Alcohol consumption and serum uric acid are synergistically associated with renal dysfunction among community‐dwelling persons

Abstract Background Serum uric acid (SUA) is a key risk factor contributing to renal failure, a serious public health problem. However, few studies have examined whether the interactive relationship between alcohol consumption and SUA is independently associated with the estimated glomerular filtration rate (eGFR). Methods Our sample comprised 742 men aged 69 ± 11 years (mean ± standard deviation) and 977 women aged 69 ± 10 years from a rural area. We cross‐sectionally examined the relationships between the confounding factors of alcohol consumption and SUA with renal function denoted by eGFR estimated using CKD‐EPI (Chronic Kidney Disease Epidemiology Collaboration) equations modified by a Japanese coefficient. Results In both genders, eGFR increased with a rise in alcohol consumption. This tendency was more pronounced in participants with hyperuricemia, where SUA was greater than 7.0 mg/dL in men and greater than 6.0 mg/dl in women (men: F = 41.98, p < 0.001; women: F = 41.98, p < 0.001). A multiple linear regression analysis showed that alcohol consumption (men: β = 0.112, p < 0.001; women: β = 0.060, p = 0.011) and SUA (men: β = −0.282, p < 0.001; women: β = 0.317, p < 0.001) were significantly and independently related to eGFR. Further, the interactive relationship between alcohol consumption and SUA (men: F = 6.388, p < 0.001; women: F = 5.368, p < 0.001) was a significant and independent indicator of eGFR. Conclusions These results suggested that alcohol consumption and SUA were synergistically associated with renal dysfunction among community‐dwelling persons.


| INTRODUC TI ON
Serum uric acid (SUA) is one of the major risk factors contributing to renal dysfunction, a severe public health problem. Patients with chronic kidney disease (CKD) generally report high SUA levels. A recent meta-analysis revealed a direct relationship between elevated baseline SUA levels and incident CKD. 1 Longitudinal changes in SUA are interactively and independently associated with declining renal function in community-dwelling older adults. 2 Several studies have shown a consistent relationship between moderate alcohol consumption and health benefits, including a reduced risk of type 2 diabetes, 3 coronary heart disease, 4 ischemic stroke, 5 cancer mortality in men, 6 and all-cause mortality. 7 Researchers have also investigated the impact of alcohol consumption on various renal disorders. However, the findings on this impact have been inconsistent. A study of 1,658 nurses concluded there was no correlation between alcohol consumption and renal dysfunction. 8 Examining a large cohort of healthy men, Schaeffner et al. 9 10 showed that moderate alcohol consumption was inversely related with the risk of renal dysfunction. Buja et al. 10 demonstrated a Ushaped relationship between alcohol consumption and the incidence of renal impairment in women who drink more than 24 g of alcohol per day. Two retrospective analyses showed a correlation between moderate alcohol consumption and increased risk of renal dysfunction 11 or end-stage renal disease. 12 Further, alcohol consumption leads to hyperuricemia as a result of the high purine content of certain types of alcoholic beverages, 13 increased urate production from purine nucleotide degradation during ethanol catabolism, and lactic acid inhibition of renal urate excretion. 13 However, to the best of our knowledge, few studies have examined the interactive effects of alcohol consumption and SUA levels on renal dysfunction in Japanese populations. 14 This study first examined the relationship between the confounding factors of alcohol consumption and SUA and renal function denoted by the estimated glomerular filtration rate (eGFR). Second, it investigates whether the interactive relationship between alcohol consumption and SUA is independently related to eGFR using crosssectional data from community-dwelling persons.

| Subjects
This cross-sectional study was designed as part of a research project conducted by researchers at the Nomura Welfare Center. 15 Survey participants included individuals who underwent an annual community health examination at the Nomura Welfare Center in a rural region of Ehime Prefecture, Japan. This study excluded all individuals who were on SUA-lowering drugs or who had a baseline eGFR of less than 10 ml/min/1.73 m 2 . Data on medical history, current status, and medications (eg, antihypertensive, antilipidemic, antidiabetic, and SUA-lowering medications) were obtained during interviews conducted using a structured ques-

| Evaluation of Risk Factors
Data on demographic characteristics and confounding factors were collected from the participants' clinical files. Participants wore light clothing and removed their shoes for the height and body weight measurements. We divided weight (kg) by height squared (m 2 ) to calculate body mass index (BMI). Smoking status was defined as the product of cigarette packs smoked per day and the number of years of smoking (packs/years). Participants were categorized as non-smokers, ex-smokers, light smokers (<20 packs/year), or heavy smokers (≥20 packs/year). We measured daily alcohol consumption in units of sake equivalent to 22.9 g of ethanol. Accordingly, participants were classified as non-drinkers, occasional drinkers (<1unit/day), daily light drinkers (1-2 units/day), or daily moderate drinkers (2-3 units/day). We used an appropriately sized cuff around the upper right arm of participants to estimate systolic blood pressure (SBP) and diastolic blood pressure (DBP) and took two estimates with an interval of 5 min. We used the mean of the two consecutive measurements for analysis. Participants were asked to fast overnight before triglyceride (TG), high-and lowdensity lipoprotein cholesterol (HDL-C and LDL-C), SUA, and hemoglobin A1c (HbA1c) levels were measured. We used the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation modified with a Japanese coefficient to estimate glomerular filtration ratio (eGFR). The equation for men with creatinine (Cr) ≤0.9 mg/dl is 141 × (Cr/0.9) −0.411 × 0.993 age × 0.813; for those with Cr >0.9 mg/dl, it is 141 × (Cr/0.9) −1.209 × 0.993 age × 0.813. For women with Cr ≤0.7 mg/dl, the equation is 144 × (Cr/0.7) −0.329 × 0.993 age × 0.813; for those with Cr >0.7 mg/dl, it is 144 × (Cr/0.7) −1.209 × 0.993 age × 0.813. 16 Hyperuricemia was defined as SUA levels greater than 7.0 mg/dl for men or 6.0 mg/dl for women. 17 CKD was determined by the presence of dipstick-positive proteinuria (≥1+) or a low eGFR (<60 ml/ min/1.73 m 2 ). 18 Cardiovascular diseases (CVD) included ischemic heart disease, ischemic stroke, and peripheral vascular disease.

