Hyperuricemia is a metabolic problem that has become increasingly common worldwide over the past several decades. The association of hyperuricemia and gout with other medical conditions such as hypertension, chronic kidney disease, dyslipidemias and cardiovascular disease has been recognized for over 100 years [1••]. Until the past decade, the association between uric acid and these serious medical problems was considered to be a simple clustering of conditions that had similar risk factors, including lifestyles that were heavy on excesses of food and drink and light on exercise. Although a direct causal role of uric acid was suggested by Mohamed in the earliest description of essential hypertension , no scientific hypothesis for this association was put forward until recently. A new understanding of how uric acid is transported in and out of cells, along with animal studies of the vascular effects of soluble uric acid and a plethora of epidemiologic trials demonstrating serum urate to be an independent risk factor in the development of hypertension, cardiovascular disease, chronic kidney disease, stroke and possibly the metabolic syndrome have led to a reappraisal of the role of uric acid in human health and disease .
Evolutionary origin of hyperuricemia
The causes of hyperuricemia in humans are usually divided between overproduction and underexcretion of uric acid. In reality, all humans are hyperuricemic compared with all other mammals except for the great apes. This is caused by a series of genetic mutations to the uricase gene and the promotor between 15 and 20 million years ago . Most mammals with a functioning uricase gene have serum urate levels in the 1–2 mg/dl range. Nonhuman primates and primitive humans not exposed to western diets have serum urates in the 2–4 mg/dl range compared with serum urates of 4–10 mg/dl in modern humans on a western diet [5•]. Several theories have been proposed to explain how this enzymatic mutation conveyed a survival advantage to the species. These include uric acid's potential roles as a neurostimulant, an antioxidant or a mechanism for raising blood pressure. The structural similarity between uric acid and caffeine and other neurostimulatory molecules has raised the possibility that this mutation in uricase led to some increase in alertness and intelligence that would have offered evolutionary advantage .
Another hypothesis of selective advantage of having an elevated serum urate level is that uric acid functions as an antioxidant, which partially made up for the loss of ability to endogenously produce vitamin C . Many mammals lost this ability approximately 15–30 million years prior to the loss of uricase enzyme [5•]. This mutation involved the final enzyme in the pathway of vitamin C biosynthesis, L-gulonolactoneoxidase. Uric acid, like vitamin C, functions as an antioxidant and is thought to play a key role in the protection against oxidative stress by blocking lipid peroxidation, DNA damage and alkylation and membrane injury [5•,8–10].
The final hypothesis of how an elevated uric acid may impart a survival advantage to our species has to do with its effect on blood pressure. In a hypothesis, a higher blood pressure would allow for greater cerebral blood perfusion when our ancestors assumed an upright position . The survival advantage offered by a higher uric acid level during the mid-Miocene period when dietary sources of vitamin C and sodium were low have been lost in modern man. It is now very possible that the survival advantages offered to our ancestors are now the sources of disease in modern man [5•].
Vascular comorbidities associated with hyperuricemia
The prototypic picture of a gouty patient is that of an obese, middle-aged man with a propensity for overindulgence in food and alcoholic beverages. This person is also commonly afflicted with hypertension, kidney disease, diabetes mellitus and a predilection for other vascular problems such as coronary artery disease and vascular stroke . Of course, not all gouty patients fit the morphometric description of this prototype or suffer the vascular consequences listed above. What is true of all gouty patients, however, is that they have a history of hyperuricemia. The incidence of hyperuricemia in the world's population has steadily increased over the past 40 years and varies from country to country. Data from recent epidemiologic studies reveal that between 10 and 20% of most western populations are hyperuricemic, defined as a serum urate equal to or greater than 7.0 mg/dl. The likelihood of individuals with hyperuricemia developing gout depends primarily on the degree of uric acid elevation. Patients with a serum urate of greater than 9 mg/dl have an accumulated incidence of experiencing gout in 5 years of 22% . This percentage declines as serum urate levels decline.
