High serum uric acid/creatinine ratio is a useful predictor of hypertension among Japanese community-dwelling persons

Abstract

Background

The correlation between serum uric acid/creatinine (SUA/Cr) ratio and hypertension risk has not been well studied. This study aims to examine whether the SUA/Cr ratio is a predictor of hypertension.

Methods

This cohort study comprised 171 men aged 64 ± 11 (mean ± standard deviation) years and 266 women aged 65 ± 10 years recruited for a survey at the community-based annual medical check-up. The main outcome was the presence of hypertension (antihypertensive medication) and having systolic blood pressure (SBP) ≥ 140 mmHg and diastolic blood pressure (DBP) ≥ 90 mmHg.

Results

The baseline SUA/Cr ratio was significantly correlated only with DBP at 3 years in men (r = 0.217, P = 0.004) and women (r = 0.126, P = 0.040), and with both SBP (r = 0.103, P = 0.031) and DBP (r = 0.15, P = 0.001) in the overall participants of men and women. A plausible prognostic cut-off of SUA/Cr ratio (≥ 7.41) was found and was the same in women and in all participants. Multivariable logistic regressions showed that SUA/Cr ratio was significantly linked with hypertension (as a categorical variable, SUA/Cr ratio-2 vs. SUA/Cr ratio-1: odds ratio [OR], 1.68; 95% confidence interval [CI], 0.66–4.30; P = 0.275, SUA/Cr ratio-3 vs. SUA/Cr ratio-1: OR, 2.86; 95% CI, 1.08–7.60; P = 0.035, SUA/Cr ratio-4 vs. SUA/Cr ratio ratio-1: OR, 4.05; 95% CI, 1.32–12.5; P = 0.031, and SUA/Cr ratio ≥ 7.41 vs. SUA/Cr ratio < 7.41: OR, 2.25; 95% CI, 1.32–3.84; P = 0.003). Significant ORs were found for age < 65 years, women, and BMI <25 kg/m², but no interactions were identified within each group.

Conclusions

These results suggest that the baseline SUA/Cr ratio could be an important predictor for the incidence of hypertension in Japanese community-dwelling persons.

BACKGROUND

Hypertension, or high blood pressure (BP) prevalence, has increased significantly in the recent past and is an important public health concern in Japan [1] and other countries [2,3] due to its strong association with heart disease, stroke [4], other cardiovascular disease (CVD) [5], chronic kidney disease (CKD) [6], and dementia [7]. However, approximately 90% of hypertensive cases constitute essential hypertension [8], and the etiology of its onset is not fully understood.

Uric acid (UA), the final metabolite of human endogenous purine breakdown, plays a role in free radical damage [9]. Additionally, the enzymes responsible for UA production are also implicated in oxidative stress [9]. Various experimental and epidemiological studies have demonstrated that elevated serum uric acid (SUA) levels in humans are linked to systemic inflammation [10], endothelial dysfunction [11], insulin resistance [12], diabetes [13], and hypertension [14]. The hypothesis that SUA activates the intrarenal renin-angiotensin system (RAS), potentially leading to damage of pre-renal blood vessels, has also been proposed [15]. These studies offer direct evidence that SUA might indeed be a genuine mediator of hypertension and its progression [15]. Nevertheless, the relationship between SUA levels and the onset of hypertension is influenced by factors such as race, gender, age [16], body mass index (BMI) [17], lipid levels [18], and other confounders, leading to some studies reporting contradictory findings. Serum creatinine (Cr) level, an indicator of detecting glomerular filtration rate (GFR) (e.g., renal function), and an elevated serum Cr level was found to be associated with increased risk of CVD and all-cause and CVD mortality [19]. SUA levels are significantly influenced by renal function, and high SUA is recognized as a biomarker for reduced renal function [20]. SUA normalized by renal function (SUA to creatinine [SUA/Cr] ratio), a new biomarker, is regarded as an excellent indicator of net SUA production [21]. To the best of our knowledge, there are few studies showing an association between baseline SUA/Cr ratio and incident hypertension [22], and the relationship remains controversial.

