Does Hypertension Mediate the Association of the Serum Uric Acid-to-Albumin Ratio with Mortality in U.S. Adults? A Prospective Cohort Study

1. Introduction

The identification of novel biomarkers for the early detection of increased mortality risk represents a significant unmet need in the field of biomedical research. The pursuit of such biomarkers is driven by the potential to improve disease prevention strategies and enhance early interventions, which could ultimately lead to a reduction in morbidity and mortality rates. The limitations of traditional risk assessment tools, which rely on clinical parameters and a restricted set of baseline biomarkers, are evident in their inability to fully capture the intricate biological processes underlying diseases. This underscores the significance of this research [1]. The pursuit of simple and effective biomarkers is of paramount importance for enhancing our ability to predict, prevent, and manage a range of health conditions, thereby improving public health outcomes.

Uric acid (UA), the final product of purine metabolism, has been linked to endothelial dysfunction and heightened chronic inflammatory responses. Consequently, UA is regarded as a risk factor for atherosclerosis and coronary artery disease (CAD) [2] . A substantial body of evidence from numerous studies has demonstrated a direct causal relationship between serum uric acid levels and blood pressure [3,4]. Serum albumin, the most abundant protein in the human body, plays a role in anti-inflammatory processes and the elimination of free radicals [5,6]. The uric acid-to-albumin ratio (UAR) is a biomarker that reflects the balance between uric acid and serum albumin levels and is associated with various pathological conditions, including inflammation and oxidative stress, both of which are known factors contributing to hypertension and its related complications [2,7,8]. A high uric acid-to-albumin ratio (UAR) may serve as a predictive marker for the severity of hypertension, indicating that it may reflect underlying pathophysiological changes that predispose individuals to adverse cardiovascular events [9]. Recent studies have underscored its predictive value for mortality in patients with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) [7,8]. It has the potential to serve as a prognostic indicator for long-term cardiac mortality in patients with unstable angina and those undergoing percutaneous coronary intervention (PCI) 9 . Furthermore, elevated UAR values have been linked to impaired collateral circulation in patients with non-ST-elevation myocardial infarction [10,11]. In sum, the prognostic role of UAR in cardiovascular disease has been firmly established.

However, no studies have reported an association between UAR and mortality risk in the general population, nor has the potential mediating effect of hypertension on the relationship between UAR and mortality been investigated. In light of the aforementioned knowledge gap, the present study seeks to elucidate the potential association between UAR and all-cause and cause-specific mortality risk in the general population. To this end, data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 will be employed. Furthermore, the study will explore the mediating role of hypertension in this relationship.

2. Research population and methods

2.1. Participants characteristics

The characteristics of the participants in this cohort study were derived from the NHANES database (1999-2018). This database is a cross-sectional study that collected health and nutrition information related to representative demographic statistics, physical examinations, disease questionnaires, and survival follow-up. The study included 52,534 participants aged 18 years and older with complete serum albumin, uric acid, and follow-up data on death. (Figure 1)

2.2. Variables and outcomes

In this study, UAR was defined as the ratio of uric acid (mg/dL) to albumin (g/dL). Covariates included demographic factors such as age, race and ethnicity, gender, poverty income ratio (PIR) and education level; lifestyle factors such as body mass index (BMI, kg/m²), smoking status (former or never), and physical activity; and health questionnaires on hypertension, diabetes, hypercholesterolemia, heart disease, stroke, and cancer. All variables are publicly available on the NHANES website. The primary outcome was all-cause mortality, while specific-cause mortality constituted the secondary outcome. The follow-up period for survival was from the date of the interview to December 31, 2019.

2.3. Statistical analysis

1. The mean ± standard deviation (SD) and percentage were calculated for continuous and categorical variables, respectively. 2. The relationship between UAR levels or hypertension and the risk of mortality was evaluated using Cox proportional hazard models. 3. Subgroup analyses were conducted to investigate the relationship between UAR and all-cause mortality, stratified by age, gender, BMI, race and ethnicity, education level, PIR, physical activity, and smoking status. The P-value for the interaction is determined through a logarithm likelihood ratio test. 4.To assess the non-linear association between UAR and the hazard of all-cause death, restricted cubic spline (RCS) regression was employed, and the Kaplan-Meier curve was used for the overall survival. 5. The causal mediation analysis enables the calculation of the number of mediated effects produced by hypertension. All results were statistically significant with a p-value less than 0.05 (two-tailed). The data were analyzed using the statistical software packages R (version 4.2.0) and EmpowerStats.