Hyperuricemia is linked to a wide spectrum of metabolic and vascular conditions, including hypertension, renal disease, metabolic syndrome and both coronary and cerebral vascular disease . It has also been well documented that uric acid levels correlate with traditional vascular risk factors such as older age, male sex, obesity, dyslipidemia and insulin resistance . This complex relationship between hyperuricemia and numerous vascular risk factors has been interpreted by many to show that the relationship between uric acid and vascular disease may, in fact, be epiphenomenal rather than causal.
The argument against uric acid being an independent risk factor for vascular disease
Over the past 25 years, many large and well designed studies have focused on the relationship between serum urate and the likelihood of developing vascular diseases. Several of these studies have concluded that uric acid is a ‘predictive marker’ for developing cerebrovascular disease [16–19], renal disease [20,21] or hypertension [22,23]. The types of multivariate analyses used to distinguish dependent risk factors from independent risk factors vary between these studies. Inadequate control or weighing of known risk factors for vascular disease is frequently cited for inconsistent conclusions by these studies [1••,24•]. The primary argument against a causal role for uric acid is that changes in the kidneys caused by hypertension and the drugs used to treat hypertension both lead to hyperuricemia rather than the other way around. From this viewpoint, hyperuricemia is epiphenomenal to hypertension. By extension, the subsequent tissue damage caused by hypertension leading to cardiovascular disease, chronic kidney disease and stroke makes uric acid epiphenomenal to these medical conditions.
Reasons for reappraisal
The debate about uric acid being a direct cause of vascular disease or tissue damage is epitomized in the publications about uric acid-associated kidney disease over the past 50 years. On the basis of a very high incidence (79–99%) of interstitial and vascular disease in autopsied kidneys from gouty patients, Talbott coined the term ‘gouty nephropathy’ to describe this condition [24•,25]. This concept was extended by Klinenberg et al. in 1975  when they described similar renal involvement in patients with asymptomatic hyperuricemia. This was followed by two decades of opposition to the idea that noncrystalized uric acid could be responsible for tissue damage or that even localized deposits of urate crystals could account for generalized renal dysfunction. This led to a rejection by many in the nephrology community that uric acid had a direct toxic effect to kidneys other than that associated with kidney stones or postchemotherapy acute urate nephropathy. There was no perceived model or mechanism by which soluble uric acid could inflict damage to endothelial cells or other vascular tissues. Therefore, all damage observed with hyperuricemia and gout was assumed to be caused by the associated hypertension .
Beginning in the mid to late 1990s, several studies in a rat model of mild hyperuricemia showed that renal microvascular changes would develop when hyperuricemia was induced. Direct effects of uric acid on endothelial and vascular smooth muscle cells suggested that uric acid could cause microvascular damage independent of hypertension or the presence of urate crystals . Further studies went on to show that hyperuricemic rats exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal nitric oxide synthetase . Despite these observations in the animal model, there continued to be skepticism about a direct role for uric acid in endothelial dysfunction, as it was not clear how a compound generally viewed to be an extracellular solute could exert its effect intracellularly. Our understanding of specific urate transport was greatly enhanced in 2002 with the identification of the renal urate-anion exchange transporter, URAT-1 . The action of this specific uric acid transporter is now felt to be primarily responsible for renal tubular reabsorption of uric acid in the proximal convoluted tubule and regulation of blood urate levels. The expression of URAT-1 on cell surface is restricted to the renal tubular epithelium but expression has recently been demonstrated in endothelial cells and vascular smooth muscle cells of afferent renal arterioles being one of the few sites other than renal tubular epithelium . This observation made a direct intracellular function of uric acid at least feasible.
In addition to these molecular discoveries and animal models that support a direct metabolic effect of soluble urate, many recent publications have revealed hyperuricemia to predict the development of hypertension [31–34,35••,36–38], diabetes [39,40] and obesity [41•,42•,43]. Well designed and controlled studies have also shown uric acid to be an independent risk factor for both cardiovascular disease [44–48] and kidney disease [21,22,48].
