Mounting Evidence Casts Uric Acid as Central Player in Cardiovascular Disease

After a "long-standing clinical and basic science quest," a group of "tenacious investigators" (as a September editorial in Hypertension puts it), are casting uric acid in a far broader role than it currently assumes in medical science. During an impassioned presentation at the American College of Rheumatology meeting in Washington earlier this month, Richard Johnson MD described a long line of clinical and animal studies that collectively portray uric acid as "a major risk factor for cardiovascular disease," the central villain in the mystery that links hypertension, kidney failure, and diabetes.

Johnson, who is professor of medicine at the University of Colorado in Denver, echoed the editorial in calling for large, well-designed clinical trials to test the hypothesis that lowering uric acid levels in the correct way, early enough in the course of disease, could accomplish far more than "merely" preventing gout.

The great apes are the only mammals that develop gout, because they alone lack uricase, the enzyme that breaks down uric acid. Uric acid in turn inhibits an enzyme that breaks down fat. Johnson speculated that lacking uricase proved an adaptive advantage millions of years ago, because for fruit-eating mammals inhibiting the breakdown of fat would act against starvation. This has obvious disadvantages when overabundance, not starvation, is the problem. However, proving the case against uric acid in animal studies was a challenge until the advent of knockout gene technology, which allowed scientists to mimic the human condition by creating other animals that also lack uricase.

Besides the link to hypertension, Johnson said that 44 studies now show uric acid contributing to kidney disease, diabetes, or metabolic syndrome. The evidence he cited specifically associates high uric acid levels to:

Hypertension. In a small randomized study by pediatric nephrologist Daniel I. Feig MD of the University of Alabama (a long-time research collaborator with Johnson) and nurse Beth Soletsky, urate lowering therapy achieved substantial reductions in blood pressure among obese, pre-hypertensive teens and pre-teens.This is the latest of several studies to link urate lowering to reductions in blood pressure.

In the editorial in Hypertension, Andrew Whelton MD, scientific director of the research consulting and medical communications firm ScienceFirst LLC, credits Feig, Johnson, and coworkers with "unraveling the major mechanism that links hyperuricemia to hypertension." (The evidence suggests that acting early against uric acid, as with pre-hypertensive adolescents, can prevent hypertension from developing, but that reducing uric acid will fail to correct established hypertension.)

Metabolic syndrome. Whelton referred to a "problematic" detail in Feig's study, that young subjects in the treatment group lost weight while those in the control group gained some. In the context of Johnson's remarks at the ACR meeting, this would appear to fit a much larger picture in which uric acid production, stimulated by the activity of fructose in sugar, contributes to metabolic syndrome. The proposed mechanism involves uric acid inhibition of AMP-activated kinase, an enzyme central to fatty acid oxidation and lipogenesis. Anin vitro study by Johnson's team validating this concept in hepatic cells appeared earlier this month in the journal PLoSOne.

Kidney damage.  In a retrospective study published last March, Johnson collaborated with researchers at New York's Mount Sinai Hospital to study uric acid in patients undergoing cardiac surgery. They found that preoperative serum uric acid levels correlated with subsequent acute kidney injury, higher postoperative serum creatinine values, and lengths of stay. This follows a 2010 report from a team in Madrid that carried out a randomized trial testing allopurinol versus placebo among 113 patients with chronic kidney disease. The drug decreased C-reactive protein and slowed disease progression, as well as reducing the risk for cardiovascular events. 

These are just pilot studies, Johnson said, adding a somewhat superfluous caution for his rheumatologist audience: "Don't just give your patients allopurinol. You could give them Stevens-Johnson syndrome. You could kill them!"

Rheumatologist James Figueroa MD of Harrington MA rose to the microphone at discussion time in defense of the general principle. He said he had rescued numerous patients from dialysis by acting aggressively against uric acid.

"Holding back until we get the studies is somewhat of an injustice to the public," he said later. "Time and time again, I've seen this work for a slightly overweight azotemic. You can't let it go on too long, but if you get aggressive about diet and alcohol, the kidney can return to normal values. Otherwise, they're on dialysis. This is a shame."

Large randomized trials of these questions are certainly in order, observed rheumatologist Michael H. Pillinger MD of New York University Medical Center, who presented a poster elsewhere at the meeting showing that colchicine is associated with a decreased rate of myocardial infarction among gout patients.

"We have an agent [that reduces uric acid]. We don't have to invent it," he remarked. "Why would you not know? If you used it in a study, you'd know."