| Statistical analysis
We performed statistical analyses using SPSS Statistics version 26 for Windows (IBM Japan). If data were normally distributed, continuous variables were denoted as mean ± standard deviation (SD); if not (eg, for TG and HbA1c), the variables were represented as median (interquartile range) values. Parameters with non-normal distributions were analyzed following log-transformation. We divided the participants into two groups based on the presence or absence of hyperuricemia. Next, we analyzed the differences in means and prevalence between the two groups by conducting Student's t tests on continuous data and χ 2 tests on categorical data. A multiple linear regression analysis was conducted to examine the impact of all confounding factors (ie, age; BMI; smoking habit; alcohol consumption; exercise regime; history of CVD, SBP, TG, SUA, and LDL-C and HDL-C levels; and the use of antihypertensive, antilipidemic, HbA1c, or antidiabetic medication) on eGFR in both genders. Finally, we employed a general linear model to examine the synergistic effect of alcohol consumption (eg, non-drinkers, occasional drinkers, daily light drinkers, and daily moderate drinkers) and SUA (eg, men, <7.0 mg/dl and ≥7.0 mg/dl; women, <6.0 mg/dl and ≥6.0 mg/ dl) on eGFR. A p-value less than 0.05 was considered statistically significant.

| RE SULTS
3.1 | Participants' background characteristics stratified by gender and hyperuricemia status. Table 1   3.2 | Relationship between alcohol consumption and eGFR stratified by gender and hyperuricemia status. 3.3 | Relationship between background characteristics and eGFR stratified by gender.

| Adjusted eGFR based on hyperuricemia status, stratified by gender and alcohol consumption.
As shown in Table 4, for both genders, participants with hyperuricemia displayed a higher multiple-adjusted eGFR with increasing alcohol consumption. In addition, we observed that interaction between alcohol consumption and SUA affects eGFR.

| DISCUSS ION
This study examined the association of alcohol consumption and SUA with renal function (ie, eGFR) in the general population. The findings reveal a relationship between various confounding factors and eGFR, which is consistent with previous research. 19 More specifically, this study demonstrates that age, alcohol consumption, antihypertensive medication, TG, and SUA all have a significant relationship with eGFR. In addition to these direct associations, the interaction between alcohol consumption and SUA was found to be a significant and independent determinant of eGFR. This research, to the best of our knowledge, is the first to demonstrate that alcohol consumption and SUA have an interactive effect on renal dysfunction, and that alcohol consumption modifies the relationship between SUA and renal dysfunction.
About 20.8% of men reported having hyperuricemia, compared to 12.6% of women, which is consistent with results of previous studies. 20 21 The difference can be explained by the presence of estrogen in women, which increases uric acid excretion. 22 Hyperuricemia is an independent risk factor contributing to renal dysfunctions such as microalbuminuria 23 and CKD 24 25 . 26 27 However, studies have shown that increased SUA is a consequence of coexisting risk factors such as hypertension, obesity, dyslipidemia, and insulin resistance. 28 Nevertheless, a growing Abbreviatiions: β, standard coefficient; eGFR, estimated glomerular filtration rate.

TA B L E 2 Relationship between background characteristics and eGFR of participants by gender
Studies have associated alcohol consumption with aggravated CKD 12 33 or increased all-cause mortality in patients with CKD. 34 Numerous experimental studies have confirmed that alcohol consumption damages the glomeruli and renal tubules, leading to albuminuria and reduced GFR, although some research has determined the opposite. 35 Alcohol consumption increases the production of reactive oxygen species (ROS), and this contributes to lipid peroxidation and damages antioxidant capacity. 36 The long-term consumption of alcohol activates the RAS and increases sympathetic nervous system activity, which elevates the SBP and damages the normal structure of the glomeruli. 37 These factors potentially cause renal injury through hemodynamic disorders and inflammation. 38 However, some clinical studies have shown an association between moderate alcohol consumption and a reduced incidence of CKD 39 and end-stage renal disease. 40 That is, moderate alcohol consumption lowers the risk of type 2 diabetes and curbs rises in HDL-C, which are both closely related to CKD, 35  This study is subject to several important limitations. First, we used a cross-sectional design and were unable to establish causality. In conclusion, this cross-sectional study highlights the possibility that a moderate consumption of alcohol is not related to an increased risk of renal dysfunction in either gender. In fact, it shows that moderate alcohol consumption is inversely related with renal dysfunction.
This indicates that alcohol consumption and SUA were synergistically associated with renal dysfunction among community-dwelling persons.
The mechanisms underlying this association warrant further research. Abbreviations: eGFR, estimated glomerular filtration rate.
*The net effect of each interaction was estimated using a general linear model.

TA B L E 3 Effect of interaction between
drinking status and serum uric acid level on the eGFR of participants by gender

ACK N OWLED G EM ENT
This work was supported in part by a grant-in-aid from the Foundation for Development of Community (2020).

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets analyzed in this study are available from the corre-  Note: Multiple-adjusted odds ratio for all confounding factors listed in Table 2. Data for triglycerides and hemoglobin A1c were skewed and were logtransformed for analysis. Numbers in bold indicate significance.