Association of Hyperuricemia with Cardiovascular Risk Factors and Cardiac Structural Changes in Patients Undergoing Maintenance Hemodialysis in Southwest China

Introduction

Maintenance hemodialysis (MHD) is one of the primary methods of renal replacement therapy for patients with end-stage renal disease. Hemodialysis technology has been advancing rapidly; however, patients undergoing MHD have a poor quality of life and long-term survival rate, with deaths primarily caused by cardiovascular diseases (CVD) [1]. A 19-year follow-up study revealed a close correlation between uric acid levels and mortality in patients with chronic kidney disease (CKD) [2]. Furthermore, epidemiological studies have reported that the incidence of CVD increases with increased uric acid levels, and hyperuricemia is closely associated with CVD onset and progression [3,4]. A meta-analysis in Japan revealed a J- or U-shaped relationship between uric acid levels and cardiovascular mortality [5]. Corry et al [6] conducted animal experiments and revealed that uric acid can stimulate the renin-angiotensin system, to promote the proliferation of vascular smooth muscle and induce oxidative stress, resulting in endothelial dysfunction and atherosclerosis. The authors suggested that hyperuricemia is a vital independent risk factor for CVD. Nagahama et al [7] conducted a cohort study involving 9914 participants and observed a higher prevalence of 2 or more CVD risk factors in the hyperuricemia group, compared with the normal uric acid group. Furthermore, they found a close association between hyperuricemia and obesity, hypertension, and dyslipidemia. Regardless of sex, patients with hyperuricemia were more likely to have a cluster of CVD risk factors. In addition, studies have demonstrated a close correlation between uric acid levels in patients with end-stage renal disease and the degree of coronary artery stenosis observed on coronary angiography [8,9], and some studies revealed that hyperuricemia is a predictive factor for the occurrence and mortality of ST elevation myocardial infarction [10,11]. Collectively, these findings suggest that the presence of hyperuricemia is an important risk factor for CVD occurrence in patients undergoing MHD.

However, studies have demonstrated that uric acid is harmless and beneficial to humans. A study involving 4637 patients from 6 countries demonstrated that increased uric acid levels were negatively correlated with all-cause mortality and cardiovascular mortality [12], because uric acid levels are associated with the nutritional status of patients. For patients undergoing MHD, uric acid is a good nutritional marker that is closely associated with body composition, muscle function, and overall health. Therefore, an increase in uric acid levels can lead to a decrease in all-cause and cardiovascular mortality [13]. Although many studies have indicated that high uric acid levels can lead to endothelial dysfunction in CVD [14], one clinical study focusing on diabetes demonstrated that uric acid can exhibit antioxidant effects and confer endothelial protection [15]. However, findings on the association between hyperuricemia and CVD risk in patients undergoing MHD remain inconsistent. Importantly, the most existing research has been conducted in Western populations, with limited data available from Chinese patients undergoing MHD. Given the differences in genetic profiles, dietary habits, and clinical practice between populations, findings from Western studies may not be directly applicable to Chinese patients. Therefore, in the present study, we investigated the prevalence of hyperuricemia in patients undergoing MHD and assessed the relationship between hyperuricemia and CVD risk factors in Southwest China. Through comprehensive analysis of cardiovascular risk factor profiles in relation to hyperuricemia status, we aim to provide new insights into the complex interplay between uric acid levels and cardiovascular health in Chinese patients undergoing MHD. These findings will contribute essential evidence for developing population-specific treatment strategies for hyperuricemia, improving the prevention of cardiovascular complications, and reducing cardiovascular mortality in Chinese patients undergoing MHD.

Material and Methods

PATIENTS AND METHODS:

The research protocol for this study was approved by the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University Ethics Committee, Luzhou, China (BY2023038). Given the unique and complex physiological changes experienced by patients on MHD, this observational study was designed to specifically characterize relationships and associations within this population, as direct comparisons with healthy individuals would not fully capture the nuanced challenges inherent to their condition. A total of 122 patients on MHD were initially evaluated for study eligibility during the recruitment period. Twenty-three patients were subsequently excluded from the final analysis owing to the use of urate-lowering medications, which could potentially confound the assessment of naturally occurring hyperuricemia and its associations with cardiovascular parameters. Thus, this study was designed as a single-arm cohort and included 99 patients (55 men, 44 women; mean age, 59.62±12.15 years) undergoing MHD at the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University were included. The primary diseases were primary kidney disease (n=47), diabetic nephropathy (n=22), hypertensive nephropathy (n=19), chronic obstructive kidney disease (n=2), polycystic kidney disease (n=6), lupus nephritis (n=1), Sjogren syndrome (n=1), and other causes (n=1). The oldest patient was aged 81 years and youngest was 24 years. Hemodialysis was performed 3 times per week, with each session lasting 4 h. Vascular access was either an autogenous arteriovenous fistula or a long-term catheter. The key baseline characteristics of patients in this study, including age, body weight, height, and dialysis duration, are present in Table 1.

The inclusion criteria were as follows: (1) regular hemodialysis treatment for ≥3 months, 3 times per week, 4 h each session; (2) age ≥18 years; (3) no severe underlying heart disease before initiating the first dialysis initiation; and (4) voluntary participation and signing of informed consent form.

The exclusion criteria were as follows: (1) acute or chronic infectious diseases; (2) severe malnutrition, with a plasma albumin level of <30 g/L; (3) active liver disease or systemic autoimmune diseases; (4) pregnancy; (5) malignant tumors and hematological diseases; (6) ketoacidosis and lactic acidosis; and (7) current use of drugs that affect uric acid metabolism, including allopurinol, febuxostat, benzbromarone, and potassium canrenoate.

All patients received erythropoiesis-stimulating agents, antihypertensive drugs, and antidiabetic medications based on their clinical conditions. Furthermore, they did not use any drugs that affected uric acid metabolism within 1 month.

The general characteristics of the patients, including sex, age, dialysis duration, primary cause of kidney failure, smoking, alcohol consumption, and exercise, were collected using a questionnaire. Fasting venous blood samples were collected at the end of the study to measure the indicators uric acid, high-sensitivity C-reactive protein (CRP), triglyceride, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), homocysteine, calcium, phosphorus, and parathyroid hormone (PTH). On the day of blood collection, blood pressure, height, weight, abdominal fat thickness, and waist circumference were measured. The thickness of abdominal fat was measured using a calibrated Harpenden skinfold caliper.

Echocardiography was performed before patients started the study and on the day of the last blood collection after dialysis, to measure left ventricular posterior wall thickness, interventricular septum thickness, left ventricular end-diastolic diameter, and left ventricular ejection fraction (LVEF). The average values of the 4 biochemical indicators, 4 physical examination indicators, and 2 echocardiography indicators were calculated.

Groups were divided based on smoking habits, exercise, abdominal fat thickness, waist circumference, body mass index (BMI), systolic blood pressure, and uric acid levels. The groups were further divided based on high or low uric acid levels, followed by a comparison of the biochemical and echocardiography indicators among the groups.

A history of heavy smoking was defined as smoking >11 cigarettes daily for >1 year or regular heavy smoking previously, with a smoking cessation time of <20 years. Exercise habits were defined as engaging in aerobic activities (eg, walking, jogging, dancing, tai chi) for 30 to 45 minutes per day on at least 5 days per week. The abdominal fat thickness groups were defined as follows: low, <5 mm for men and <12 mm for women; normal, 5–15 mm for men and 12–20 mm for women; and high, >15 mm for men and >20 mm for women. The waist circumference groups were as follows: normal, <85 cm for men and <80 cm for women; and high, ≥85 cm for men and ≥80 cm for women. The BMI groups were defined as follows: normal, <23.9 kg/m²; overweight, 24.0–27.9 kg/m²; and obese, ≥28.0 kg/m². Normal systolic blood pressure was <140 mmHg; and elevated systolic blood pressure was <140 mmHg.

LABORATORY EXPERIMENTS:

Blood samples were collected from the patients who underwent MHD. Samples for complete blood counts were collected every 3 weeks. Blood samples for total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were collected at the end of the study from each group. Hyperuricemia was defined according to the Multidisciplinary Expert Consensus on the Diagnosis and Treatment of Hyperuricemia-Related Diseases in China (2023 edition). The diagnostic criteria were established as serum uric acid levels exceeding 420 μmol/L (7.0 mg/dL) on 2 separate fasting measurements under normal dietary conditions [16].

