Abstract
Importance: High uric acid (UA) is hypothesized to worsen kidney and cardiovascular disease morbidity via activation of systemic inflammation. Clinical trials of UA modification report reduction of the inflammatory marker high sensitivity C-reactive protein (hs-CRP) as an outcome measure, but studies have not demonstrated that hyperuricemia independently increases hs-CRP when adjusted for important confounders such as body mass index (BMI), sex, and age.Objective: To identify clinical risk factors for elevated hs-CRP, including but not limited to hyperuricemia, through a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 2015–2018.Results: In the final multivariate logistic regression model, the exposure with the strongest effect on the odds of elevated hs-CRP was BMI in the fourth quartile, OR = 13.1 (95% CI 6.25–27.42), followed by female sex (OR = 4.9, 95% CI 2.92–8.34), hyperuricemia (OR = 2.2, 95% CI 1.36–3.45), urine albumin creatinine ratio (ACR; OR = 1.5, 95% CI 1.09–2.18), poor overall health (OR = 1.4, 95% CI 1.18–1.58), and interactions between hyperuricemia and sex (OR = 1.4, 95% CI 1.05–1.83), and between BMI and sex (OR = 1.2, 95% CI 1.03–1.47). Notably, chronic kidney disease (CKD) and CKD surrogates were not associated with hs-CRP despite urine ACR maintaining a significant independent effect.Conclusions: In this national population-based study, we demonstrated that hyperuricemia significantly increases the odds of elevated hs-CRP, independent from BMI, female sex, urine ACR, and overall health status. Further study is recommended to better understand the sex difference in this association and the role of albuminuria, but not CKD, in systemic inflammation.
Highlights
Recent epidemiologic studies have found that elevated serum uric acid (UA), or hyperuricemia, is independently associated with hypertension, acute kidney injury, and both accelerated decline and increased mortality of patients with chronic kidney disease (CKD) [1,2,3,4]
The high sensitivity C-reactive protein, on the other hand, is an acute phase protein and considered a “downstream” inflammatory molecule released by the liver in response to IL-6 when activated by the Nod-like receptor proteinase 3 (Nlrp3) inflammasome and other inflammatory states
A linear relationship existed between the continuous variables of serum UA and high sensitivity C-reactive protein (hs-CRP), but with minimal correlation (R2 = 0.008, p < 0.001)
Summary
Recent epidemiologic studies have found that elevated serum uric acid (UA), or hyperuricemia, is independently associated with hypertension, acute kidney injury, and both accelerated decline and increased mortality of patients with chronic kidney disease (CKD) [1,2,3,4]. One mechanism by which hyperuricemia is proposed to contribute to morbidity and mortality is through direct activation of inflammation This proinflammatory response occurs below the historically-accepted definition of hyperuricemia, which is a sex-specific serum UA level i.e., associated with clinical gout disease and around the point of supersaturation of UA in serum >7 mg/dl [5,6,7,8,9]. Both soluble and crystalline UA activate the Nod-like receptor proteinase 3 (Nlrp3) inflammasome, which triggers the systemic release of proinflammatory cytokines interleukin (IL)-1β, IL-18, and IL-6 [10,11,12,13,14,15,16]. This is a necessary step to demonstrate whether hs-CRP is an appropriate outcome measure in UA reduction trials
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