We therefore developed new indices using SUA/Cr ratio and evaluated the relationship between baseline SUA/Cr ratio and incident hypertension among individuals living in Japanese communities, using data from a cohort study over 3 years.

METHODS

Study participants

The present study was a prospective cohort conducted as part of the Nomura study [23]. Participants were recruited through an annual community-based survey by the Nomura Health and Welfare Center in a rural town in Ehime Prefecture, Japan. Initiated in 2014, the study includes 1,832 community-dwelling individuals aged 22 to 95 years. Follow-up assessments are conducted every 3 years. Blood samples were collected only from respondents who participated in the initial medical interview. Data on medical history, current health status, and medication use (including antihypertensive, antidyslipidemic, antidiabetic, and SUA-lowering medications) were gathered through structured interviews. Participants with missing values (10 men and 25 women) were excluded. A total of 652 individuals were eligible for follow-up, excluding 1,145 individuals with hypertension in 2014. During the 3-year follow-up, 215 patients dropped out, and data were finally obtained from 437 patients. Fig. 1 presents a flowchart of participant inclusion. This study adheres to the Declaration of Helsinki, and written informed consent was obtained from each participant, with the approval of the Ehime University Medical School Ethics Committee (Institutional Review Board approval number: 1402009).

Fig. 1. Flowchart.

Initiated in 2014, the study included 1,832 community-dwelling individuals aged 22 to 95. Participants with missing values (10 men and 25 women) were excluded. A total of 652 individuals were eligible for follow-up, excluding 1,145 individuals with hypertension in 2014. For the longitudinal analyses, a sub-cohort of the 2014 cycle was used, including only participants in whom hypertension was not prevalent at baseline in 2014 (n = 437).

Evaluation of risk factors

Information on demographic characteristics and risk factors was gathered from clinical files at baseline and the 3-year follow-up. BMI was calculated by dividing body weight (in kilograms) by height squared (in meters). Smoking status was determined by multiplying the number of cigarette packs smoked per day by the number of years smoked (pack-years), and participants were categorized as never smokers, past smokers, light smokers (< 20 pack-years), and heavy smokers (≥ 20 pack-years). Daily alcohol consumption was measured in sake brewing units, with 1 unit equivalent to 22.9 grams of ethanol. Participants were categorized as never drinkers, occasional drinkers (< 1 unit/day), daily light drinkers (1–2 units/day), and daily heavy drinkers (2–3 units/day). We measured systolic blood pressure (SBP) and diastolic blood pressure (DBP) on the upper right arm of participants in a seated position using an automatic oscillometric BP recorder (BP-103i; Colin, Aichi, Japan) after they had rested for at least 5 minutes. The appropriate cuff bladder size was selected based on arm circumference at each visit. The average of two consecutive measurements were used for analysis. Hypertension was defined as being on antihypertensive medication and having SBP ≥ 140 mmHg and DBP ≥ 90 mmHg, in accordance with the definitions of the Joint National Committee 7. Triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), SUA, hemoglobin A1c (HbA1c), and Cr were measured in a fasting state. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, adjusted by a Japanese coefficient: for males with Cr ≤ 0.9 mg/dL, 141 × (Cr/0.9)^−0.411 × 0.993^age × 0.813; for males with Cr > 0.9 mg/dL, 141 × (Cr/0.9)^−1.209 × 0.993^age × 0.813; for females with Cr ≤ 0.7 mg/dL, 144 × (Cr/0.7)^−0.329 × 0.993^age × 0.813; and for females with Cr > 0.7 mg/dL, 144 × (Cr/0.7)^−1.209 × 0.993^age × 0.813 [24]. Additionally, ischemic stroke, ischemic heart disease, and peripheral vascular disease were classified as CVDs.