STATISTICAL ANALYSIS:

SPSS software (version 17.0) was used for the data analysis. All continuous variables were expressed as mean±standard deviation, whereas categorical variables were expressed as percentages. Continuous variables between 2 groups were compared using the independent samples t test, whereas the percentages of categorical variables between 2 groups were compared using the chi-square test. To control for type I error inflation due to multiple comparisons in univariate analyses, the Bonferroni correction was applied. The significance level was adjusted by dividing 0.05 by the number of comparisons performed. Only P values below this adjusted threshold were considered statistically significant for univariate tests. Multiple linear and logistic regression analyses were used for multivariate continuous and categorical variables. The significance level was set at α=0.05. A P value of <0.05 indicated statistically significant differences.

Results

HYPERURICEMIA RATIO IN PATIENTS UNDERGOING MHD:

Ninety-nine patients who underwent MHD were included in this study. Among them, 80 patients had hyperuricemia and 19 had normal uric acid levels, resulting in a hyperuricemia prevalence of 80.9%.

HEAVY SMOKING AND PHYSICAL INACTIVITY CONTRIBUTED TO HYPERURICEMIA OCCURRENCE IN PATIENTS UNDERGOING MHD:

The blood uric acid levels were higher in patients with a history of heavy smoking than in those without (Table 2). Since a statistically significant difference in sex composition was observed between the 2 groups (P<0.05), further subgroup analyses were conducted based on sex. Regardless of sex, patients with a history of heavy smoking had higher blood uric acid levels than those without a history of heavy smoking (Table 2), and the difference was statistically significant (P<0.05). Moreover, patients with physical inactivity had higher blood uric acid levels than those with active exercise habits (Table 3).

ABDOMINAL WALL THICKNESS AND HYPERTENSION WERE ASSOCIATED WITH HYPERURICEMIA IN PATIENTS UNDERGOING MHD:

The group with higher abdominal fat thickness had significantly higher blood uric acid levels than the groups with normal and lower abdominal fat thickness (Table 4). In addition, the group with higher systolic blood pressure had higher blood uric acid levels than did the group with normal systolic blood pressure (Table 5), with statistically significant differences (P<0.05). After grouping based on BMI, blood uric acid levels were not significantly different among the 3 groups (P>0.05; Table 6).

Logistic regression analysis revealed that heavy smoking (odds ratio [OR]=2.500, 95% CI: 1.760, 8.219, P=0.013), higher abdominal fat thickness (OR=0.498, 95% CI: 1.073, 1.225, P<0.001), greater waist circumference (OR=1.177, 95% CI: 1.087, 1.274, P<0.001), and increased systolic blood pressure (OR=1.123, 95% CI: 1.063, 1.185, P<0.001) were all closely associated with higher blood uric acid levels (Table 7).

ASSOCIATION BETWEEN MULTIPLE BLOOD BIOCHEMICAL INDEXES AND HYPERURICEMIA IN PATIENTS UNDERGOING MHD:

The group with increased uric acid levels had higher triglycerides, CRP, PTH, and homocysteine levels but lower HDL levels than that with normal uric acid levels, with statistically significant differences (P<0.05). Moreover, HDL levels were progressively reduced in association with increasing uric acid levels (Table 8). Multiple linear regression analysis revealed a positive correlation between blood uric acid levels and triglycerides, CRP, PTH, and homocysteine levels (P<0.05), and negative correlation between blood uric acid levels and HDL levels (Table 9).

PATIENTS WITH HYPERURICEMIA UNDERGOING MHD HAD A HIGHER RISK OF IMPAIRED CARDIAC FUNCTIONS:

Left ventricular posterior wall thickness, interventricular septum thickness, and left ventricular end-diastolic diameter were higher in the group with elevated uric acid levels than in the group with normal uric acid levels (P<0.05); these indices progressively increased with increasing uric acid levels. LVEF was lower in the group with elevated uric acid levels than in the group with normal uric acid levels (P<0.05) and was progressively lower with increasing uric acid levels (Table 10).