At the very heart of the controversy regarding the role of uric acid in vascular disease is the relationship between hyperuricemia and hypertension. As the argument could always be made that any vascular changes in the heart, brain or kidney might be caused by hypertension, it was important to establish a direct causal relationship between hyperuricemia and hypertension. Going beyond the epidemiologic studies, Feig et al.[49••] have recently demonstrated that lowering uric acid in adolescents with newly diagnosed essential hypertension results in a reduction in blood pressure. This observation uniquely supports the hypothesis that soluble uric acid may be an important etiologic factor in vascular disease.
Uric acid and hypertension
The strong association between hypertension and hyperuricemia has been recognized for more than a century. Studies from the 1950s and 1960s showed the prevalence of hyperuricemia in hypertensive patients to be between 20 and 40% . The prevalence of hypertension among gouty patients is between 25 and 50%. In 1972, Kahn et al. found that a rising level of serum urate is an independent risk factor for hypertension. The following year, Klein et al. demonstrated a linear relationship between serum urate levels and systolic blood pressure in both black and white patients. Seven large epidemiologic studies [31,35••,36,38,39,41•,53] published over the past 7 years have found that serum urate levels predict the later development of hypertension. The two most recent of these studies are the Normative Aging Study by Perlstein et al. and the evaluation of the Multiple Risk Factor Intervention Trial (MRFIT) Study by Krishnan et al.[35••].
The Normative Aging Study  showed that the serum urate level independently predicted the development of hypertension when using age-adjusted and multivariate models that included body mass, abdominal girth, alcohol use, serum lipids, plasma glucose and smoking status. It also took into account renal function and insulin resistance. In this longitudinal cohort study of healthy adult men from the Boston area, the risk of developing hypertension was linear in its relationship to serum urate levels.
A recent analysis of the MRFIT data [35••] investigated the risk of developing hypertension over a 6-year follow-up period in men who were normotensive at the outset but had baseline hyperuricemia. These patients had no evidence of glucose intolerance or the metabolic syndrome. Again, in this model, adjustments were made for the effect of serum creatinine, BMI, age, blood pressure, proteinuria, tobacco and alcohol use as well as serum lipids. The results of this study showed that normotensive men with a baseline hyperuricemia had an 80% excess risk for developing hypertension compared with those who did not have hyperuricemia.
The preponderance of recent epidemiologic studies looking at hypertension and hyperuricemia has concluded that uric acid is an independent risk for the development of hypertension. But the frequent clinical observation that adult patients taking allopurinol do not have consistent improvement in their hypertension has made many question this direct effect. The recently published studies by Feig et al.[49••] demonstrating that hypertension in adolescents could be controlled by urate lowering may provide an explanation for this paradox. Relying on what was seen with the rat models of hyperuricemia, this group of investigators suggest that essential hypertension in its earliest stages is uric acid-sensitive but sodium-insensitive. With persistence of hypertension over a period of time, structural changes occur within the kidney and essential hypertension becomes uric acid-insensitive and sodium-sensitive. This explanation would fit the observation that uric acid levels are associated with hypertension but lowering uric acid in adults does not have a beneficial effect.
Hyperuricemia and chronic kidney disease
Two large prospective studies from Japan have recently examined the relationship between serum urate levels and the development of kidney disease. Using multivariate analysis to adjust for age, blood pressure, BMI, proteinuria, hematocrit, hyperlipidemia, fasting glucose and creatinine, Iseki et al. screened 48 177 Japanese adults and calculated the cumulative incidence of end-stage renal disease (ESRD) according to quartiles of baseline serum urate levels for each sex. The calculated incidence of ESRD per thousand screenees was 1.22 for men without hyperuricemia (less than 7.0 mg/dl) versus 4.64 for men with hyperuricemia (greater than or equal to 7.0 mg/dl). For women using a cut-off urate level of 6.0 mg/dl, the incidence of ESRD per thousand screenees was 0.87 for those with low urate levels versus 9.0 for those with higher urate levels.
