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The role of hyperuricemia and gout in kidney and cardiovascular disease

July 1, 2008|Cleveland Clinic Journal of Medicine
N. Lawrence Edwards, MD
Author and Disclosure Information

N. Lawrence Edwards, MD
Professor of Medicine and Vice Chairman, Department of Medicine, University of Florida Chief, Rheumatology Section, Malcom Randall VA Medical Center, Gainesville, FL

Correspondence: N. Lawrence Edwards, MD, Department of Medicine, University of Florida, 1600 S.W. Archer Road, D2-39, Gainesville, FL 32610-0221; edwarnl@medicine.ufl.edu

Dr. Edwards reported that he has no affiliations with or financial interests in commercial organizations that pose a potential conflict of interest with this article.

Dr. Edwards received honoraria for participating in the symposium that formed the basis of this supplement and for writing this article. The honoraria were paid by Fallon Medica LLC, a medical communication company, on behalf of TAP Pharmaceutical Products, the underwriter of this supplement. TAP had no input on the content of presentations at the symposium or on this article.

This article is based on Dr. Edwards’ lecture on this subject at the symposium that formed the basis of this supplement. Dr. Edwards reported that he prepared his lecture, Fallon Medica transcribed his lecture, and he alone developed the transcript into this article without assistance from undeclared contributors.The article underwent formatting and nonsubstantive copyediting by Fallon prior to submission to the Journal.

ABSTRACT

Elevated serum urate levels are recognized as leading to gouty arthritis, tophi formation, and uric acid kidney stones. While serum urate elevations have long been associated with renal disease, they are not usually considered to have a causal role in kidney dysfunction. However, recent epidemiologic studies have identified serum urate elevations as an independent risk factor for chronic kidney disease. Hyperuricemia has also been found to be an independent risk factor for cardiovascular disease and hypertension. An animal model of mild hyperuricemia has shed new light on a potential mechanism of microvascular changes leading to endothelial dysfunction, a precursor to both coronary artery disease and hypertension. Additional animal studies and recent epidemiologic findings have provided further evidence that soluble urate is a risk factor for nonarticular disease.

KEY POINTS

  • Hyperuricemia significantly increases the risk of renal failure and end-stage renal disease.
  • Larger, more rigorous trials are under way to assess preliminary findings suggesting that urate-lowering therapy might normalize blood pressure in hypertensive adolescent patients.
  • Use of urate-lowering therapies to treat hyperuricemia is not currently supported in patients with kidney disease, heart disease, or hypertension in the absence of gout or uric acid kidney stones.

ASSOCIATION OF HYPERTENSION AND HYPERURICEMIA

The strong association between hypertension and hyperuricemia has been recognized for more than a century. In his original description of essential hypertension in 1879, Frederick A. Mohamed noted that many of his subjects came from gouty families.7 Studies from the 1950s and 1960s showed the prevalence of hyperuricemia in hypertensive subjects to be between 20% and 40%.8,9 The prevalence of hypertension among gouty patients is Hyperuricemia predicts ESRD between 25% and 50%.10 In 1972, Kahn et al found that a rising level of serum urate is an independent risk factor for hypertension.11 A year later, Klein et al demonstrated a linear relationship between serum urate level and systolic blood pressure in both black and white subjects.12

Six large epidemiologic studies published over the past 7 years have found that serum urate level predicts the later development of hypertension.13–18 The most recent of these is the Normative Aging Study,18 which showed that the serum urate level independently predicts the development of hypertension when using age-adjusted and multivariate models that include body mass, abdominal girth, alcohol use, serum lipid levels, plasma glucose level, and smoking status.

A potential mechanism emerges

No clear causal or mechanistic link between elevated serum urate and the development of hypertension was evident until a rat model of mild hyperuricemia was found to be associated with the development of an initial salt-insensitive hypertension that was reversible with restoration of normal urate levels.19 However, if the urate-induced hypertension was allowed to persist, the rat would develop a salt-sensitive hypertension that was irreversible even if normouricemia was reestablished.19

This mechanism was tested in a small pilot study of 5 children with previously untreated essential hypertension who received monotherapy with allopurinol for 1 month.20 All 5 children had substantial drops in their continuously monitored ambulatory blood pressure, and 4 of the 5 developed normal blood pressure (as assessed by continuous monitoring). After the allopurinol was stopped, the blood pressure of all 5 children rebounded to baseline levels.20 A larger blinded, randomized, placebo-controlled crossover trial using the same intervention with similar results has been presented recently at national meetings.21

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND HYPERURICEMIA

There is considerable documentation that urate levels correlate with many recognized cardiovascular risk factors, including age, male gender, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and insulin resistance. Because of these relationships, the observed association between serum urate elevations and cardiovascular disease was considered to be “epiphenomenal” and not causal. Many older epidemiologic studies that demonstrated the increased cardiovascular risk associated with higher urate levels used traditional statistical techniques that could not prove the “independence” of urate as a risk factor.22

An independent effect is finally documented

Three studies published in the past several years demonstrate an independent risk relationship between hyperuricemia and cardiovascular disease, including acute myocardial infarction.23–25

Multivariate regression analysis of the Multiple Risk Factor Intervention Trial (MRFIT) database demonstrated hyperuricemia to be an independent risk factor for acute myocardial infarction.23

Similarly, the Italian Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study showed that after adjustment for age, sex, diabetes, serum lipid levels, serum creatinine, left ventricular hypertrophy, blood pressure, and diuretic use, serum urate levels in the highest quartile were associated with increased risk of all cardiovascular events (relative risk [RR] = 1.73) and fatal cardiovascular events (RR = 1.96) compared with urate levels in the second quartile.24

Finally, follow-up of 4,385 participants in the Rotterdam Study over an average of 8.4 years revealed that high urate levels were a strong predictor of both myocardial infarction and stroke, even after adjustment for other vascular risk factors.25

CONCLUSIONS

Based on the preponderance of recent epidemiologic studies, it appears that an elevated serum urate level is an independent risk factor for kidney disease, hypertension, and cardiovascular disease. The precise mechanisms for urate-induced tissue injury remain unclear, and no large study to date has convincingly demonstrated that lowering serum urate levels can prevent or lessen the risk of these potentially severe complications of hyperuricemia.

It should also be emphasized that the treatment of hyperuricemia with medications such as allopurinol or probenecid is currently not indicated in patients with hypertension, kidney disease, or heart disease. The use of these agents is supported only in the treatment of gout, the treatment of uric acid kidney stones, and the prevention of tumor lysis syndrome.

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