3. Results

3.1. Basic characteristics of the population

In Table 1, a total of 52,534 participants were classified into three groups based on the UAR tertiles. The mean age across all groups was 47.50 years, with the oldest group observed in T3 (51.82 years). There was a notable male predominance, particularly in T3, where 65.82% of participants were male. Significant differences in the distribution of race and ethnicity were observed across the UAR tertiles, with the highest proportion of Non-Hispanic Blacks observed in T3 (24.36%). Significant differences were observed in poverty income ratio and education level across the groups.

The mean BMI and UAR values were significantly higher in T3, with mean BMI values of 31.23 kg/m² and mean UAR values of 1.64. The prevalence of smoking, hypertension, diabetes, heart disease, stroke, cancer, and high cholesterol exhibited a progressive increase across UAR tertiles, with the highest rates observed in T3. It is noteworthy that the mean uric acid level was 6.79 mg/dL in T3, which was significantly higher than the other groups. Conversely, the mean albumin levels were lowest in T3 (4.16 g/dL).

3.2. Logistic regression analyses

Table 2 presents the hazard ratios (HR) for mortality associated with UAR levels and hypertension. In the fully adjusted Model 3, a significant positive association was observed between higher UAR and increased mortality risk, with an HR of 1.91 (95% CI, 1.77-2.05) for the overall UAR. The highest UAR tertile (T3) exhibited the highest HR of 1.37 (95% CI, 1.27-1.49) in comparison to the reference tertile (T1). Furthermore, hypertension demonstrated a robust correlation with mortality, with an HR of 1.44 (95% CI, 1.36-1.53) in Model 3.

The appendix table provides a detailed examination of the relationship between UAR and mortality, both overall and in specific causes. Table A1 demonstrates that after adjusting for numerous potential confounding factors in Model 3, there is a statistically significant association between UAR and all-cause mortality, with an HR of 1.91 (95% CI, 1.77-2.05). This relationship is also observed for several cause-specific mortalities, with UAR demonstrating a particularly strong link to heart disease and nephropathy, where the HRs are 1.52 (95% CI, 1.33-1.73) and 2.44 (95% CI, 1.59-3.77), respectively. The association between malignant neoplasm and diabetes also remains significant, with hazard ratios of 1.28 (95% confidence interval, 1.09-1.51) and 1.59 (95% confidence interval, 1.17-2.16), respectively. Furthermore, we have included data on the hazard ratios for cause-specific mortality by UAR tertiles. (Table A2).

Table 3 illustrates the robust correlation between UAR and hypertension. In the unadjusted Model 1, elevated UAR was associated with an increased risk of hypertension, with an odds ratio (OR) of 4.61 (95% confidence interval [CI], 4.36-4.87). After adjusting for demographic factors in Model 2 and further for lifestyle and metabolic variables in Model 3, the association remained significant, with odds ratios of 3.73 (95% confidence interval, 3.50-3.97) and 2.69 (95% confidence interval, 2.49-2.92), respectively. The odds of hypertension increased progressively across UAR tertiles, with the highest tertile (T3) showing the strongest association in Model 3 (OR, 2.03; 95% CI, 1.89-2.18).

3.3. Stratified analyses and interaction tests

As shown in Figure 2, the stratified analysis verified that the UAR level was positively correlated with all-cause death, and all p-values for interaction>0.05, indicating that the association between the UAR level and all-cause death was not affected by confounding factors.

3.4. Dose‒response and Kaplan-Meier curves

In Figure 3, A nonlinear relationship between UAR and the risk of all-cause mortality was identified using the Cox model with restricted cubic spline analysis(A). Kaplan-Meier curves for overall survival according to UAR tertiles are presented (B).

3.5. Mediation analysis of hypertension

Table 4 presents the results of the mediation analysis examining the role of hypertension in the relationship between UAR and all-cause mortality. The total estimate effect of UAR on mortality was found to be -234.86 (95% CI: -269.03, -202.50), indicating a strong association. Hypertension partially mediated this effect, with a mediation effect estimate of -14.34 (95% CI: -18.02, -10.67). The direct effect of UAR, independent of hypertension, was also significant, with an estimate of -220.52 (95% CI: -253.98, -188.51). The proportion of the effect mediated by hypertension was 6.09% (95% CI: 4.68%, 7.72%), indicating that while hypertension contributes to the UAR-mortality link, the majority of the effect is direct. The analysis was adjusted for a number of confounding variables, including age, gender, race and ethnicity, BMI, smoking status, physical activity, education, poverty income ratio, high cholesterol, and diabetes. This adjustment serves to strengthen the validity of the observed associations. The model utilized for the mediation analysis is illustrated in Figure 4.