Tomita et al. investigated the relationship between serum urate levels and various health hazards in a prospective cohort study that followed 49 413 male Japanese railroad workers over an average 5.4 years. They found a strong association between serum urate levels and renal failure, even when adjusted for covariant effects. Patients having uric acid levels greater than 8.5 mg/dl demonstrated an eight-fold increase in risk of renal failure relative to patients with moderate urate levels (5.0–6.4 mg/dl).
Several studies [54–56] have shown that urate-lowering therapy in patients with renal insufficiency may in fact improve renal function or decrease the speed of deterioration in patients with chronic kidney disease.
Hyperuricemia and cardiovascular disease
Hyperuricemia has been demonstrated in multiple recent studies to be an independent risk factor for atherosclerotic disease in general and for coronary artery disease in particular . In the National Health and Nutrition Examination Survey III (NHANESIII), over 16 000 patients were evaluated and uric acid levels in excess of 6 mg/dl were viewed to be an independent risk factor for coronary heart disease. In the same study, a serum urate level over 7 mg/dl was shown to be an independent risk factor for stroke . In the Systolic Hypertension in the Elderly Program of 4372 patients , uric acid again was shown to be an independent risk factor for cardiovascular events overall. When comparing the lowest quartile of serum urate levels against the highest quartile, there was a 32% increase in cardiovascular events overall and this was even higher in white men. It was determined that an increase in serum urate of 1 mg/dl from baseline to 12 months was associated with a 72% increase in risk of cardiovascular event.
From multiple studies, it appears the relationship between uric acid and cardiovascular disease is quite strong and is especially pertinent in patients who are at high risk for heart disease and also in women. A mechanism for direct causal relationship between uric acid and cardiovascular events remains to be determined.
Hyperuricemia and the metabolic syndrome
The clinical association of diabetes and obesity with hyperuricemia and gout has been well recognized. Hyperuricemia associated with the metabolic syndrome has been attributed to insulin resistance and hyperinsulinemia in this disease. Insulin is known to reduce renal excretion of uric acid leading to the assumption that hyperuricemia is epiphenomenal in the metabolic syndrome. However, recent studies have shown that hyperuricemia precedes the development of obesity, diabetes and even hyperinsulinemia. In one study of nonobese patients who developed metabolic syndrome [58•], those with hyperuricemia were noted to be at a 10-fold increase in risk compared with those with normal uricemia.
When a large registry of gout patients was examined in both the UK and in Germany, the comorbidities most commonly found to be associated with gout were obesity in the UK and diabetes in Germany [41•]. There appears to be a direct linear association between these metabolic conditions and the degree of hyperuricemia.
Although the clinical evidence to establish a direct link between uric acid and the metabolic syndrome is relatively small compared with data demonstrating association with hypertension, kidney disease and heart disease, there is support in animal models of metabolic syndrome for a direct role of uric acid [43,59]. There is also some evidence suggesting that lowering serum urate levels can reverse features of the metabolic syndrome . The question raised in these studies is whether the benefit seen with urate lowering is caused by the reduction in uric acid itself or if by inhibiting xanthine oxidase, the production of superoxide, hydrogen peroxide and hydroxoradicals is decreased resulting in endothelial dysfunction.
In this article, I have described a steadily growing literature on the association of hyperuricemia with several forms of vascular disease. The preponderance of data is now on the side that hyperuricemia is an independent risk factor for the development of hypertension, kidney disease, cardiovascular disease and stroke. Although mechanisms for a causal relationship between soluble uric acid and these various medical problems are not entirely clear, animal studies are providing some mechanistic insight. It is tempting for the clinician to view these data as an invitation to lower serum uric acid levels to decrease the risk of morbidity and mortality from vascular disease but a cautionary note should be made. Drugs that are currently available to lower serum urate levels, including allopurinol and probenecid, have side effects and this risk cannot justify their use in the treatment of asymptomatic hyperuricemia. I do believe that in the near future, cohorts of patients that are at unusual risk for these uric acid-associated vascular problems may be identified and this might shift the risk: benefit ratio in the direction of treatment.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 192).
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