Uric Acid and Atherosclerosis in Patients with Chronic Kidney Disease: Recent Progress, Mechanisms, and Prospect

Abstract

Background

Chronic kidney disease (CKD) is a prevalent global health concern, significantly linked to increased cardiovascular morbidity and mortality. Among various risk factors, uric acid (UA) has emerged as a potentially modifiable contributor to cardiovascular complications in CKD patients.

Summary

Elevated serum uric acid levels frequently occur in individuals with CKD and are associated with the development of atherosclerosis (AS). Uric acid has been demonstrated to exacerbate inflammatory processes, promote oxidative stress, and cause endothelial dysfunction, which are critical factors that drive the formation of atherosclerotic plaques. Furthermore, high uric acid levels can worsen renal function, establishing a detrimental cycle that amplifies cardiovascular risk.

Key Messages

This review investigates the complex interconnection between UA and AS in patients with CKD, highlighting the underlying mechanisms and therapeutic considerations. A more profound comprehension of this relationship is essential for enhancing cardiovascular health and outcomes in this vulnerable population.

Introduction

Uric acid (UA), which functions as an important accelerator in the evolution of the human stress response, intelligence, and upright walking [1], is now mainly considered as an antioxidant. However, the overaccumulation of UA can lead to serious consequences [2], such as chronic kidney disease (CKD), diabetes mellitus (DM), coronary heart disease, hypertension, and stroke. Elevated UA level coincides with CKD progression. Meanwhile, poor kidney function will also result in hyperuricemia.

As a leading cause of death and disability worldwide, atherosclerosis (AS) can supervene with many other common diseases and aggravate the risk of them. In previous studies [3–6], there is strong evidence of a link between higher UA level and AS progression. Furthermore, the risk of premature death in CKD patients mainly comes from cardiovascular diseases, which obviously includes AS. Life quality of CKD patients also decreases as the GFR declines [7]. Given the concern about the rising prevalence and incidence of CKD, it is necessary to investigate the relationship between UA levels and AS in patients with CKD. In this review, we will discuss recent progress, mechanisms, prospect of UA level, and AS in patients with CKD, to guide prevention, diagnosis, and long-term treatment.

Uric Acid Metabolism in CKD Patients

UA is the final product of purine metabolism in human body. Figure 1 shows the metabolic pathway of UA. There are two sources of UA: 1/3 from the exogenous diet and 2/3 from the endogenous synthesis. UA is produced primarily in the liver, with a portion coming from the small intestine. Purine metabolism occurs mainly in the liver, and xanthine oxidase (XO) encoded by the xanthine oxidoreductase (XOR) gene is the key rate-limiting enzyme in this process. Hypoxanthine produced by purine metabolism can be sequentially oxidized by XO to form xanthine and UA. In mammals, uricase is present in the liver, which further breaks down UA into more soluble allantoic acid for excretion. In all, 70% of the UA synthesized by the body is reabsorbed and excreted by the renal tubules after glomerular filtration, and the remaining 30% is excreted from the gastrointestinal tract (shown in Fig. 1).

Fig. 1.

UA metabolism. 5-Phosphoribosyl 1-pyrophosphate (PRPP) can be transformed into inosine monophosphate (IMP). IMP, adenosine monophosphate (AMP), and guanosine monophosphate (GMP) can be transformed into each other. XO is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine, and xanthine to UA. It is inhibited by allopurinol and febuxostat. The gene for uricase has been inactivated in humans. Rasburicase and pegloticase can restart the process, transforming UA into allantoic acid, a more soluble form.

UA homeostasis is composed of the interaction and balance of routine intake, de novo synthesis, recycling, degradation of XO, and excretion of kidney and gastrointestinal tract. Once the balance is disturbed, hyperuricemia will probably follow. When UA concentration exceeds 380 μmol/L, the risk of UA crystallization and precipitation rises [8]. Hyperuricemia can be divided into 3 types based on different pathogeneses: overproduction type, underexcretion type, and mixed type (shown in Fig. 1). More than 90% hyperuricemia patients belong to the underexcretion type, suffering from renal insufficiency [9, 10]. Diseases, drugs, and hereditary factors can lead to decreased renal excretion of UA, resulting in hyperuricemia.

Glomerular filtration or tubular secretion dysfunction may be present in approximately 90% of patients with hyperuricemia and gout [11]. In CKD patients, damage to the renal vascular endothelium, tissue ischemia, and hypoxia, resulting in increased expression of hypoxanthine and purine oxidase, causing increased production of UA. Elevated lactate level decreases UA excretion. Decreasing glomerular filtration rate and impaired tubular function lead to hyperuricemia because of abnormal UA filtration, reabsorption, and secretion. Diuretics, which reduce blood volume, lead to hyperuricemia by increasing the net reabsorption of UA.

Epidemiological evidence suggests that renal underexcretion is the main cause of hyperuricemia [12]. Disruption of UA homeostasis leads to fluctuations in UA levels, making it more likely to cause hyperuricemia. When mounting evidence shows that hyperuricemia is one of the independent risk factors for CKD, cardiovascular disease, and DM, it is urgently necessary to address the importance of UA homeostasis.