Statistical analysis

Statistical analysis was conducted using IBM SPSS Statistics Version 26 (Statistical Package for the Social Sciences Japan, Tokyo, Japan) and JMP Trial 18.1.1 (JMP Statistical Discovery LLC, Cary, NC, USA). Unless otherwise noted, all values are presented as mean ± standard deviation (SD). For parameters with non-normal distributions (such as TG and HbA1c), data are presented as median (quartile range). Parameters with non-normal distributions were logarithmically transformed for all analyses. Subjects were divided into 4 groups based on the SD of baseline SUA/Cr ratio by gender (SUA/Cr ratio-1 [men/women], < 5.34/< 5.60; SUA/Cr ratio-2, 5.34–7.33/5.60–7.34; SUA/Cr ratio-3, 7.34–9.09/7.35–9.05; SUA/Cr ratio-4, > 9.09/> 9.05). Student’s t-test or analysis of variance were used for continuous data and the χ² test for categorical data. The areas under the receiver operating characteristic (ROC) curves were calculated for each variable to determine the predictors of new-onset hypertension. An ROC curve displays the relationship between sensitivity (true positive rate) and 1–specificity (false positive rate) for each marker being evaluated. The most effective markers produce ROC curves that are shifted leftward, with areas under the curve approaching 1. In contrast, markers that lack diagnostic value are represented by diagonal lines, with areas under the ROC curves around 0.5. Likelihood ratios were also computed, with the positive predictive value (PPV) defined as sensitivity by multiplied (1–specificity), and the negative predictive value (NPV) as (1–sensitivity) by multiplied specificity. To identify the best cutoff points for hypertension risk, optimal cutoff point is the point on the ROC curve closest to (0, 1) and the value corresponding to the smallest index was considered the optimal cutoff. Multiple logistic regression analysis was employed to assess the impact of baseline SUA/Cr ratio categories and confounding factors (including gender, age, smoking habits, alcohol consumption, the prevalence of CVD, LDL-C, TG, HDL-C, antidyslipidemic medication, HbA1c, antidiabetic medication, and eGFR) on the incidence of hypertension in the cohort study of the 3-year follow-up. The relationship between the SUA/Cr ratio and the development of hypertension was graphically illustrated by the predictive profile of the generalized linear model. Sensitivity analyses were performed to determine if the observed association between baseline SUA/Cr ratio and all-cause mortality was consistent. Next, a likelihood ratio test was conducted to determine the interaction between SUA/Cr ratio and subgroup variables. All confounding variables, except the effect variable, were adjusted in the interaction test performed to analyze the effect variable. A P-value of < 0.05 was considered to indicate statistical significance.

RESULTS

Baseline characteristics of study participants by SUA/Cr ratio categories

The baseline characteristics of the participants are illustrated in Table 1. The participants comprised 171 men aged 64 ± 11 years and 266 women aged 65 ± 10 years. Age and Cr were lower with increasing SUA/Cr ratio, while alcohol consumption, eGFR, and SUA were higher with increasing SUA/Cr ratio. No group differences were observed for other confounders.

Table 1. Baseline characteristics of study participants according to SUA/Cr ratio categories.

Baseline characteristics		SUA/Cr ratio categoriesa (N = 437)				P-valueb
		SUA/Cr-1 (n = 54)	SUA/Cr-2 (n = 171)	SUA/Cr-3 (n = 148)	SUA/Cr-4 (n = 64)
Age (yr)		67 ± 10	65 ± 10	64 ± 10	60 ± 12	0.003
Gender (men)		18 (33.3)	70 (40.9)	58 (39.2)	25 (39.1)	0.802
BMI (obesity, ≥ 25.0 kg/m2)		6 (11.1)	19 (11.1)	13 (8.8)	5 (7.8)	0.827
Smoking status (%)						0.539
	Never	75.9	74.9	72.3	65.6
	Past	16.7	14.6	11.5	17.2
	Light	1.9	3.5	8.1	6.3
	Heavy	5.6	7.0	8.1	10.9
Alcohol consumption (%)						0.004
	Never	63.0	52.0	43.2	43.8
	Occasional	24.1	24.6	31.1	18.8
	Light	9.3	9.4	7.4	4.7
	Heavy	3.7	14.0	18.2	32.8
History of cardiovascular disease		3 (5.6)	3 (1.8)	5 (3.4)	2 (3.1)	0.529
Systolic blood pressure (mmHg)		121 ± 13	120 ± 12	122 ± 12	121 ± 11	0.547
Diastolic blood pressure (mmHg)		71 ± 8	72 ± 8	72 ± 8	74 ± 8	0.362
Antihypertensive medication (%)		0	0	0	0	1.000
TG (mg/dL)		82 (61–109)	78 (61–109)	84 (59–114)	82 (60–113)	0.772
HDL-C (mg/dL)		69 ± 16	68 ± 18	68 ± 17	66 ± 18	0.797
LDL-C (mg/dL)		122 ± 31	123 ± 27	122 ± 32	115 ± 24	0.277
Antidyslipidemic medication		10 (18.5)	23 (13.5)	26 (17.6)	8 (12.5)	0.603
HbA1c (%)		5.6 (5.4–5.8)	5.6 (5.3–5.8)	5.6 (5.4–5.9)	5.6 (5.5–5.9)	0.383
Antidiabetic medication		3 (5.6)	5 (2.9)	7 (4.7)	3 (4.7)	0.779
eGFR (mL/min/1.73 m2/year)		68.5 ± 14.1	74.3 ± 8.9	78.7 ± 8.4	83.9 ± 9.2	< 0.001
Cr (mg/dL)		0.82 ± 0.33	0.74 ± 0.15	0.66 ± 0.12	0.61 ± 0.12	< 0.001
SUA (mg/dL)		3.7 ± 1.2	4.8 ± 1.0	5.3 ± 1.0	6.2 ± 1.3	< 0.001
SUA-lowering medication		2 (3.7)	2 (1.2)	3 (2.0)	1 (1.6)	0.676

Data presented are mean ± standard deviation. Data for TG and HbA1c are skewed and presented as median (interquartile range) values and were log-transformed for analysis. Data shown are number (%) not otherwise specified.

SUA, serum uric acid; Cr, creatinine; BMI, body mass index; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; eGFR, estimated glomerular filtration ratio.

^aSubjects were divided into 4 groups based on the SD of baseline SUA/Cr ratio by gender (men/women): SUA/Cr ratio-1, < 5.34/< 5.60; SUA/Cr ratio-2, 5.34–7.33/5.60–7.34; SUA/Cr ratio-3, 7.34–9.09/7.35–9.05; SUA/Cr ratio-4, > 9.09/> 9.05.

^bP-value: Student’s t-test was used for continuous variables and the χ²-test for categorical variables. Bold values indicate significance (P < 0.05).

Relationship between SUA/Cr ratio and BP in the cohort study followed for 3 years

As shown in Fig. 2, the baseline SUA/Cr ratio was significantly correlated only with DBP at 3 years in men (r = 0.217, P = 0.004) and women (r = 0.126, P = 0.040), and with both SBP (r = 0.103, P = 0.031) and DBP (r = 0.158, P = 0.001) in the overall participants of men and women.

Fig. 2. Relationship between SUA/Cr ratio and blood pressure in the cohort study followed for 3 years.

The baseline SUA/Cr ratio significantly correlated with SBP (r = 0.103, P = 0.031) and DBP (r = 0.158, P = 0.001) in the cohort study followed for 3 years.

SUA, serum uric acid; Cr, creatinine; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Optimal SUA/Cr ratio value for predicting the development of hypertension

To establish the optimal SUA/Cr ratio and cutoff values for the development of hypertension, ROC curves were analyzed, and the area under the curve (AUC) for the SUA/Cr ratio in relation to the incidence of hypertension was calculated (Fig. 3). In women (AUC, 0.611; 95% confidence interval [CI], 0.532–0.690, with an optimal cutoff of 7.41) and in all participants (AUC: 0.588, 95% CI: 0.525–0.650, with an optimal cutoff of 7.41), the predictive values for developing hypertension were similar for the SUA/Cr ratio. Table 2 shows the sensitivity, specificity, PPV, NPV, and accuracy of the baseline SUA/Cr ratio when using the optimal cutoff point for predicting the development of hypertension.

