Serum Uric Acid Levels and Their Association with Renal Function Decline and Kidney Disease Progression in Middle-Aged and Elderly Populations: A Retrospective Cohort Study

Introduction

In recent years, chronic kidney disease (CKD) has emerged as a major global public health problem and has been recognized as the tenth leading cause of death worldwide.¹ According to the latest data from the World Health Statistics 2021, the worldwide adult prevalence of CKD is 7.1%, with particularly high prevalence rates, approximately 9.7%, observed in the Asia-Pacific region. CKD can significantly diminish patients’ quality of life and impose substantial medical and socio-economic burdens.^2,3

Previous studies have extensively explored numerous risk factors associated with CKD, including hypertension, diabetes, obesity, hyperuricemia, hyperlipidemia, smoking, kidney infections, and inadequate medication.^4–6 Among these risk factors, the relationship between high serum uric acid (SUA) levels and decreased kidney function has generated great interest. A comprehensive review article focuses on elucidating the underlying cellular and molecular pathophysiological mechanisms by which uric acid activates the NLRP3 inflammasome, resulting in kidney damage.⁷ Several prospective studies had stratified participants according to SUA levels and found a positive association between SUA levels and the prevalence of CKD.^8–14 In a retrospective cohort study conducted in Japan, it was observed that deviations from normal serum urate levels could lead to a decline in estimated glomerular filtration rate among healthy Japanese men.¹⁵ However, relatively few studies have examined the association between SUA and early-stage decline in renal function, namely the association between SUA and a decrease in eGFR in individuals without CKD. Therefore, the use of new methods and models to further investigate or predict the association and strength of the relationship between SUA and CKD and decreased eGFR is necessary to shed more light on the relationship between SUA and kidney disease. Additionally, population-based studies have highlighted gender differences in the relationship between SUA and CKD,^16–19 with women consistently found to have lower levels of SUA than men, because estrogen stimulates urinary urate excretion.¹⁷ Hence, SUA levels and CKD incidence may be different between men and women. Furthermore, some studies have suggested that women in their postmenopausal stage may be more susceptible to CKD and hyperuricemia.^20,21 Despite these observations, little is known about the underlying mechanisms of these gender differences and the role of hormonal changes during menopause in the development of CKD. Therefore, it is necessary to investigate this link in middle-aged and elderly populations of both sexes, particularly women in their pre-and post-menopausal stages.

In this community-based population cohort study, we aimed to investigate the relationship between SUA levels and the prevalence of CKD and decreased kidney function in individuals without CKD, with a particular emphasis on gender differences and women in the pre-and post-menopausal stages. The insights generated by this research will be valuable for the prevention and treatment of CKD and declining renal function.

Methods

Study Design

We conducted a dynamic retrospective cohort study using data collected from participants who received free health check-ups at community health centers in China as part of the “Public Basic Health Services Project”. The study included 12,498 adults aged 40 years or older who underwent physical examinations at a health center located in Hangzhou, Zhejiang Province between May 2010 and December 2018. During the study period, participants underwent physical examinations biennially, with each participant having completed at least three physical examinations. After excluding those who had less than three times of physical examinations (n = 166), those with missing blood pressure (BP), SUA, FBG, TC, eGFR information (n=384), and those with eGFR<60 mL/min/1.73m² at baseline (n=1730). Ultimately, a total of 10,218 participants were enrolled in the study, including 3773 males and 6445 females (Figure 1). The retrospective study was approved by the Ethics Committee of Hangzhou Normal University (Reference No. 20220009) and was conducted in accordance with the Helsinki Declaration. Informed consent was waived as the data received from the community health centers was anonymized by removing identification information.

Figure 1 Flowchart of the participant inclusion. Abbreviation: eGFR, estimated glomerular filtration rate.

Data Measurement

Each participant underwent an in-person interview conducted by a trained nurse using a standardized questionnaire to collect demographic information. Weight and height were measured using calibrated scales and a stadiometer. Blood pressure was measured using a calibrated mercury sphygmomanometer. Two consecutive measurements were taken with a 2-minute interval, and the average of the two readings was calculated as the final value.

Before venous blood sample collection, all participants were required to fast for at least eight hours. Serum creatinine, SUA, FBG, and TC levels were measured for each participant using standard clinical laboratory methods.

