Detailed association between serum uric acid levels and the incidence of chronic kidney disease stratified by sex in middle-aged adults

Highlights

• The association of serum uric acid (SUA) levels with the increase in the risk of chronic kidney disease (CKD) incidence differed by sex.

• The range of SUA levels associated with an increase in the risk of CKD incidence varied by sex.

Abstract

Background and aims

Chronic kidney disease (CKD) is a global health burden. Previous studies have shown a J- or U-shaped association between serum uric acid (SUA) and cardiovascular mortality. We assessed the risk of CKD incidence in a refined SUA category in middle-aged adults stratified by sex.

Methods

We analyzed data from 138,511 participants <65 years old (29.6% women; mean age 44.1 years) without CKD at baseline acquired from the JMDC database. The Cox model was used to assess the adjusted hazard ratio (HR).

Results

During the mean follow-up period of 4.68 years, 12,589 participants developed CKD. The fully adjusted HRs (95% confidence interval [CI], p-value) for CKD incidence in men with SUA <4.0, 10.0–10.9 and ≥ 11.0 mg/dL compared to men with SUA 4.0–4.9 mg/dL were 1.13 (1.01–1.26, p = 0.030), 1.98 (1.32–2.97, p = 0.0010), and 3.74 (1.68–8.35, p = 0.0013), respectively. The fully adjusted HRs for CKD incidence in women with SUA <4.0, 8.0–8.9, and ≥9.0 mg/dL compared to women with SUA 4.0–4.9 mg/dL were 1.08 (1.01–1.16, p = 0.032), 2.39 (1.07–5.35, p = 0.034), and 3.20 (0.80–12.8, p = 0.10), respectively.

Conclusions

Both high and low SUA levels were identified as risk factors for CKD incidence in middle-aged men and women. The association of SUA levels with the increase in the risk of CKD incidence differed by sex, and the range of SUA levels associated with an increase in the risk of CKD incidence varied by sex.

Introduction

Chronic kidney disease (CKD) is a major global health burden. Globally, CKD incidence, and disability and death due to CKD have been increasing [1]. According to previous studies, serum uric acid (SUA) levels have shown a J- or U-shaped association with all-cause and cardiovascular mortality [2,3].

With regard to the association of SUA with the kidney, high SUA levels may serve as an independent risk factor for CKD [[4], [5], [6], [7], [8], [9], [10], [11]]. Although high SUA levels may be involved in CKD incidence in middle-aged individuals, there is little evidence regarding the association between SUA and CKD incidence in this population. Some studies have indicated a possible association between SUA levels and CKD risk in cohorts with a mean age between 40 and 50 years. Participants in these cohort studies were categorized broadly according to their SUA levels and the CKD risk of the group with SUA ≥7 mg/dL was not clear [7,9,10]. Moreover, in these studies, the CKD incidence was defined using only the eGFR (estimated glomerular filtration rate) levels. Nonetheless, in the Hisayama study, based on 2059 participants, which investigated the influence of SUA levels on the incidence of kidney dysfunction and albuminuria in the general Japanese population, the mean age was 59 years [4]. Precise evidence regarding the association between high SUA levels and CKD risk can contribute to early CKD prevention in middle-aged individuals.

Sex and baseline eGFR can also be strong confounding factors for the association between SUA and the risk of CKD incidence. Women have lower SUA levels than men because estrogen stimulates urinary urate excretion [12,13]. Hence, SUA levels and CKD incidence may be different between men and women.

Uric acid, a purine metabolism product, is reabsorbed and excreted in the renal proximal tubule after being filtered. Patients with CKD have decreased uric acid urinary excretion and elevated SUA levels [14]. While the inclusion of participants with eGFR close to 60 mL/min/1.73 m² in the evaluation of the association between SUA levels and CKD incidence could lead to reverse causality, all previous studies included these individuals and only adjusted the results for baseline eGFR levels [[4], [5], [6], [7], [8], [9]].

We, therefore, examined the association between SUA levels and CKD incidence in middle-aged adults stratified by sex, based on a longitudinal analysis with multiple measurements of serum creatinine (SCr) acquired from a large-scale health checkup of a general Asian population. Then, we excluded participants with eGFR <70 mL/min/1.73 m² due to their extremely high risk of CKD incidence [15]. Furthermore, we also assessed the association between low SUA levels and elevated risk of CKD incidence since this piece of information in middle-aged Asian individuals had been scarce [8,9].