In recent studies, hyperuricemia is noted as a key risk factor associated with AS. Among patients with CKD, the increased risk of premature mortality mainly comes from AS. Considering the worldwide high occurrence and mortality of AS and CKD, more attention should be paid to maintaining UA homeostasis, especially in CKD patients.

Relationship and Recent Progress between Uric Acid and Atherosclerosis in CKD Patients

As mentioned above, more than 90% of patients with hyperuricemia have kidney problems. The reason may lie in some harmful physiological effects of UA, including but not limited to oxidative stress, adipose inflammation, vascular smooth muscle cell (VSMC) proliferation, inhibition of nitric oxide (NO) production, and endothelial dysfunction [13–17]. Despite the direct pathophysiological mechanism, hyperuricemia can also worsen hypertension and DM [18, 19], which are well-known correlation factors of CKD and AS. Besides, CKD will decrease the excretion of UA, and its connection with hyperuricemia is complicated and intimate. There is a significant overlap in population affected by the two diseases. Approximately half of patients with CKD developed hyperuricemia when they started dialysis [20]. The prognosis is highly correlated with the existence of AS in CKD patients. Considering the strong correlation between the UA level and AS, the findings in this network seem to matter.

The prevalence of cardiovascular morbidity and mortality is higher in patients with CKD, especially those with end-stage renal disease, than in the general population. Numerous factors are believed to contribute to an acceleration of the atherogenic process in patients with CKD. In addition to the frequent presence of traditional factors for AS (such as age, smoking, and dyslipidemia), the effects of uremia-specific factors need to be considered. For example, studies in past 10 years have shown that a direct association can be found between serum cholesterol level and AS-related mortality in general population. However, 2 randomized controlled trials in patients on hemodialysis failed to show a significant improvement in AS outcomes, although serum cholesterol levels have been effectively reduced by statins [21, 22]. This suggests that the same risk factor may have different or even opposite effects in different populations. It should be noted that asymptomatic AS was made apparent by the progress of CKD, through increasing number of plaques. Despite the large number of clinical studies between the two populations, specific differences in AS and UA between the populations remain elusive because of the number of confounding factors.

UA-lowering therapy is a conventional treatment [23] for hyperuricemia in patients with or without CKD, and many studies [24, 25] have shown improvements in slowing of CKD progression and reduced risks of cardiovascular events [26] after the therapy. A cohort study noted that the extent of coronary artery calcification was proportional to the concentration of circulating UA. According to many studies, elevated serum UA levels are a traditional predictor for the presence and progression of AS [27–31]. UA-lowering therapy can delay AS progression [32, 33].

In patients with CKD, many clinical trials [34–36] reported that the use of allopurinol can significantly lower the risk and mortality of AS in patients with CKD. 3 clinical trials evaluated the effect of reducing serum UA level of CKD patients and found a 60% reduction in cardiovascular events compared with the control group [35–37]. In a large-scale cohort study conducted in Kailuan that included 27,707 patients with CKD, Li found that a higher concentration of UA was associated with a higher risk of myocardial infarction, heart failure, and all-cause mortality among individuals with CKD, following a dose-response manner [38].

Some specialists found that UA-lowering therapy hits the target not by reaching a proper UA concentration [32], but by a great reduction in serum UA levels [33]. That suggests that a change of UA level may be more important than a simple concentration of serum UA in AS management. Nonetheless, scientists [6, 34, 39–42] have failed to reach an agreement on whether there are exact benefits brought to patients with CKD directly by a reduction in serum UA level through small or large trials of various qualities. Most Western specialists do not recommend treating asymptomatic hyperuricemia in patients with CKD, whereas Asian experts in China, Japan, and Korea recommend active treatment [43].

Serum UA level in early CKD patients can be used to estimate the ischemic heart disease occurrence, even in stages earlier than G3a [44]. In moderate CKD stage, AS also got an increased prevalence [45–47], which is closely related to high serum UA levels [48]. The serum UA level in patients with CKD may take part in various pathways that lead to AS [49, 50].

Potential Mechanisms Linking Uric Acid to Atherosclerosis in CKD Patients

Oxidative Stress

UA plays a major physiological role in extracellular antioxidation and intracellular net pro-oxidation. Under physiological conditions, UA is an important antioxidant in the blood. But when the level of serum UA exceeds the physiological concentration, it activates the oxidative stress response and promotes the occurrence and development of cardiovascular diseases. Excessive levels of UA can be rapidly taken up by endothelial cells, promoting the production of angiotensin II (Ang II) and the expression of Ang II type 1 receptor, activating the renin-angiotensin system (RAS), which in turn induces oxidative stress, causing senescence and apoptosis of endothelial cell [14], and proliferation of VSMC via MAPK/ERK pathway [51]. This effect can be inhibited by the angiotensin-converting enzyme inhibitor captopril and the Ang II receptor blocker (ARB) losartan [13]. RAS plays an important role in the enhanced susceptibility to AS seen across the spectrum of CKD [52], which suggests that hyperactivated RAS and high serum UA levels may promote AS progression together in patients with CKD [13, 14, 53].

PI3K/Akt pathway regulates the distribution of the UA secretory protein adenosine triphosphate (ATP)-binding cassette superfamily G member 2 (ABCG2) in cells. High serum UA level aggravates the accumulation of UA in endothelial cells by activating oxidative stress in endothelial cells, inhibiting the phosphorylation of Akt, and decreasing the membrane translocation of ABCG2 and UA efflux [54].

In the process of UA metabolism, which involves redox reactions, XO plays an important role in the conversion of purine to UA. Normal cellular function and damaging effects may be impacted by the dynamic equilibrium of reactive oxygen species (ROS) [55] that take part in cellular signaling pathways, inflammatory regulation [56], vasoconstriction, and dilation [57]. Expression of XO increases during serum UA level elevation, which directly induces oxidative stress through a series of reactions. In the end, these reactions would thereby participate in the onset and progression of many cardiovascular diseases [55]. XO inhibitor, allopurinol, can suppress the formation of foam cell and AS [55]. Hence, in the internal environment of oxidative stress in patients with CKD, antioxidant ability of UA may change into stimulating oxidative stress, which facilitates the formation and progression of AS.

Inflammation

Chronic inflammatory response is a key component of AS. Elevated serum UA levels will stimulate the release of inflammatory cytokines, exacerbating chronic systemic inflammation that is already present in CKD patients. Cross-sectional studies [31] have already found that serum UA levels are probably associated with many inflammatory indicators, such as C-reactive protein (CRP) and interleukin-6 (IL-6) [58]. Except for the direct effects of serum UA, several studies have discovered that UA may be related to the translation of CRP mRNA in endothelial cells [59]. Additionally, serum UA levels in CKD patients starting dialysis rise every time CRP and intercellular cell adhesion molecule-1 (ICAM-1) elevates [60], indicating the relevance of UA to inflammation in patients with CKD.

Macrophage and endothelial cells are central to AS because they regulate cholesterol traffic and inflammation in the arterial wall. CKD affects macrophage function both directly and indirectly. Direct effects include the upregulation of scavenger receptors and decreased cholesterol efflux via the NF-κB pathway. Indirect effects include inflammatory [61] and oxidative insults to the endothelium that cause increased recruitment, trapping, and decreased egress of arterial macrophages [52].

In macrophages, a study of Harvard University found a novel mechanism by which the uremic toxin indoxyl sulfate (IS) induces proinflammatory activation of macrophages and accelerates AS in CKD. Specifically, in patients with CKD, IS has been demonstrated to cause AS by activating macrophage inflammation via the organic anion-transporting polypeptide 2B1 (OATP2B1)-ubiquitin-specific protease 5 (USP5)-Delta-like 4 (Dll4)-Notch signal pathway [62]. Meanwhile, high UA levels take part in enhancing the activity of Notch signal pathway [63]. It can be postulated that elevated UA levels in patients with CKD contribute to an increased susceptibility to AS.

In endothelial cells, UA promotes the phosphorylation of RAS and ERK by upregulating renin receptors, which promotes the production of inflammatory mediators and monocyte adhesion. Probenecid could block the inflammation via this pathway [53]. UA can induce the nuclear translocation and activation of NF-κB, stimulating the production of chemokines and adhesion factors, including MCP-1, IL-8, VCAM-1, and ICAM-1. These chemokines and adhesion factors finally promote the migration and adhesion of monocytes to endothelial cells [64]. High-mobility group box 1(HMGB1) is an inflammatory mediator released during cellular damage. UA activates endothelial cells causing nuclear HMGB1 acetylation initiating its translocation and release. Once released, HMGB1 may further stimulate its own release while also exacerbating the endothelial cell inflammatory response [65]. IS, a uremic toxin, induces a proinflammatory response in endothelial cells via Nox4 and aryl hydrocarbon receptor (AhR) and leads to AS. In this network, IS would inhibit the production of NO through Nox4 and accelerate chronic inflammation via the AhR-RB/E2F axis by releasing MCP-1, IL-8, E-selectin, and ICAM-1 [66]. The combined effect of IS and UA may result in an increased risk of AS in CKD patients, particularly in the context of renal function deterioration.

In VSMC, Price et al. [67] found that urate transporter 1 (URAT1), a UA transporter expressed on the VSMC membrane, rapidly takes up extracellular UA, which could be the reason for UA promoting VSMC proliferation. UA increased cyclooxygenase 2 (COX-2) and MCP-1 levels via the NF-κB and ERK1/2 (p44/42 MAPK) and p38 MAPK pathways in time-dependent patterns, thus inducing the inflammation of VSMC [68]. In studies on rats with CKD, it has been demonstrated that elevated serum lipopolysaccharide binds to the TLR-4 (Toll-like receptor-4) present on the VSMCs. This binding activates NF-κB and NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome signals, which ultimately leads to the process of calcification of VSMCs. The presence of UA in CKD patients may contribute to the acceleration of AS through the NF-κB pathway.