Diagnostic Criteria

Hypertension was defined as the presence of either SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, or having been previously diagnosed with hypertension and currently receiving anti-hypertensive treatment. Hyperglycemia was defined as FBG ≥7.0 mmol/L or self-reported diabetes. Dyslipidemia was defined as TC ≥6.22 mmol/L.²² According to the BMI classification criteria of the Chinese population,²³ obesity was defined as BMI ≥28 kg/m². Hyperuricemia was defined as SUA ≥416μmol/L (70 mg/L) in men and SUA ≥357μmol/L (60 mg/L) in women. The CKD incident was defined as an eGFR of less than 60 mL/min/1.73m². The modified equation for eGFR according to the Chinese eGFR Collaboration²⁴ for Chinese patients with chronic diseases:

Statistical Analysis

The normality of continuous variables’ distribution was assessed using the Shapiro–Wilk tests. Continuous variables with normal distribution are presented as the mean ± standard deviation, while those with non-normal distribution are presented as the median (interquartile range). Categorical variables are expressed as frequency (percentages). The group differences for continuous variables were compared using Analysis of Variance (ANOVA) and the Kruskal–Wallis test, while the Chi-square test was used for categorical variables. Given the significant gender differences in SUA levels, all analyses were stratified by gender. SUA within the normal range was divided into four groups based on the SUA quartiles (Q1-Q4). Hyperuricemia was grouped as the fifth group. The detailed grouping information is SUA Q1 (SUA<237μmol/L), Q2 (237≤SUA<278μmol/L), Q3 (278≤SUA<325μmol/L), Q4 (325μmol/L≤SUA) for women, and Q1 (SUA<297μmol/L), Q2 (297≤SUA<348μmol/L), Q3 (348≤SUA<403μmol/L) and Q4 (403μmol/L≤SUA) for men, all using the first quartile (Q1) as the reference group. A generalized additive mixture effects model (GAMM) presented trends between SUA and eGFR. The model was adjusted for Age, BMI, FBG, SBP, DBP, TC, and Cr. The GEE models are used to account for correlation among responses from multiple time points per participant, using an exchangeable correlation matrix.²⁵ In this study, crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for CKD, controlling for SUA levels. In the multivariable models, variables such as age, BMI, and biological information were included to obtain adjusted ORs and 95% CIs. This approach allows for a more accurate assessment of the relationship between these variables and CKD, while controlling for other factors. Furthermore, stratified analyses were conducted while taking into account women’s menopausal status, age, and obesity status. All analyses were performed using SPSS version 26.0 and R software version 4.2.1. A two-sided p-value<0.05 was considered statistically significant.

Results

Baseline Characteristics of Participants

The baseline characteristics of the study participants are presented in Tables 1 and 2. A total of 10,218 participants (3773 men and 6445 women) aged 40 years and older were included, As the baseline SUA levels increased, SBP, DBP, FBG, TC, and Cr showed a trend towards an increase in both sexes and a decrease in eGFR. In addition, SUA levels were relatively high in older subjects of both sexes, and the proportion of obesity, hypertension, hyperglycemia, and dyslipidemia was higher in subjects with higher SUA levels compared with lower SUA levels.

Table 1 Baseline Characteristics of the Men Participants According to Different SUA Levels

Table 2 Baseline Characteristics of the Women Participants According to Different SUA Levels

A Strong Correlation Between Alterations in SUA and Fluctuations in eGFR

The GAMM analysis depicting the association between SUA and eGFR in individuals aged 40 and above, is illustrated in Figure 2. Following adjustment for age, BMI, SBP, DBP, FBG, and TC, a significant association between SUA and eGFR was observed. Notably, the SUA-eGFR association demonstrated a decreasing trend in both genders. Specifically, a nonlinear association (F=578.0, P<0.05) was observed in females, while an approximately linear relationship (F=169.3, P<0.05) was observed in males, suggesting that elevated SUA levels are associated with renal function decline.

Figure 2 Effect of serum uric acid on estimated glomerular filtration rate. Abbreviation: eGFR, estimated glomerular filtration rate.

Baseline SUA Levels and Risk of Incident CKD

During the follow-up period, 292 (2.9%) participants (155 men and 137 women) developed incident CKD. Models 1 and 2 showed significant associations of incident CKD with 4th quartiles of SUA. Model 3 showed a 2.16-fold (95% CI: 1.31–3.58, P= 0.003) increased risk of CKD in the highest SUA quartile for men and 2.76-fold (95% CI: 1.59–4.78, P< 0.001) for women compared to the lowest quartile (Table 3). Additionally, the population was categorized into four groups based on the mean and standard deviation of serum uric acid to investigate the relationship. Consistent findings were observed, as stated previously, and a detailed description of the groupings and results can be found in Table S1.