4. Discussion

The relationship between uric acid to albumin ratio (UAR) and mortality has received increasing attention in recent years, particularly as researchers seek to identify novel biomarkers that may aid in the early detection of individuals at risk for adverse health outcomes. Our study provides compelling evidence of the relationship between UAR, hypertension and mortality, demonstrating that higher UAR levels are significantly associated with an increased risk of all-cause mortality and specific cause-related mortality, particularly heart disease and nephropathy. This finding is consistent with previous research that has established UAR as a potential prognostic marker in cardiovascular health.

A number of studies have demonstrated the role of UAR in predicting cardiovascular outcomes. For example, Kalkan et al. reported that elevated UAR is associated with increased mortality in patients with ST-elevation myocardial infarction (STEMI) [8]，and Yin et al. demonstrated that elevated UAR is an independent predictor of poorly developed coronary collateral circulation in patients with non-ST-elevation myocardial infarction (NSTEMI) [12], suggesting that UAR may serve as a valuable prognostic indicator in acute coronary syndromes. Similarly, Zhang et al. reported that UAR serves as a novel predictor of coronary slow-flow phenomenon in patients with chronic coronary syndromes, further supporting the role of UAR in cardiovascular risk assessment [2]. In addition, Li et al. identified UAR as an independent predictor of long-term cardiac mortality in patients with unstable angina after percutaneous coronary intervention (PCI) [9]，and Sultana et al. evaluated UAR as a marker of coronary artery disease severity in acute coronary syndrome, suggesting its potential utility in identifying high-risk patients [13]. These findings highlight the potential of UAR as a biomarker that reflects the underlying pathophysiological processes associated with cardiovascular disease.

Hypertension is a well-established risk factor for cardiovascular disease and mortality, and its interplay with UAR is worthy of particular note. Our findings reinforce the notion that UAR could serve as a valuable tool for risk stratification in clinical practice, as they underscore the graded relationship between UAR tertiles and hypertension risk. This is particularly significant in light of the shortcomings of conventional risk assessment instruments, which may not fully encompass the intricate biological mechanisms underlying disease pathogenesis. The identification of UAR as a potential biomarker for the early identification of individuals at higher risk of adverse health outcomes could facilitate targeted interventions aimed at reducing cardiovascular risk. The present study revealed a robust correlation between hypertension and mortality, with a hazard ratio of 1.44, indicating that individuals with hypertension are at a markedly elevated risk of mortality. This finding is consistent with the results reported by Liu et al., who identified UAR as a significant factor associated with quantitative flow ratio, a measure of coronary artery function, in patients with suspected coronary artery disease [14]. The mediation analysis conducted in the present study demonstrated that hypertension plays a partial mediating role in the relationship between UAR and mortality, with a mediation effect estimate of -14.34 and a proportion mediated of 6.09%. This suggests that UAR may influence mortality risk through both hypertension-dependent and -independent pathways. This finding is consistent with the work of Özgür et al., who identified UAR as a predictive marker of short-term mortality in patients with acute kidney injury, thereby highlighting its relevance beyond cardiovascular contexts [10] .

The mechanisms underlying the association between uric acid levels, hypertension, and mortality are complex and likely involve inflammatory processes, oxidative stress, and endothelial dysfunction. Uric acid is recognized for its pro-inflammatory properties. Elevated uric acid levels have been demonstrated to contribute to endothelial dysfunction and increased vascular resistance, which are key factors in the development of hypertension and subsequent cardiovascular events [3,15,16]. Furthermore, albumin possesses antioxidant properties and plays a crucial role in maintaining vascular integrity. Low serum albumin levels can indicate systemic inflammation and poor nutritional status, further complicating the clinical picture [17,18,19]. The uric acid-to-albumin ratio (UAR) is a biomarker that reflects the balance between uric acid and serum albumin levels and is associated with various pathological conditions, including inflammation and oxidative stress, both of which are known factors contributing to hypertension and its related complications, thereby reinforcing the association between inflammation, oxidative stress and the mortality relationship.

It is essential to contextualize the findings of our study within the framework of its inherent strengths and limitations. A significant advantage is the large sample size of general population and the comprehensive adjustment for potential confounding variables, which enhances the generalizability of the findings. Nevertheless, as with any observational study, we are unable to establish causality and must consider the possibility of residual confounding despite our extensive adjustments. Furthermore, the focus of our study on a single population may restrict the generalizability of our findings to other demographic groups.

5. Conclusions

The results of our study indicate a significant correlation between UAR, hypertension, and mortality, suggesting that UAR may serve as a potential biomarker for early risk identification. This highlights the necessity for further investigation into UAR-targeted antioxidant interventions for the improvement of clinical outcomes.