A double blind placebo controlled randomized trial of the effect of acute uric acid changes on inflammatory markers in humans: A pilot study

Toshiko Tanaka, Yuri Milaneschi, Yongqing Zhang, Kevin G Becker, Linda Zukley, Luigi Ferrucci, Toshiko Tanaka, Yuri Milaneschi, Yongqing Zhang, Kevin G Becker, Linda Zukley, Luigi Ferrucci

Abstract

Uric acid has been linked with increased risk of chronic disease such as cardiovascular disease and this association has been attributed to a pro-inflammatory effect. Indeed, observational studies have shown that high uric acid is associated with high level of pro-inflammatory cytokines in the blood. However, whether high uric acid directly affects inflammation or rather represents a parallel defensive antioxidant mechanism in response to pathology that causes inflammation is unknown. To determine whether acute increase or decrease uric acid levels affects inflammation in healthy individuals, a randomized, placebo-controlled, double blind clinical study of uric acid or rasburicase with 20 healthy volunteers in each treatment-placebo group was conducted at the National Institute on Aging (NIA) Clinical Research Unit (CRU) at Harbor Hospital in Baltimore, MD. Change in inflammatory response was assessed by administering an oral lipid tolerance before and after the treatment of uric acid, rasburicase and placebo. Following uric acid administration, there was an accentuated increase in IL-6 during the oral lipid tolerance test (P<0.001). No significant differences were observed after lowering of uric acid with rasburicase. No side effects were reported throughout the trial. In health individuals, acute increase in uric acid results in an increased IL-6 response when challenged with lipid load. Such effect of amplification of inflammatory response may explain the higher risk of chronic diseases observed in subclinical hyperuricemia in observational studies.

Trial registration: ClinicalTrials.gov NCT01323335.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. COSORT flowchart for the uric…
Fig 1. COSORT flowchart for the uric acid and rasburicase study.
Fig 2. Changes in uric acid levels…
Fig 2. Changes in uric acid levels during uric acid or rasburicase administration.
Concentrations of uric acid was measured at 0, 1, 2, 4, 8, 12, and 24 hours following the administration of 500mg uric acid (A) and 0.15 mg/kg rasburicase (B) is displayed. The treatment group is displayed as dotted line (uric acid or rasburicase) and the placebo group as the solid lines. Mean and standard errors are displayed.during uric acid infusion, there was a significant difference in the change in IL-18 (Ptreatment*time = 0.0006; S2A Fig) and CRP (Ptreatment*time = 0.045; S3B Fig) over time by treatment. For IL-18 the slope was more negative in the uric acid group compared to placebo group (βtreatment*time12 = -36.2, P = 0.0002) at the 12th hour. For CRP, at the 8th and 12th hour, there slope for uric acid group was lower than the placebo group (βtreatment*time8 = -0.14, P = 0.04, βtreatment*time8 = -0.18, P = 0.007). There were no significant differences in change of other markers by uric acid treatment group.
Fig 3. Changes in IL-6 levels during…
Fig 3. Changes in IL-6 levels during uric acid or rasburicase infusion and oral lipid tolerance test pre- and post- intervention.
The level of IL-6 was measured at 0,2,4,6 and 8 hours during the oral lipid tolerance test a day before (A,D) and after (C,F) following the administration of uric acid (A-C) or rasburicase (D-F). During the intervention, IL-6 was measured at 0, 1, 2, 4, 8, 12, and 24* hours after the administration of 500mg of uric acid (B) or 0.15mg/kg of rasburicase (E). The effect of treatment (PTx), time (PTime) and slope of change over time by treatment group (PTxTime) from the mixed effect model is presented at the bottom of each figure. Differences in the postprandial pattern of IL-6 before and after treatment is displayed (C,F). The treatment group is displayed as triangles and the placebo group as the circles. The mean and standard errors are displayed. *The 24-hour time point after intervention is the baseline, or time 0 of the oral lipid tolerance test conducted the following day.
Fig 4. Volcano plot of gene expression…
Fig 4. Volcano plot of gene expression changes by rasburicase treatment.
The level of gene expression was assessed at baseline and after 12 and 24 hours after infusion of 0.15mg/kg of rasburicase. The difference in gene expression by treatment group is displayed. The genes in the interferon signaling pathway that are significantly differentially expressed are shown (filled triangles).

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