Table 3 Risks for the Incidence of CKD Development According to the Quartiles of Baseline SUA Levels

Nonlinear Association Between SUA and the Development of CKD

Based on the point estimates of the odds ratios for Q2 in the aforementioned tables, which investigated baseline SUA and the progression of CKD being less than 1, it indicates a potential non-linear association between SUA and CKD progression. To visually depict this relationship, we generated spline curves presenting the risk of CKD in both men and women using SUA as a continuous variable (Figure 3), revealing a distinctive nonlinear association. Threshold and saturation effects analyses showed that the inflection point for SUA was 300μmol/L for males and 252μmol/L for females. Both higher and lower levels of SUA may contribute to an increased risk of developing CKD.

Figure 3 Risks for the incidence of CKD development according to SUA levels. Abbreviations: SUA, serum uric acid; eGFR, estimated glomerular filtration rate.

Subgroup Analysis

We stratified men by age, using 65 years as the cutoff point, and found a significant association between high SUA levels and CKD in both age groups. Women were stratified by menopausal status, using 51 years as the cutoff point. Participants who were younger than 51 years did not exhibit a significant association between SUA and CKD. However, participants aged 51 years and above demonstrated a significant association between SUA levels and CKD. In the stratified analysis by body mass index (BMI), we observed a positive association between SUA and CKD only in the non-obese population, while no effect was found in the obese population (see Tables S2–S4).

Discussion

The results of our study are consistent with prior investigations on the adverse effects of elevated SUA levels on renal function. Specifically, we found that elevated SUA levels are associated with a linear reduction in eGFR in men and a non-linear reduction in women. Hyperuricemia may interfere with glomerulus blood flow and autoregulation, leading to inflammation, fibrosis, and urate deposition in the kidneys.²⁶ This is consistent with prior research, as reported by Liu et al and Isabel O Oliveira et al, which demonstrated that elevated UA was associated with a decline in eGFR.^27,28

Our study provides further evidence that higher baseline SUA levels are associated with an increased risk of incident CKD. In this context, our findings are consistent with those of previous research, including a population-based study by Ye et al¹⁴ and a national cohort study and updated meta-analysis by Wu et al.²⁹ In particular, the latter study highlighted that higher baseline SUA levels were associated with an increased risk of CKD in middle-aged and older Chinese adults. This positive association was subsequently confirmed in a meta-analysis of several cohort studies. Moreover, several studies have identified SUA as a risk factor for the development of kidney disease in specific populations such as diabetic, non-diabetic, hypertensive, and non-hypertensive populations.^11,30–34 Given that hyperuricemia can interact with other risk factors, such as metabolic syndrome, diabetes, and hypertension, to accelerate the progression of declining renal function,^33,35–37 prompt identification of high-risk patients is crucial to reduce the burden of CKD. Furthermore, our study revealed a non-linear relationship between SUA levels and the risk of CKD. Particularly, low levels of uric acid were found to be associated with an increased risk of CKD. Supporting this finding, a cross-sectional study conducted on a Japanese population provided evidence linking hypouricemia to decreased renal function.³⁸ It has been hypothesized that the decreased antioxidant capacity resulting from hypouricemia further elevates the risk of reduced renal function.³⁹ This is consistent with previous studies indicating associations between hypouricemia and various inflammatory and degenerative diseases, such as acute graft-versus-host disease, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and multiple sclerosis. These associations are considered to be a consequence of the reduced antioxidant capacity. Furthermore, considering the high incidence of hyperuricemia among middle-aged women,^20,21 we stratified women by menopausal status. Our study confirmed a significant association between SUA levels and CKD in postmenopausal women, suggesting that SUA is an independent risk factor for CKD. Therefore, it is necessary to consider the impact of menopausal status on the association between SUA and CKD when developing prevention and treatment strategies.

There are a few limitations in our study. Firstly, the number of potentially observable confounders that could be included was small, such as smoking, alcoholic consumption, physical activity, and dietary habits, which may cause over-estimations on the associations between SUA and CKD in this study. Secondly, our study was based on a single-center investigation and included only adults aged 40 years and older residing in the community, which should be cautious when extrapolating our findings to other populations. Thirdly, the absence of drug histories regarding medications that can potentially influence uric acid levels, such as thiazide diuretics, allopurinol, and probenecid, poses a limitation in evaluating their impact on our findings. To further comprehend the relationship between SUA levels and the development of CKD, it is recommended for future research to prioritize the collection of medication data. Our study has several strengths, such as a large sample size, a long follow-up period, and a prospective design. Overall, our findings contribute to the growing body of evidence on the negative impact of elevated SUA on renal function and further emphasize the need for timely identification and management of high-risk patients to prevent the development of CKD.

Conclusion

This community-based retrospective cohort study reveals a significant association between SUA levels and a decline in GFR. Higher SUA levels were associated with an increased risk of incident CKD in Chinese middle-aged and elderly adults, particularly in postmenopausal women. These findings underscore the importance of monitoring SUA levels, in the prevention and management of CKD.