Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.
OBJECTIVE
Higher serum uric 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 serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting.


METHODS
In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/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 included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping.


RESULTS
Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m2) 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 in mean (±SD) 24-hour systolic BPs from baseline 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.
Renal Division.|Channing Division of Network Medicine, and.
Ciaran J
CJ
McMullan
Renal Division.|Channing Division of Network Medicine, and.
Lea
L
Borgi
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Naomi
N
Fisher
Renal Division.|Channing Division of Network Medicine, and.
Gary
G
Curhan
Renal Division.|Channing Division of Network Medicine, and.
John
J
Forman
D000328:Adult; D000493:Allopurinol / Q000009:adverse effects / Q000627:therapeutic use*; D000804:Angiotensin II / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory; D001900:Boston; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011339:Probenecid / Q000009:adverse effects / Q000627:therapeutic use*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood*; D014528:Uricosuric Agents / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D015415:Biomarkers; D014528:Uricosuric Agents; D000804:Angiotensin II; D014527:Uric Acid; D000493:Allopurinol; D012083:Renin; D011339:Probenecid
BP; Uric acid; allopurinol; placebo controlled; probenecid; randomized controlled trials; renin angiotensin system; urate; urate lowering therapy