Discussion

Approximately 80% of the uric acid in the human body is endogenously produced because it is the final product of purine metabolism via the oxidation of xanthine by xanthine oxidase. Approximately two-thirds of uric acid is excreted via the kidneys, whereas the remaining one-third is eliminated via the intestines. Uric acid excretion by the kidneys involves filtration, reabsorption, and secretion. Any anomalies in uric acid generation or excretion can result in hyperuricemia [17].

Although hyperuricemia in patients undergoing hemodialysis is most commonly attributed to diminished renal excretion, urate homeostasis involves a complex interplay of production and elimination, including renal proximal tubular reabsorption/secretion and intestinal excretion. Recent genome-wide association studies and meta-analyses have identified over 30 genetic variants that affect serum urate levels, most of which influence urate transporter function [18,19]. However, only a small proportion of hyperuricemia cases are caused by Mendelian disorders of purine metabolism, such as phosphoribosylpyrophosphate synthetase superactivity (PRPS1; OMIM #300661) and hypoxanthine-guanine phosphoribosyltransferase deficiency (HPRT1; OMIM #308000) [20,21]. In addition, dysfunction of urate transporters – including URAT1 (SLC22A12), GLUT9 (SLC2A9), and particularly ABCG2 (also known as BCRP) – plays a pivotal role in disorders of urate metabolism. Among these, ABCG2 serves as a crucial determinant of extra-renal urate excretion. Genetic variants in ABCG2, such as the common rs2231142 (p.Q141K) allele, markedly reduce urate transport capacity and have been shown to exert a significant effect on serum urate levels, especially in individuals with impaired or absent renal function [22]. Dysfunctional ABCG2 variants are linked not only to earlier onset of hyperuricemia or gout but also to increased mortality among patients undergoing MHD [23,24]. Notably, several studies report that the influence of ABCG2 variants on hyperuricemia risk can exceed that of traditional environmental factors such as obesity or alcohol intake [25]. These genetic factors may explain the marked inter-individual variability in urate levels and clinical outcomes among patients undergoing MHD, who are often anuric and thus primarily dependent on intestinal urate excretion. Additionally, a cross-sectional study using NHANES Data (2011–2018) showed that aspirin intake can also influence hyperuricemia in specific individuals [26]. Therefore, integrating genetic information with clinical care could improve precision management of hyperuricemia in this population. Thus, the lack of genetic analysis in the present study was a limitation, and further research into these genetic factors may enhance our understanding of the underlying causes of hyperuricemia and associated CVD risks in patients undergoing MHD.

In the present study, we observed that heavy smoking, heavy alcohol consumption, and physical inactivity may have contributed to the elevated blood uric acid levels in patients with CKD. Many studies have demonstrated a close association between hyperuricemia and smoking; an elevated uric acid level correlates with longer smoking duration and higher cigarette consumption [27]. In patients with normal renal function, the uric acid regulatory system increases its excretion, thereby maintaining relatively stable blood uric acid levels. However, in patients with CKD, the pathway of uric acid excretion via the kidneys is obstructed, and smoking products can increase blood uric acid levels. Nevertheless, additional studies are warranted to understand the specific effects of smoking quantity and duration on blood uric acid levels in patients with CKD.

Moderate aerobic exercise can promote uric acid excretion. Aerobic exercise can also improve microcirculation, alleviate microcirculation disorders induced by various toxins and inflammation, decrease hypoxia-induced lactate production, increase uric acid solubility in the blood, and improve uric acid clearance during dialysis. Nevertheless, excessive exercise intensity can accelerate adenosine triphosphate degradation and increase lactate production in the muscles under hypoxic conditions, thereby decreasing blood pH and significantly increasing blood uric acid levels, potentially triggering gout [28]. Therefore, these individuals should be encouraged to engage in regular moderate aerobic exercise.