Inflammasomes, including NLRP1 (NACHT, LRR, and PYD domain-containing protein 1), NLRP3, IPAF (NLR proteins ICE protease-activating factor), and AIM2 (absent in melanoma 2) inflammasome, play an important role in the progression of AS. UA can activate oxidative stress and NLRP3 inflammasome by activating ROS and K+ efflux and further induce endothelial cells injury and proliferation of VSMC in the early stage of CKD [69, 70]. In human peripheral blood mononuclear cells, high serum UA levels can activate AS progression and inflammation by suppressing the AMP-activated protein kinase pathway and stimulating the secretion of IL-1β meditated by NLRP3 [71]. In CKD patients, endotoxins interact with TLR on innate immune cells, leading to the NF-κB-and-MAPK-dependent overproduction of proinflammatory factors [72]. The CANTOS trial of canakinumab has shown that inhibiting NLRP3-IL-1-IL-6 pathway can be beneficial in CKD patients with AS [73]. As a part of the upstream of this pathway, UA would participate in the AS progress of patients with CKD. Once serum UA levels exceed 6.8 mg/dL, monosodium urate would be formed. Studies have found that monosodium urate triggers the inflammation, and may also contribute to the pathogenesis of AS [50].

Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association of CKD. Treatment effect of statins varies in AS patient with or without CKD, which suggests that the higher residual inflammatory risk in CKD patients still play an important role in prognosis of AS patients. The inflammatory risk was measured by the level of a number of inflammatory predictors, including CRP and IL-1 to IL-6 [74]. Using UA-lowering agents may provide some novel thoughts about decreasing level of inflammation.

Endothelial Function

Normal endothelial function is important for the balance of vasoconstriction and dilatation. NO, a molecule closely related to endothelial function, is released less during CKD progression that results in endothelial dysfunction, cardiovascular, and kidney damage [75]. Normal endothelial function maintenance relies on NO produced by endothelial nitric oxide synthase (eNOS) [76], including regulating vessels tone and controlling cell inflammation and thrombosis [77]. The NF-κB pathway is deeply involved in this process [78]. Endothelial dysfunction has an impact on early development of AS, even earlier than the morphology change in the vascular wall [79].

When the bioavailability of NO decreased, endothelial dysfunction followed and the risk of AS increased. UA will decrease the NO bioavailability in different ways. For instance, some achievements suggest that AS may be caused and mitigated by serum UA levels through different pathways. Therefore, a variety of pharmacological options are available from different prospects for the prevention and treatment. UA can react rapidly and irreversibly with NO to produce 6-amino uracil, which consumes large amounts of NO [80]. Moreover, endothelial cells possess transporters of UA [81], allowing UA to be generated from endothelial cells, and cause inflammation by releasing cytokines like PDGF and MCP-1. What follows is the stimulation of LDL oxidation. After that, UA may deposit in plaque where sediment could be foci for calcification, accelerating AS. Moreover, UA deposits themselves can accelerate AS [20]. UA activates protein kinase C, phosphorylates and inactivates Thr495, the inhibitory site of eNOS, and prevents it from the NO synthesis [82]. Insulin can promote the phosphorylation and activation of eNOS and the production of NO via the phosphatidylinositide3-kinase-protein kinase B pathway. UA blocks the downstream signal of insulin by promoting the phosphorylation of Ser307, the inhibitory site of insulin receptor substrate 1, reducing NO synthesis [83]. There is more than one metabolic pathway involved. UA induces the activation of transcription factor nuclear factor-κB and upregulates its target gene miR-155, causing a decrease in the mRNA stability of eNOS and a decrease in the NO production [84]. Arginase is an enzyme, which can compete for l-arginine [85]. In endothelial cells, UA increases the affinity of arginase for l-arginine and consequently reduces NO synthesis by promoting urea production [86]. Energy metabolism also plays an important role in it. Synthesis of ATP decreases, which is the consequence of inhibiting the tricarboxylic acid cycle by UA, resulting in impaired endothelial function [87]. Endothelial dysfunction can also be triggered by mitochondrial calcium overload due to the activation of mitochondrial Na⁺/Ca²⁺ exchanger (NCXmito) by a high concentration of UA [88].

AhR, which is also known as the dioxin receptor, may act as an endogenous effector for IS [89]. Previous reports have demonstrated that the AhR plays a role in mediating IS-induced expression of the endothelial cell adhesion molecule E-selectin [90]. AhR activation induces Notch1 and Notch2 in lymphoid cells [91]. Furthermore, evidence suggests that the AhR pathway is activated in patients and mice with CKD [92]. An in vitro study conducted on a breast cancer cell line demonstrated that the antioxidant effect of UA facilitated the scavenging of ROS, thereby reducing AhR expression. It has been demonstrated that UA stones form in the bladders of AhR knockout mice in the laboratory of Fujii-Kuriyama in an increasingly large quantity. It is postulated that AhR affects nucleic acid degradation in bladder cells, leading to the formation of UA stones [93]. Despite the absence of renal lesions and normal blood UA levels in the mice, the relationship between AhR and UA may have a different impact on CKD patients. This suggests that UA may act on the AS process in CKD patients from multiple signal pathway loci and multiple cells. AS is the most common underlying complication driven by low-density lipoproteins (LDLs), disturbing vascular integrity. Carbamylation of lysine residues, occurring primarily in the presence of CKD, affects functional properties of LDL. Typically, carbamylation of LDL induces endothelial dysfunction via lectin-like-oxidized LDL receptor-1 activation and increased ROS production, leading to eNOS uncoupling [94]. This indicates that a new mechanism may be responsible for AS development and progression in patients with CKD and hyperuricemia.