Fig.3. Optimal SUA/Cr ratio value for predicting incident hypertension.

ROC curve analysis for determining the SUA/Cr ratio cutoff value predictive of incident hypertension is shown. The curved line is the ROC curve.

ROC, receiver operating characteristic; SUA, serum uric acid; Cr, creatinine; AUC, area under the curve; CI, confidence interval.

Table 2. The sensitivity, specificity, PPV, NPV and accuracy for predicting the development of hypertension of baseline SUA/Cr ratio.

Groups	No. of patients	SUA/Cr ratio (cutoff point)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)
Men	171	7.34	58.5	54.6	56.0	56.8	56.6
Women	266	7.41	60.0	58.3	59.0	59.3	59.2
Total	437	7.41	58.3	57.2	57.7	57.8	57.8

PPV, positive predictive value; NPV, negative predictive value; SUA, serum uric acid; Cr, creatinine.

Odds ratios (ORs) and 95% CI for predicting the development of hypertension of participants according to baseline SUA/Cr ratio

Table 3 presents the prevalence and OR of hypertension for SUA/Cr ratio category in women and all participants. In the cohort study (SUA/Cr ratio-1 [men/women], < 5.34/< 5.60; SUA/Cr ratio-2, 5.34–7.33/5.60–7.34; SUA/Cr ratio-3, 7.34–9.09/7.35–9.05; SUA/Cr ratio-4, > 9.09/> 9.05), the number of incident hypertension was 4 (11.1%), 18 (17.8%), 21 (23.3%), and 12 (30.8%) in women and 7 (13.0%), 32 (18.7%), 38 (25.7%), and 19 (29.7%) in all participants, respectively. Men were omitted because no significant relationship was found. The incidence of hypertension was found to increase with increasing concentrations of baseline SUA/Cr ratio. Adjusted models were created for the different variable sets: Model 1 was unadjusted; Model 2 was adjusted for age and gender; and Model 3 was further adjusted for obesity, smoking status, alcohol consumption, history of CVD, TG, HDL-C, LDL-C, antidyslipidemic medication, HbA1c, antidiabetic medication, eGFR, and the SUA/Cr ratio (as a categorical variable). Among women, the results were as follows: comparing SUA/Cr ratio-4 to SUA/Cr ratio-1, the OR was 6.16 (95% CI, 1.40–27.1; P = 0.016) and comparing SUA/Cr ≥ 7.41 to SUA/Cr ratio < 7.41, the OR was 2.50 (95% CI, 1.26–4.95; P = 0.009). Among all participants, the results were: SUA/Cr ratio-3 compared to SUA/Cr ratio-1 had an OR of 2.86 (95% CI, 1.08–7.60; P = 0.035), SUA/Cr ratio-4 compared to SUA/Cr ratio-1 had an OR of 4.05 (95% CI, 1.32–12.5; P = 0.015), and SUA/Cr ratio ≥ 7.41 compared to SUA/Cr ratio < 7.41 had an OR of 2.25 (95% CI, 1.32–3.84; P = 0.003). Supplemental Fig. 1 showed that the SUA/Cr ratio was non linearly associated with the risk of hypertension (P = 0.0083).

Table 3. ORs and 95% CI for incident hypertension of participants according to baseline SUA/Cr ratio.