We observed that higher abdominal fat thickness, waist circumference, and systolic blood pressure may all contribute to increased blood uric acid levels in patients with CKD. In individuals with abdominal obesity, visceral fatty acids can enter the bloodstream via the portal vein, increasing triglyceride levels and improving the de novo synthesis of purines via the phosphoribosyl pyrophosphate pathway, thereby accelerating uric acid production [29]. Studies have demonstrated a positive correlation between blood uric acid levels and visceral fat content [30,31], showing that individuals with a high BMI accounted for only 32.4% of the total population, while those with a greater waist circumference and significantly higher abdominal fat thickness accounted for 78.8% and 67.7% of the population, respectively. Although most patients with CKD have a normal body weight, they can accumulate fat around their abdominal area, suggesting abdominal obesity. Therefore, measuring waist circumference and abdominal fat thickness can help effectively identify abdominal obesity. Abdominal obesity is a risk factor for hyperuricemia [32]. Therefore, abdominal obesity and hyperuricemia are mutually causative factors and closely related. Epidemiological studies have demonstrated a close relationship between hyperuricemia and primary hypertension, with blood uric acid levels increasing with higher clinical grades of hypertension [33]. This may be due to increased blood pressure leading to systemic arteriosclerosis in patients with CKD, resulting in inadequate tissue perfusion and excessive lactate production owing to local tissue hypoxia. This decreases uric acid solubility in the blood, decreases uric acid clearance during dialysis, and subsequently increases blood uric acid levels.

In the present study, we observed that hyperuricemia in patients with CKD was closely associated with increased triglycerides, CRP, PTH, and homocysteine levels and decreased HDL levels. Furthermore, we observed a positive correlation between triglyceride and blood uric acid levels, and a negative correlation between HDL and blood uric acid levels. This is because the metabolites produced during purine metabolism, including reactive oxygen species, can lead to lipid metabolism disorders. Lipid metabolism can also accelerate adenosine triphosphate degradation, thereby increasing uric acid production. Hyperuricemia can be significantly associated with lipid metabolism disorders and CVD development. Studies have demonstrated a close correlation between serum CRP levels in patients with CKD and cardiovascular events, cardiovascular mortality, and overall mortality; this suggest that CRP is an independent risk factor for CVDs and long-term prognosis in patients with CKD. A meta-analysis reported that uric acid activates the NF-κB signaling pathway in vascular smooth muscle cells, promotes inflammation, and eventually leads to cardiovascular events [34,35]. CRP is an inflammatory indicator that promotes the entry of inflammatory cells into the vascular endothelium, thereby aggravating tissue hypoxia and increasing uric acid production [36]. Therefore, CRP level is a risk factor for hyperuricemia. Hyperuricemia and CRP interact with each other to induce vascular inflammation, and are significantly associated with the occurrence and development of vascular sclerosis and CVD. Several studies have demonstrated a positive correlation between PTH and uric acid levels in patients with CKD [37–39]. This may be due to PTH inhibiting the sodium/hydrogen exchange protein in the renal tubules, thereby decreasing uric acid excretion [40,41]. This relationship is significant in patients undergoing MHD who have a significantly decreased glomerular filtration rate. Hyperuricemia can inhibit the expression of renal 1-alpha-hydroxylase by activating the NF-kB signaling pathway, thereby increasing PTH levels [42]. Elevated homocysteine levels can increase intracellular S-adenosylhomocysteine [43], which can induce DNA damage and release purine nucleotides, increasing uric acid levels via the degradation of purine nucleotide metabolism [44,45]. In patients undergoing MHD, a positive correlation has been observed between blood uric acid and homocysteine levels [46]. The interplay and mutual effects of the two can result in abnormal endothelial function, accelerate atherosclerosis, and induce and exacerbate CVD [46,47].

The role of uric acid as a pro-inflammatory and pro-oxidative agent is now well established, particularly in the context of its contribution to endothelial dysfunction and the development of atherosclerosis [48]. Beyond these vascular effects, emerging evidence highlights a broader metabolic impact of hyperuricemia. Recent metabolomic studies have demonstrated that elevated serum urate is associated with significant alterations in lipid metabolism. Specifically, hyperuricemia has been linked to increased circulating levels of glycerophospholipids and triglycerides, along with decreased concentrations of lysophosphatidylcholines [49]. Such lipidomic changes can exacerbate cardiovascular risk by promoting atherogenic lipid profiles and disturbing cellular membrane composition, further implicating urate in the pathogenesis of cardiometabolic disease. Interestingly, the role of uric acid in vascular health appears to be bidirectional. While hyperuricemia promotes endothelial dysfunction, recent studies suggest that hypouricemia can also impair endothelial function, potentially via disruptions in ceramide metabolism – a class of bioactive lipids involved in cell signaling and apoptosis. Low levels of uric acid have been associated with inappropriate increases in ceramide species, which are themselves implicated in vascular injury and atherogenesis. This emerging concept underscores the necessity of maintaining uric acid homeostasis, as elevated and diminished levels can have deleterious effects on endothelial integrity and cardiovascular risk [50]. Overall, the complex interplay between uric acid, lipid metabolism, and ceramide signaling deepens our understanding of its multifaceted role in CVD, extending beyond its well-recognized pro-inflammatory and pro-oxidative effects. Notably, for patients undergoing MHD, hyperuricemia and hypouricemia can have harmful implications for endothelial function and cardiometabolic health. These findings emphasize the clinical importance of maintaining uric acid homeostasis in patients undergoing MHD, as deviations in either direction could adversely influence vascular integrity and overall prognosis.

