Relationship between serum uric acid levels and complement functional activity

Uric acid (UA) is the end product of purine metabolism and a substance that promotes a chronic inflammatory process. One of the mechanisms of inflammation associated with the UA is the ability of its crystals, mainly monosodium urate, to activate NLRP3 inflammasomes, classifying UA and its salt crystals as damage-related molecular patterns (DAMPs). These crystals also activate the complement system, leading to increase in C3a, C4a, and C5a concentrations and excessive consumption of complement system proteins. It has been known for a long time that UA is able to activate complement, but the relationship between hyperuricemia and complement system functional activity, which can be assessed by complement-mediated hemolysis, remains unclear. In this study, we have made an attempt to estimate the UA concentration that does not lead to spontaneous complement system activation. The study assessed the relationships between the parameters of complement functional activity and some blood biochemical data with UA concentration ([UA]) using correlation analysis. The rate (V_lys) and time of 50% hemolysis (T₅₀) were considered as indicators of complement functional activity, and their relationship was demonstrated using exponential functions y = a*e^[x], which takes the form y = [UA]*e^[C3]. Concentration of C3 is the argument of the function, base of degree is the base of the natural logarithm, and the proportionality coefficient equal to the UA concentration. Correlation analysis showed the inverse dependent between function values and the corresponding values of T₅₀ (r = -0.83, p < 0.0001) in the range of UA concentration exceeding 370 umol/L, which is near to the upper limit of the normal level for women and is within the normal range for men. Thus, the approach to assess the effect of UA on complement activation using the analysis of the complement hemolytic activity is effective to demonstrate the pathogenetic function of UA in the development of the inflammatory process without involving inflammasomes through the direct effects on complement activation processes. The relationships demonstrated suggest that the upper limits of the range of “normal” UA concentrations are arbitrary, and their revision is likely advisable.