Variables			Baseline SUA/Cr ratioa
			SUA/Cr-1	SUA/Cr-2	P-value	SUA/Cr-3	P-value	SUA/Cr-4	P-value	P for trend	Cutoff point (men ≥ 7.41 vs. women < 7.41)	P-value
Women
	No. of subjects		36	101		90		39			121/145
	Hypertension	n (%)	4 (11.1)	18 (17.8)	0.435	21 (23.3)	0.144	12 (30.8)	0.049	0.150	33 (27.3)/22 (15.2)	0.022
	Unadjusted analysis	OR (95% CI)	Reference	1.74 (0.55–5.52)	0.351	2.44 (0.77–7.68)	0.129	3.56 (1.03–12.3)	0.045	0.144	2.10 (1.15–3.84)	0.016
	Age & gender-adjusted analysis	OR (95% CI)	Reference	1.80 (0.56–5.74)	0.324	2.50 (0.79–7.93)	0.119	4.10 (1.16–14.5)	0.028	0.095	2.18 (1.19–4.02)	0.012
	Multivariable-adjusted analysisb	OR (95% CI)	Reference	2.11 (0.60–7.51)	0.247	3.13 (0.86–11.4)	0.084	6.16 (1.40–27.1)	0.016	0.058	2.50 (1.26–4.95)	0.009
Total (men + women)
	No. of subjects		54	171		148		64			202/235
	Hypertension	n (%)	7 (13.0)	32 (18.7)	0.412	38 (25.7)	0.058	19 (29.7)	0.044	0.071	56 (27.7)/40 (17.0)	0.008
	Unadjusted analysis	OR (95% CI)	Reference	1.55 (0.64–3.74)	0.333	2.32 (0.97–5.57)	0.060	2.84 (1.09–7.39)	0.033	0.066	1.87 (1.18–2.96)	0.008
	Age & gender-adjusted analysis	OR (95% CI)	Reference	1.67 (0.69–4.09)	0.258	2.61 (1.08–6.35)	0.034	3.69 (1.38–9.89)	0.009	0.018	2.05 (1.28–3.28)	0.003
	Multivariable-adjusted analysisb	OR (95% CI)	Reference	1.68 (0.66–4.30)	0.275	2.86 (1.08–7.60)	0.035	4.05 (1.32–12.5)	0.015	0.031	2.25 (1.32–3.84)	0.003

Data for triglycerides and hemoglobin A1c are skewed and were log-transformed for analysis. Bold values indicate significance (P < 0.05).

OR, odds ratio; CI, confidence interval; SUA, serum uric acid; Cr, creatinine.

^aSubjects were divided into 4 groups based on the standard deviation of baseline SUA/Cr ratio by gender (men/women): SUA/Cr ratio-1, < 5.34/< 5.60; SUA/Cr ratio-2, 5.34–7.33/5.60–7.34; SUA/Cr ratio-3, 7.34–9.09/7.35–9.05; SUA/Cr ratio-4, > 9.09/> 9.05.

^bMultivariable-adjusted for all confounding factors: adjusted for age, gender (in total case), obesity, smoking status, alcohol consumption, history of cardiovascular disease, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, antidyslipidemic medication, hemoglobin A1c, antidiabetic medication, and estimated glomerular filtration rate.

ORs and 95% CI for incident hypertension of participants according to baseline SUA/Cr ratio (continuous variable) by sensitivity analysis

Table 4 shows hazard ratios and 95% CIs of baseline SUA/Cr ratio for incident hypertension of the participants stratified by age, gender, obesity, eGFR, and SUA-lowering medication. Significant ORs were found for age < 65 years, women, and BMI < 25 kg/m², but no interactions were identified within each county.

Table 4. ORs and 95% CI for incident hypertension of participants according to baseline SUA/Cr ratio (continuous data) by sub-analysis.

Baseline SUA/Cr ratio (N = 437)		No.	Normotension/Hypertension		P for interaction
			OR (95% CI)	P-value
Age					0.948
	< 65 yr	187	1.35 (1.04–1.75)	0.024
	≥ 65 yr	250	1.20 (0.96–1.51)	0.113
Gender					0.886
	Men	171	1.12 (0.85–1.48)	0.424
	Women	266	1.33 (1.07–1.64)	0.010
Obesity					0.580
	Body mass index < 25 kg/m2	394	1.24 (1.04–1.47)	0.018
	Body mass index ≥ 25 kg/m2	43	1.48 (0.74–2.97)	0.265
eGFR					-
	< 60 mL/min/1.73 m2/year	29	-	-
	≥ 60 mL/min/1.73 m2/year	408	1.28 (1.09–1.52)	0.003
SUA-lowering medication					-
	Yes	8	-	-
	No	429	1.25 (1.06–1.47)	0.008

Multivariable-adjusted for all confounding factors: adjusted for age, body mass index, smoking status, alcohol consumption, history of cardiovascular disease, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, antidyslipidemic medication, hemoglobin A1c, antidiabetic medication, and eGFR. Data for triglycerides and hemoglobinA1c are skewed and were log-transformed for analysis. Bold values indicate significance (P < 0.05).

