The Relationship Between Uric Acid and Inflammatory Markers

Uric acid (UA) is a terminal product of purine metabolism with strong antioxidant properties. UA has sizeable concentrations in biologic fluids only in humans and primates because they have a non-functional mutation of the enzyme uricase that, in other animals, transforms UA to allantoin. It has been hypothesized that this mutation has emerged evolutionarily because through this mechanism, humans can counteract the excessive oxidative stress that occurs in many critical pathologic conditions. Partially in contrast with this theory, high levels of UA have been associated with a number of negative health outcomes, including cardiovascular as well as all-cause mortality. Although it is possible that the UA elevation is merely a marker of critical health because it is an inducible antioxidant, researchers have questioned whether UA has beneficial or detrimental effect on health status. For example, we recently demonstrated that higher UA levels are cross-sectionally associated with higher levels of pro-inflammatory markers, and predict the increase in inflammatory markers over a 3-year follow-up. Understanding whether UA exerts a protective or detrimental effect on health is important in deciding whether mild hyperuricemia should or should not be aggressively treated. Unfortunately, observational studies cannot fully address this question. In fact, we cannot exclude that the cross-sectional and longitudinal association between UA, inflammatory markers and negative health outcomes, may simply reflect the fact that UA is an inducible antioxidant that is produced in response to increasing oxidative stress. To verify the hypothesis that UA activates inflammation, we plan to conduct two complementary randomized controlled trials, each one including 10 treated and 10 control subjects. In the first trials, subjects with low UA will be administered 500 mg of UA intravenously. In the second trials, subjects with moderately elevated UA will be administered a single acute dose of Rasburicase. Then inflammatory markers will be measured at multiple points in time, for a total of 32 hours. We hypothesize that an acute increase in the circulating levels of UA will be followed by increasing levels of inflammatory markers. At the same time, an acute reduction of UA levels will be followed by a progressive reduction of inflammatory markers. This study should provide information that will help clinicians to decide whether to or not to treat mild hyperuricemia.