]. Even if treatment of asymptomatic patients without comorbities is still not recommended, large population studies such as the multicenter Uric Acid Right for Heart Health (URRAH) Study showed that the optimal SUA cut-off for reducing CV mortality was under 5.6 mg/dL [111,112,113].

The recommended first-line treatment was allopurinol, unless the patient had the genetic variant HLA-B*5801, which is commonly found in Han Chinese, South East Asians, and African Americans [102].

The second line treatment is febuxostat [102]. If the target SUA level is not reached, a combination therapy with a uricosuric agent can be considered. However, uricosurics cannot be used in patients with a history of nephrolithiasis or with uricosuria levels higher than 700–800 mg/24 h. Finally, recombinant uricase such as pegloticase can be used in patients with refractory gout for a maximum of 6 months [102,114].

As previously mentioned, in the modern era, a holistic view of CV risk appears mandatory. Few medications used to treat other CV risk factors have been shown to collaterally reduce SUA levels. Two examples are the insulin-sensitizing troglitazone, used to treat patients with type 2 diabetes, and the fibrate fenofibrate, mainly used in the treatment of hypertriglyceridemia [115,116]. Knowing the UA-lowering properties of medications commonly used to treat other CV risk factors could help avoiding polytherapy and possible drug interactions, in particular in the elderly.