Abstract
Background and Aims
While previous studies have reported the association between serum uric acid (SUA) and chronic kidney disease (CKD) incidence, the sex differences in this association remain controversial. Therefore, we examined the association between SUA levels and CKD incidence in middle-aged adults stratified by sex using data from a large-scale health check-up.
Method
We analyzed information from the JMDC database, which included the annual health check-up data of Japanese employees and their dependents aged <75 years. Among those individuals, we analyzed data from 138,511 individuals without CKD, kidney disease, or a history of cardiovascular disease at baseline. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or proteinuria. We divided the participants into 9 and 7 groups according to SUA levels for men and women, respectively. A Cox model was applied to assess the adjusted hazard ratios (HRs) for CKD incidence in each SUA level group using an SUA concentration of 4.0–4.9 mg/dL as the reference after adjusting for age, body mass index, current or ex-smoker, current or ex-drinker, diabetes mellitus, dyslipidemia, systolic blood pressure, use of anti-hyperuricemic drugs, and baseline eGFR.
Results
The mean participant age was 44.1 years, and 29.6% were women. The mean SUA levels were 5.9 mg/dL and 4.1 mg/dL in men and women, respectively. During the mean follow-up period of 4.68 years, 12,589 participants developed CKD. The age-standardized incidence rates for CKD were 17.88/17.80 per 1000 person-years in men/women with SUA concentrations of 4.0–4.9 mg/dL, 209.76 per 1000 person-years in men with SUA ≥11.0 mg/dL, and 73.38 per 1000 person-years in women with SUA ≥ 9.0 mg/dL. The fully adjusted HRs (95% confidence interval [CI], P value) for CKD incidence in the groups with SUA concentrations of <4.0, 10.0–10.9, and ≥11.0 mg/dL compared with those with SUA of 4.0–4.9 mg/dL among men 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. In women, the fully adjusted HRs for CKD incidence in the groups with SUA concentrations of <4.0, 8.0–8.9, and ≥9.0 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. Similar results were observed when we performed the sensitivity analysis excluding 8,411 individuals with hypertensive treatment from the main analysis. The HRs for the outcomes caused by the onset of eGFR <60 mL/min/1.73 m2 or proteinuria separately were similar to those for the main results.
Conclusion
The results of the present study demonstrated an increased risk of CKD in men with SUA concentrations of <4.0 and ≥10.0 mg/dL and <4.0 and ≥8.0 mg/dL in women compared to those with SUA concentrations of 4.0–4.9 mg/dL after adjusting for various covariates. Both high and low SUA levels were risk factors for CKD in middle-aged men and women. Hyperuricemia was demonstrated to cause renal injury due to the intraluminal deposition of uric acid crystals in the renal collecting duct. Hyperuricemia may also induce endothelial dysfunction, activation of the renin-angiotensin system, and induction of inflammation and stimulation of vascular smooth muscle cell proliferation by the induction of cyclooxygenase-2. However, as uric acid is one of the most important antioxidants in human plasma, low SUA levels may increase the risk of CKD incidence through decreased antioxidant activity. These mechanisms are implicated in the pathogenesis of CKD caused by high and low SUA levels. In addition, the SUA levels and ranges associated with increased risks of CKD incidence differed by sex.
The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank
