Correlation between the oxidation of uric acid and Sepsis

Abstract

Sepsis induces high mortality in patients admitted to intensive care units. It leads to high morbidity in recovered patients and has a relevant economic impact due to the length of stay and costs of treatment. The difficulty to find an effective treatment is a reflection of the diverse pathogenesis of the disease, which varies according to the individual response and characteristics of each patient. Due to this heterogeneity, a personalized treatment, conducting therapy according to specific inflammatory, metabolic and clinical changes of each patient, becomes the most appropriate alternative. Thus, we understand that the more we know about the metabolic and inflammatory status of each patient, the more assertive the therapeutic measures will be taken. Some studies have shown a positive correlation between plasma uric acid levels and a worse prognosis in Sepsis. Although this association is not always independent of a kidney injury, it is known that uric acid can also cause endothelial injury, an important involvement in Sepsis. Our research group has shown that uric acid is an important substrate for inflammatory enzymes and the oxidation of uric acid by these enzymes produces highly reactive intermediates such as urate free radical and urate hydroperoxide. The production of these oxidants has been suggested as a key mechanism in endothelial damage caused by uric acid and is potentially involved in the genesis of vascular inflammation and atherosclerosis. In addition, the oxidation of uric acid by inflammatory enzymes prevented the formation of hypochlorous acid, an important microbicide and thus decreased the ability of inflammatory cells to contain the growth of Pseudomonas aeruginosa. In this sense, we have several indications that uric acid oxidation is an important event in vascular inflammation. In fact, a preliminary clinical study by our group in collaboration with the Center for Free Radical Research (New Zealand) showed a significant increase in allantoin levels, the most stable and therefore detectable end product of uric acid oxidation in plasma from Sepsis patients. The purpose of the present project is to extend this preliminary study and identify whether there is in fact a correlation between uric acid oxidation and a worse prognosis in Sepsis. For this purpose, the levels of uric acid, its final oxidation product allantoin and the adducts between the intermediates of uric acid oxidation ans plasma albumin will be evaluated in patients admitted to the ICU of of Hospital das Clínicas. The levels of these metabolites and adducts will be compared with routine biochemical and clinical data that inform the inflammatory condition, Sepsis and the clinical evolution of the disease. We hope, through this study, to identify if uric acid and its oxidation have any contribution in the progression of Sepsis. If so, the measurement of uric acid levels, as a simple colorimetric assay, may be incorporated into the clinical routine and, thereafter, individual therapeutic measures that include the use of inhibitors of uric acid synthesis, or uricosuric drugs may be considered. (AU)