Effect of uric acid lowering on renin-angiotensin-system activation and ambulatory BP: A randomized controlled trial

Abstract

Background and objectives Higher serumuric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serumuric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. Design, setting, participants, & measurements In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adultswith serumuric acid ≥ 5.0mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints includedmean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Results Allopurinol andprobenecidmarkedly lowered serumuric acid after 4 and 8weeks compared with placebo (meanserumuric acid inallopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and5.6mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flowresponse to captopril (in ml/min per 1.73m2) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group (P=0.83), -4 (-16 to 9) in the allopurinol group (P=0.32), and 1 (-21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change inmean (±SD) 24-hour systolic BPs frombaseline to 8 weeks was-1.6 ± 10.1 with probenecid (P=0.43),-0.4 ± 6.1 with allopurinol (P=0.76), and 0.5 ± 6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. Conclusions In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.