The evidence implies that different concentrations of serum UA can have very different consequences. Maybe hyperuricemia can play an opposite role in various stages of AS.

Immune Response

White blood cells are responsible for the elimination of cholesterol-accumulative cells [78]. Train immunity, a concept put forward to describe the phenomenon of innate immune cells developing persistent hyperreactive phenotype after brief stimulation of pathogenic microorganism and endogenous molecules, such as virus and UA [95]. UA can be recognized as a dangerous molecule by pattern-recognition receptors, the sentinels of the innate immunity. Dendritic cell maturation and activation of resting T cells immediately follow downstream signaling of these receptors, which can also trigger the inflammasome and induce the secretion of proinflammatory cytokines [96]. This process may be mediated by TLR4, under the co-induction of RAS. Chronic tubular damage comes after the interaction between hyperuricemia, RAS, and innate immunity, blunting the protective effect of RAS inhibition [97]. Secretion of inflammatory mediators from innate immunity could cause irreversible damage to kidney, which is proved to relate to the cross talk between the kidneys and other organs, such as the gut. Growing evidence suggests that administration of probiotics, postbiotics, and symbiotics can ameliorate the renal inflammation and improve the renal function [98–100]. Recent researches [101, 102] have shown that hyperuricemia is capable of inducing long-term proinflammatory activation of innate immune cells, which suggests that there may be many undiscovered therapeutic targets in the immune system. These effects of UA and CKD on the inflammatory state of immune cells, although not yet directly linked to AS, suggest a possible direction.

Others

There have been a lot of Japanese researches, showing the increasing prevalence of metabolic syndrome based on serum UA levels [49]. Obesity, insulin resistance, and hypertension are all related to the increased risk of AS. A study conducted by Stanford (CA) University Medical Center shows that insulin resistance and UA concentrations are significantly related, even with the consideration of age, sex, and obesity. For this reason, the effect of UA on AS can also be achieved through insulin resistance. Patients with CKD are more likely to have hyperuricemia than those without CKD, which subsequently triggers or worsens AS [103]. In addition to the above content, AS occurred in CKD patients can be attributed to anemia, coagulopathy, metabolic disturbance, and calcium-phosphate metabolism disturbances [104]. First, chronic inflammation, which may be caused by CKD and hyperuricemia, can promote the secretion of hepcidin in the liver and disturb the absorption iron by intestine and the utilization of iron by monocytes and macrophages. As a result, iron for hemoglobin is not enough in patients with CKD. The anemia is hard to correct by erythropoietin [105, 106]. At the same time, lipid peroxidation products, which are common in patients with AS, can lead to intensification of anemia by inducing the expression of COX-2 [107]. Second, high serum UA levels can increase plasma viscosity, activate platelets, and affect exogenous coagulation [108]. Activation of platelets subsequently causes vascular remodeling and plaque formation. Once the plaque ruptures, coagulation will be disturbed again, forming a vicious circle. Third, metabolic disturbance, which will cause chronic inflammation, is positively correlated to a range of serum UA level [49]. The metabolic disturbance is proved to increase the risk of AS [109]. At last, calcium-phosphate metabolism disturbances, such as hyperphosphatemia, can accelerate the formation of AS [110, 111]. A correlation between urinary calcium and phosphorus excretion and urinary UA excretion has been found in the studies of patients with CKD, suggesting that UA excretion may compete with calcium and phosphorus [112]. The diseases mentioned above also happen to be complications of CKD, further suggesting a complex association between UA and AS in CKD population.

Ultimately, serum UA levels may influence AS development and progression in many ways, including but not limited to oxidative stress, inflammation status, endothelial function, and immunological response. More clinical trials in CKD patients are needed to demonstrate the efficacy of each element and guide further prevention, screening, and treatment.

Current UA-Lowering Treatments and Their Effects on Atherosclerosis in CKD Patients

Nonpharmacological Treatments

A balanced, healthy diet is important to control serum UA, especially for patients with kidney disease [113]. Fresh vegetables, eggs, low-fat, or skim milk are recommended. In the meantime, food rich in purines should be limited.

Drinking enough water to maintain 2,000–3,000 mL daily urine output are necessary for patients whose cardiac and renal functions are normal. But in patients with CKD, this advice should be altered. Patients are allowed to consume fruits with low fructose contents, such as strawberries, pineapples, watermelons, and peaches.

Alcohol should be limited for the effect of increasing risk of hyperuricemia, and beer, yellow rice wine, and spirits should be forbidden [114, 115]. Smoking and passive smoking should both be avoided. Meanwhile, regular physical activity is beneficial for hyperuricemia patients [116]. The patients should take at least 150-min moderate aerobic exercise each week. Additionally, the body mass index should be maintained between 18.5 and 23.9 kg/m² as the obesity increases the risk of hyperuricemia [117–119].