OR, odds ratio; CI, confidence interval; SUA, serum uric acid; Cr, creatinine; eGFR, estimated glomerular filtration rate.

DISCUSSION

In this 3-year prospective cohort study, we aimed to establish whether baseline SUA/Cr ratio predicts the onset of hypertension. We found that the baseline SUA/Cr ratio was significantly and independently linked with both the prevalence and incidence of hypertension, and it may assist clinicians in predicting BP progression. To our knowledge, few studies have suggested that the SUA/Cr ratio could be a significant potential factor for the incidence of hypertension among dwelling-persons in the community.

SUA/Cr ratio, calculated using SUA and Cr levels normalized by renal function, has emerged as a new biomarker. Studies have shown that SUA/Cr ratio is a superior predictor of all-cause mortality among hypertensive patients [25] and elderly hemodialysis patients [26]. Previous studies have associated SUA/Cr ratio with adverse health outcomes under specific conditions, such as metabolic syndrome [27,28,29], β-cell function and insulin resistance, renal dysfunction in diabetic individuals [30], and nonalcoholic fatty liver disease [31]. These adverse outcomes are recognized risk factors for hypertension, potentially contributing to its pathology.

The current study shows that a higher SUA/Cr ratio predicts a higher risk of incident hypertension among community-dwelling persons, even after adjusting for other factors such as gender, age, BMI, smoking and alcohol status, CVD history, lipid levels, antilipidemic medication, blood glucose, antidiabetic medication, eGFR, and SUA-lowering medication. In a large cross-sectional study of 8,571 individuals from the China Health and Nutrition Survey, Wang et al. [22] found that the SUA/Cr ratio was related to the prevalence of hypertension. From a total of 455 patients with Metabolic syndrome and 457 age- and gender-matched controls were included in the present retrospective study, multivariate adjustments for the confounders, SUA/Cr ratio was still an independent risk factor for hypertension (OR, 1.899; 95% CI, 1.570–2.296; P < 0.001) [27]. Furthermore, She et al. [29] found that the SUA/Cr ratio in overweight/obesity is significantly and independently linked to a higher risk of metabolic syndrome, including hypertension, hyperglycemia, and dyslipidemia. In 96,378 participants from the Kailuan study without stroke and myocardial infarction at baseline, the association between high SUA/Cr ratio and CVD was partially mediated by TG (30.74%), BMI (19.52%), total cholesterol (15.06%), high sensitivity C-reactive protein (13.06%), DBP (11.75%), and blood glucose (−16.38%) [21].

In this analysis, a SUA/Cr ratio greater than 7.41 was identified as the prognostic cut-off value for predicting the risk of developing hypertension, both in the entire cohort and among women. This is the first study to establish a specific prognostic threshold for the SUA/Cr ratio in predicting hypertension risk in a prospective manner. Previously, Wang et al. [22], in a cross-sectional study, demonstrated that only a SUA/Cr ratio greater than 5.0 was linked to an increased risk of hypertension (OR, 1.178; 95% CI, 1.086–1.278; P < 0.001). Additionally, multiple studies have shown that SUA levels tend to be significantly higher in women than men when considering the development of hypertension or kidney disease [32,33]. Moreover, Lee et al. [34] indicated that hyperuricemia raises the risk of hypertension in younger individuals (men under 60 and women under 40). This suggests that the influence of SUA on younger people may decline as they age, with other factors playing a larger role in hypertension development over time. Consequently, the link between SUA and hypertension might weaken with age, as hypertension increasingly arises from other causes [25,34]. Essentially, the effect of SUA may decrease over time as the relationship between SUA and hypertension is primarily driven by metabolic risk factors such as aging, insulin resistance, dyslipidemia, and kidney dysfunction. Although various thresholds have been proposed for the impact of CKD on the SUA/Cr ratio and hypertension development [35], the limited number of participants with CKD in this study prevented a clear determination of that effect.