In the present study of patients undergoing MHD, hyperuricemia was closely associated with decreased LVEF and increased left ventricular posterior wall thickness, interventricular septum thickness, and left ventricular end-diastolic diameter. Hyperuricemia is associated with an increased risk of cardiovascular disease and mortality [51]. This may be attributed to the ability of uric acid to impair renal microcirculation, activate the renin–angiotensin–aldosterone system, induce inflammatory responses, damage vascular endothelium, and exacerbate vascular sclerosis in patients undergoing maintenance hemodialysis, thereby increasing vascular stiffness and blood pressure. This results in increased cardiac afterload; compensatory increases in left ventricular posterior wall thickness, interventricular septum thickness, and left ventricular end-diastolic diameter; and increased myocardial contractility [52]. However, myocardial ischemia can occur after vascular sclerosis. Furthermore, increased blood pressure can increase cardiac workload and oxygen consumption, leading to myocardial cell hypoxia and irreversible damage to cardiac structure and function, thereby decreasing LVEF. Nevertheless, additional studies are warranted to confirm whether lowering uric acid levels via treatment can restore cardiac structure and function in patients undergoing MHD.

Our findings suggest several potential implications for clinical practice that may be relevant for Chinese patients undergoing MHD. Based on the strong associations we observed between hyperuricemia and multiple cardiovascular risk factors – including abdominal obesity, dyslipidemia, inflammation markers, and left ventricular structural abnormalities – it may be beneficial to consider integrating routine uric acid monitoring into cardiovascular risk assessment protocols. This approach could potentially position uric acid levels as a valuable biomarker for comprehensive cardiovascular risk stratification, expanding beyond its traditional role as a metabolic parameter. To further advance understanding in this field, several research directions appear promising. First, large-scale prospective cohort studies would be valuable for establishing causal relationships and determining optimal uric acid target ranges for cardiovascular protection specifically in Chinese MHD populations. Similarly, intervention studies examining the potential cardiovascular benefits of maintaining uric acid homeostasis could provide important evidence to inform future clinical guideline updates. Additionally, exploring the metabolomic and lipidomic profiles associated with varying uric acid levels in this population may reveal novel therapeutic targets, particularly through a better understanding of alterations in glycerophospholipid, lysophosphatidylcholine, and ceramide metabolism. Finally, multi-center studies comparing different uric acid management strategies, combined with the investigation of gene-environment interactions specific to Chinese populations, could help provide more definitive evidence for optimal clinical approaches while potentially explaining the observed variations in hyperuricemia prevalence and cardiovascular risk patterns.

Conclusions

Hyperuricemia prevalence is high in patients undergoing MHD and is associated with heavy smoking, heavy alcohol consumption, abdominal obesity, and higher systolic blood pressure. Considering CVD and cerebrovascular disease are the leading causes of mortality among patients undergoing MHD, our retrospective analysis revealed that hyperuricemia was significantly linked to several biochemical parameters (triglycerides, CRP, PTH, homocysteine, HDL) as well as changes in cardiac structure, which may contribute to the increased CVD risk. However, given the observational and retrospective nature of this study, we cannot establish a causal relationship between hyperuricemia and CVD outcomes. Hyperuricemia may serve as a marker of multimorbidity or metabolic dysfunction rather than a direct causative factor. Future prospective studies and randomized controlled trials are needed to investigate whether urate-lowering interventions could reduce CVD risk and improve long-term prognosis in patients with hyperuricemia undergoing MHD.