Pharmacological Treatments

When the effect of nonpharmacological treatments is not satisfactory, pharmacological treatments will be applied. Treatments for lowering UA are summarized in Table 1. There are two kinds of commonly used UA-lowering drugs: UA production inhibitors and UA reabsorption inhibitors. Except for these two classes of drugs, uricase and agents for urine alkalization are also important in UA-lowering therapy. Uricase decomposes the UA into smaller soluble molecules so that the kidney could excrete them. Agents for urine alkalization can increase the solubility of UA in urine, which is also a recommended way for hyperuricemia treatment.

Table 1.

Available UA-lowering therapies

	Types	Specific recommendations or drugs
Nonpharmacological treatments		Fresh vegetables, eggs, low-fat or skim milk, limited food rich in purines
		Adjusting water intake according to the kidney disease
		Fruits with low fructose contents, such as strawberries, pineapples, watermelons, and peaches
		Avoid alcohol and smoking (both active and passive smoking)
		At least 150-min moderate aerobic exercise each week and maintain a proper BMI
Pharmacological treatments	UA production inhibitors	Febuxostat, allopurinol
	UA reabsorption inhibitors	Benzbromarone, probenecid, RDEA594 (lesinurad), RDEA-3170 (RDEA684), SHR4640, verinurad, URC-102, and SAP-001
	Uricase	Rasburicase, pegloticase
	Urine alkalization	Sodium bicarbonate, citrate preparations
	Others	Losartan, fenofibrate, statins, and SGLT-2 inhibitors

BMI, body mass index; SGLT-2, sodium-dependent glucose transporters 2.

Uric Acid Production Inhibitors

Traditional UA production inhibitors include allopurinol and febuxostat, collectively called xanthine oxidase inhibitors (XOIs). They block the synthesis of UA by inhibiting the XO. Allopurinol can cause renal injury. Care should be exercised with starting dose and maintenance dose in renal insufficiency patients. This drug is contraindicated in patients with estimated glomerular filtration rate (eGFR) < 15 mL/min (G5). The safety data of febuxostat in CKD patients are better than allopurinol because it is cleared through liver. But it should be used with caution in patients with eGFR <30 mL/min (G4-G5).

Febuxostat achieves the serum UA target in a more effective and faster way than allopurinol. Both drugs are safe and well tolerated. Allopurinol can improve the endothelial function of patients with heart failure [120]. But in patients with CKD (G3) and hyperuricemia, allopurinol treatment did not change the endothelial function and oxidative stress level [121]. This is probably a consequence of the different effects of allopurinol on AS in different diseases. European clinical research explains that allopurinol and febuxostat can maintain the stability of arterial stiffness in patients with hyperuricemia [122]. However, there is evidence from Japanese studies [32] that febuxostat does not delay the carotid AS progression, compared with nonpharmacological care. A random compared trial shows that the febuxostat treatment group developed higher cardiovascular-related mortality than the allopurinol treatment group in 6,190 gout patients with cardiovascular disease [123]. This difference may arise from the different frequency of gout attacks, which in turn exacerbates AS. However, the evidence in support of this view is still lacking. The mechanism underlying this risk of death is unclear. This trial suggests that traditional first-line therapy could have yet undiscovered causal links to many related diseases. The patients involved in this trial are with gout and cardiovascular disease, being stratified according to the kidney function. So, it is reasonable to assume that the results of this trial can be appropriately extrapolated to the CKD population.

Uric Acid Reabsorption Inhibitors

Benzbromarone is commonly used in hyperuricemia patients because it can suppress the tubular reabsorption by inhibiting the URAT1. It is indicated for use in patients presenting with mild to moderate renal dysfunction or renal transplantation. Benzbromarone is contraindicated in patients with an eGFR<20 mL·min⁻¹·1.73 m⁻². Urine alkalization is indispensable to patients who are taking benzbromarone.

Probenecid can not only inhibit the tubular reabsorption of UA but also accelerate the dissolution of UA crystal. A study by Kim et al. [124] reveals that probenecid significantly reduces the risk of cardiovascular diseases. For now, the clinical use of probenecid in hyperuricemia is gradually decreasing. The cardiovascular effect of probenecid may provide the possibility to revitalize this traditional drug.

Besides the traditional medicine, there are some novel selective UA reabsorption inhibitors called RDEA594 (lesinurad). This new drug could inhibit both URAT1 and the organic anion transporter 4 (OAT4). Lesinurad can be used to treat hyperuricemia in patients who fail to achieve the target serum UA level with XOIs. However, lesinurad monotherapy is not recommended due to the higher occurrence of renal adverse events [125]. Until now, finding safe and effective UA-lowering drugs for patients with kidney disease is still an urgent problem to be solved.