The mechanisms behind an increased incident hypertension in individuals with increased SUA/Cr ratio are yet to be fully understood. SUA is produced by the enzyme xanthine oxidase and the final product of purine metabolism (adenine and guanine degradation), generating UA and eliminating free radicals, exhibiting both pro-oxidant and antioxidant characteristics. Additionally, UA induces the production of pro-inflammatory cytokines, such as C-reactive protein and tumor necrosis factor α [36], suggesting that it may influence chronic inflammatory processes. Experimental findings indicate a multifaceted yet possibly direct causative role of UA in the development of hypertension [37]. In humans, UA is eliminated through the kidneys [38], and patients with decreased GFR consequently show elevated SUA levels and have a higher likelihood of experiencing renal disease progression. Therefore, if SUA is indeed a risk factor for the progression of renal disease, baseline renal function-normalized SUA, which may indicate the net production of UA, becomes crucial as a predictor of incident hypertension.

Our study has several strengths, including its long-term follow-up, large sample size, adjustment for potential confounders, and the inclusion of sensitivity analyses. Nonetheless, certain limitations should be acknowledged. Firstly, the cohort study design does not eliminate potential causal links between baseline SUA/Cr ratio and hypertension. Additionally, the data on other factors like menopausal status and dietary habits are insufficient for inclusion in the analysis. Secondly, since confounding factors and hypertension were assessed based on a single measurement of blood and BP, there is a risk of misclassification bias. Thirdly, we could not fully exclude the impact of underlying diseases or medications for hypertension, dyslipidemia, diabetes, hyperuricemia, etc., on the findings. The effect of drug administration was accounted for by adjusting for the presence or absence of drug use, and further minimized by presenting the results of a sensitivity analysis, which included only cases not taking uric acid-lowering medications. Fourthly, with respect to the ability of the SUA/Cr ratio to predict the onset of hypertension, quartile analysis revealed a statistically significant association. However, the AUC value was low, indicating limited predictive power, even though the SUA/Cr ratio emerged as a significant predictor for new-onset hypertension. This finding may reflect localized patterns rather than broader determinants. Lastly, there is a need to consider the possibility of participants having white-coat or masked hypertension, which limits the generalizability due to demographic and referral characteristics.

CONCLUSIONS

The study demonstrated that the baseline SUA/Cr ratio levels were associated with the development of hypertension, even when adjusting for factors such as age, gender, obesity, drinking habits, smoking status, history of CVD, lipid levels, HbA1c, eGFR, and medication. The precise mechanism driving this association remains unclear. Therefore, reducing SUA/Cr ratio levels through interventions like healthier lifestyle choices or medication could be an effective approach to mitigating hypertension. Future prospective population-based research is necessary to explore the effects of lifestyle interventions and medications on SUA metabolism and eGFR.

Abbreviations

AUC

area under the curve

BMI

body mass index

BP

blood pressure

CI

confidence interval

CKD

chronic kidney disease

CKD-EPI

Chronic Kidney Disease Epidemiology Collaboration

Cr

creatinine

CVD

cardiovascular disease

DBP

diastolic blood pressure

eGFR

estimated glomerular filtration rate

GFR

glomerular filtration rate

HbA1c

hemoglobin A1c

HDL-C

high-density lipoprotein cholesterol

LDL-C

low-density lipoprotein cholesterol

NPV

negative predictive value

OR

odds ratio

PPV

positive predictive value

RAS

renin-angiotensin system

ROC

receiver operating characteristic

SBP

systolic blood pressure

SD

standard deviation

SUA

serum uric acid

TG

triglycerides

UA

uric acid

SUPPLEMENTARY MATERIAL

Supplemental Fig. 1

The predictive profile for the development of hypertension by the SUA/Cr ratio.