Except for benzbromarone and lesinurad, many highly selective URAT1 inhibitors are being developed, such as RDEA-3170 (RDEA684), SHR4640, verinurad, URC-102, and SAP-001. Among them, SHR4640 has made the fastest progress. The present study indicated a superior serum UA-lowering effect and a well-tolerated safety profile after 5-week treatment with once-daily 5 mg/10 mg of SHR4640 as compared with placebo in Chinese subjects with hyperuricemia [126]. The occurrence of renal adverse events caused by SHR4640 is dose-dependent, like many other URAT1 inhibitors. Combination with high doses of XOIs can significantly reduce the renal safety risk by reducing UA excretion by the kidneys [127]. Hyperuricemia patients were grouped into 3 groups by various medication regimens, with allopurinol, benzbromarone, or both drugs. Over the data of 8,047 gout patients, 3 groups all had a linear dose-response relationship between the numbers of defined daily doses and the risk of AS [128]. Little clinical research has been done on the relationship of other URAT1 inhibitors with AS.

Uricase

Uricases include rasburicase and pegloticase, which decompose the UA into smaller soluble molecules. They are indicated for patients with refractory gout for whom other drugs are ineffective or contraindicated. None of them are currently available in China, and they are not recommended as first-line agents. Main adverse reactions of pegloticase include serious cardiovascular events and infusion and immunogenic reactions [129]. There are no data on the use of uricase in patients with renal dysfunction.

Urine Alkalization

Maintaining urine pH within 6.2–6.9 is recommended to patients receiving UA-lowering drugs, especially the UA reabsorption inhibitor, to increase the solubility of UA in urine. In CKD patients with hyperuricemia, sodium bicarbonate will be more suitable and safer than citrate preparations [130].

Others

Losartan is often used to protect renal function by antagonizing Ang II receptor. Studies find that losartan can also lower the serum UA level by inhibiting URAT1 [131]. Many studies have confirmed the role of losartan in delaying the progression of kidney disease. In hemodialysis patients, long-term blockade of the RAS by trandolapril and losartan may prevent the acceleration of AS and have a beneficial effect on uremic dyslipidemia [132]. However, losartan’s UA-lowering effect is weak when used alone, which should be used in combination with other UA-lowering drugs. Losartan therapy may assist in lowering blood UA in peritoneal dialysis patients with hyperuricemia combined with hypertension. Lipid-lowering drugs, including fenofibrate and statins, can significantly improve renal function in patients with coronary artery disease [133] and decrease the serum UA level by regulating the endothelial NO pathway [134] and promoting UA excretion through kidney. Like losartan, these drugs are weak in lowering serum UA level by using monotherapy.

Sodium-dependent glucose transporter 2 (SGLT-2) inhibitors offer the possibility of kidney protection by reducing intraglomerular pressure, systemic blood pressure, and serum UA concentration [135]. An interesting study found that empagliflozin restores the beneficial effect of cardiac microvascular endothelial cells by reducing mitochondrial oxidative damage, leading to reduced ROS accumulation and increased endothelial NO bioavailability [136]. A randomized controlled trial found that SGLT-2 inhibitors are safe (do not increase) and may reduce the occurrence of AS [137], suggesting that SGLT-2 inhibitors can be used as the UA-lowering treatment.

Prospect and Long-Term Management of UA and Atherosclerosis in CKD Patients

The classical mechanisms of AS and UA in CKD patients, including oxidative stress, endothelial dysfunction, and inflammation, have been studied during various pathways. Considering the complexity of the internal environment in CKD patients, these findings may have been due to chance. The interactions between them also bring unpredictability to the cascade response. The studies focused on inflammasome are more deficient at present. In addition, mechanism of endothelial function relies too heavily on NO cross talk, limiting more direct observation of this mechanism from other perspectives. The booming immune-related research in recent years, on the other hand, suggests innate immunity and inflammation as a new cross-research direction.

The association between UA-lowering therapy and kidney outcomes varies by different populations [138]. However, there is no reliable evidence to suggest that UA-lowering therapy should be excluded from CKD treatment guidelines. Given the known benefits of UA-lowering therapy, such as reducing the residual risk of AS [44, 71], having a beneficial effect in ischemia-reperfusion lesion after coronary angioplasty [55], and improving blood pressure control that slowed the progression of AS and CKD [139], the use of UA-lowering drugs remains an important part of the treatment of patients with CKD. Indeed, UA-lowering therapy should be carried out in a cautious way, given that no universally appropriate serum UA concentration has been identified for each CKD patient, regardless of stage or underlying physical condition.

There is a J-shaped correlation [140] showed between serum UA levels and all-cause mortality in CKD patients. It remains unclear whether the therapeutic effect of UA-lowering drugs on AS is due to the reduction of serum UA levels or the inhibition of oxidative stress. Nevertheless, the benefits of UA-lowering therapy cannot be overlooked. In conclusion, there is still a lot of room for exploration on the optimal application dose, time to start medication, suitable crowd, and mode of administration in CKD patients.

Many traditional drugs discovered in the study of new mechanisms, such as losartan, SGLT-2 inhibitors, and statins. In response to the previously mentioned oxidative stress mechanism, losartan was found to reduce UA-induced COX-2 elevation [68]. SGLT-2 inhibitors and statins also reduce cardiovascular risk through more than one pathway. As commonly used drugs in CKD, these drugs have a wide range of use, indicating that further research could be conducted into the potential mechanisms of action of inexpensive and readily available pharmaceuticals.

The achievements suggest that AS may be caused and mitigated of serum UA levels by different pathways. Therefore, a variety of pharmacological options are available from different prospects for the prevention and treatment. Now researchers [141] think they have found a new link between gut microbiota and variation in the AS burden by using mice. Gut microbes control the AS burden through catabolizing purine, which suggests that serum UA levels are an important pathway for gut microbes to regulate AS. Ordered intestinal microbiome plays an important role in the clearance of uremic toxins like p-cresol, IS, and p-cresyl sulfate, some of which work with UA to promote the formation and development of AS [142]. The results demonstrate that subclinical AS in CKD patients may be prevented and treated by modifying the homeostasis of the gut microbiome.

At the same time, there are many new drugs discovered in the study of classical mechanisms, such as lesinurad, SHR4640, and uricase. They function in a more powerful way, which encourages us to explore a new generation of more efficient drugs. Despite the emergence of these new drugs targeting on classical or new mechanisms, research on their safety and efficacy remains inadequate. This indicates a necessity for further multicenter, long-term, large-scale clinical studies in patients with or without CKD.

As a predictor, UA can act a role in recognizing early AS in CKD patients [143]. Serum UA levels can be used to predict the progression of subclinical AS and identify the population that is at the highest risk of AS even if CKD is not clinically diagnosed [144], which is of great significance for early prevention, screening, and long-term management. Meanwhile, some scholars have turned their attention to genetics. A genetic marker of serum UA levels called the rs734553 polymorphism in the GLUT9 gene was a strong modifier of the relationship between age, IMT, and carotid internal diameter [145]. This genetic study has limited clinical significance, but it points us to new research directions. And beyond that, the level of serum UA can unite with some novel risk factors such as serum total bilirubin concentration to predict the prevalence and incidence of CKD in the general population or AS progression in CKD patients [146].

UA is closely related to oxidative stress, especially in patients with CKD who are vulnerable to oxidative stress. Accordingly, several antioxidants have been proposed to apply to further decrease oxidative stress and serum UA level. Health management has become increasingly integrated into modern life. Antioxidants have become star foods for preventing and delaying disease. Therefore, daily diets [147] containing curcumin, l-arginine, and vitamin C that are antioxidants will have potentials in preventing AS.

Most studies concluding that UA is an independent risk factor for AS have been based on non-CKD populations. Evidence of UA directly influencing AS in CKD patients from randomized controlled trials are still lack of reliable data [148]. The time to start UA-lowering therapy, the dosage of different populations at different modes of stages of CKD, different administration and dosage forms, and the optimal target level are not clear. Additionally, there are still a lack of clinical studies on the association between serum UA level and AS progression in the CKD population. Moreover, it is difficult to study the serum UA level independently because it is related to many factors. How to study independent UA factors and how to manage them in a clinically complex pathophysiological environment remain to be discovered. At last, common UA-lowering drugs have respective advantages and disadvantages, and there are not enough clinical studies on the efficacy and safety of various newly discovered drugs with related effects.

There are still some limitations. Thus, there are many reasons to believe that there could be some relationships between serum UA and AS, but further causation in CKD patients is still not clear. The specific connection may be hidden in the mechanisms just waiting for further investigations.

Conclusion

People with CKD face the risk of premature death, mainly due to cardiovascular diseases. Among many risk factors, serum UA levels are discovered to play an essential role in this process. Although many relevant studies have been conducted, they are still limited by insufficient causal relationship, small sample size, and unclear elaboration. The above research results show that serum UA levels are extensively involved in numerous aspects of the AS process in CKD patients, including oxidative stress, inflammation, endothelial dysfunction, immune response, and many other mechanisms. Appropriate UA concentrations in different internal environments are critical for patients with CKD.

Acknowledgments

We would like to express our gratitude to Luo B, Song YQ, and Lu SQ for the help during the writing of this manuscript.

Conflict of Interest Statement

The authors declare no conflict of interest.

Funding Sources

This work was supported by Grants from the National Natural Science Foundation of China (82200820), Guangzhou Science and Technology Project (202201011483 and SL2024A04J00910), 5010 Clinical Program of Sun Yat-Sen University (No. 2017007), and Key Laboratory of National Health Commission, and Key Laboratory of Nephrology, Guangdong Province, Guangzhou, China (2020B1212060028).

Author Contributions

Yuchu Liu is mainly responsible for collecting literature and drafting the review. Zeyu Li and Yuanwen Xu helped to modify the figures and revise the manuscript. Haiping Mao and Naya Huang provided supervision and revised the manuscript. All authors read and approved the final manuscript.

Funding Statement

This work was supported by Grants from the National Natural Science Foundation of China (82200820), Guangzhou Science and Technology Project (202201011483 and SL2024A04J00910), 5010 Clinical Program of Sun Yat-Sen University (No. 2017007), and Key Laboratory of National Health Commission, and Key Laboratory of Nephrology, Guangdong Province, Guangzhou, China (2020B1212060028).