Hyperuricemia (HC) refers to an abnormally high serum concentration of uric acid (>7 mg/dl in men and >6 mg/dl in women).
Mean serum uric acid has increased progressively over the last century, in many populations. In the US it increased from 19% in the period 1988-1994 to 21.5% in 2007-2008.
The prevalence increases with age and is higher in men than in premenopausal women (estrogens increase renal excretion of urate. In 2008, the eastern coastal regions of China had a prevalence of almost 13%, while in the 1980s was estimated at 0%.
CH is often related to gout, but it is increasingly accepted that values of >6.5 mg/dL or 7.0 mg/dL in men and postmenopausal women and >6.5 mg/dL in premenopausal women are clinically important markers of other diseases.
In general, since only 12% of people with a serum uric acid level between 7.0 mg/dL and 7.9 mg/dL develop gout, therapeutic interventions for asymptomatic CH are considered unwarranted unless a gout episode to occur.
However, CH is not only associated with gout, but also with various cardiometabolic diseases, such as high blood pressure, chronic kidney disease (CKD), hypertriglyceridemia, obesity, atherosclerotic heart disease, and metabolic syndrome (MS). Recent studies suggest that HC may be a risk factor for these conditions.
| Metabolism and biological activity of uric acid |
Uric acid is produced by xanthine oxidase and is the end product of purine catabolism; It is excreted mainly in urine and feces. Serum uric acid is affected by diets rich in purines and fructose , and is also produced during the degradation of nucleic acids (DNA and RNA) as well as ATP (as may occur during increased cell turnover or muscle degradation).
- As the kidney is an important site of excretion, renal failure can also lead to CH.
- Estrogens can increase urate excretion, which explains the lower levels of uricemia in premenopausal women .
It was always thought that the association of CH with cardiometabolic syndrome was due to the effect of diet, obesity and insulin resistance and, therefore, serum uric acid would not play a role in these conditions. In fact, some studies have shown that uric acid can be beneficial in cardiovascular diseases (CVD) and that it functions as an antioxidant.
However, more recent studies suggest that soluble uric acid may have a wide variety of pro-inflammatory effects . For example, uric acid has a cellular pro-oxidant effect, since its production generates reactive oxygen species.
It also has various cellular effects, such as the stimulation of growth factors, cyclooxygenase 2, chemokines (monocyte chemoattractant protein 1), C-reactive protein and thromboxane production, increasing the activity and turnover of platelets.
Uric acid also activates the renin-angiotensin system , stimulating plasma renin activity and renin expression, and activating the intrarenal pathway of the angiotensin system. These effects have been shown to be responsible for inducing many aspects of cardiometabolic disease.
Furthermore, experimental CH has been shown to induce systemic arterial hypertension , through vasoconstriction, driven by the pro-oxidant effects of uric acid on smooth muscle vascular cells, and by inhibiting nitric oxide. Likewise, uric acid has been shown to induce insulin resistance and gluconeogenesis. through inhibition of hepatic AMP-activated protein kinase.
Fatty acids can be induced by experimental CH, through the stimulation of lipogenesis and the inhibition of fatty acid oxidation, stimulated by the induction of uric acid-dependent mitochondrial oxidative stress.
Chronic kidney disease ( CKD) is primarily driven by the development of afferent arteriolar hypertrophy that impairs autoregulation and allows increased transmission of systemic blood pressure to the glomerulus.
Heart disease may be secondary to the stimulating effect that HC has on the renin-angiotensin system, which could cause high blood pressure, but uric acid has also been found in atherosclerotic plaque.
| Hyperuricemia and hypertension |
> Hyperuricemia in patients with hypertension
The relationship between CH and hypertension has been known for more than a century. CH is found in 25% of people with untreated high blood pressure and in three quarters of patients with malignant high blood pressure.
The prevalence of CH is higher in people with pronounced arterial hypertension and is associated with a higher risk of uncontrolled hypertension and resistance to treatment.
> Hyperuricemia as a risk factor for hypertension
The association of CH with arterial hypertension is independent of traditional cardiovascular risk factors, including age, obesity, hypercholesterolemia, hypertriglyceridemia, elevated low-density lipoprotein (HDL) cholesterol, diabetes, family history of hypertension, smoking, and consumption of alcohol.
In a meta-analysis of 18 prospective studies, with 55,607 participants with normal baseline blood pressure, CH was associated with an increased risk of incident hypertension. Another meta-analysis of 25 prospective and retrospective studies (n = 97,824) concluded that CH was a predictive factor for the development of hypertension, independent of sex and ethnicity (Asians vs. non-Asians).
HC may also be involved in the development of preeclampsia . Serum uric acid concentrations are higher in women with preeclampsia than in healthy pregnant women. Several physiological changes associated with pregnancy and preeclampsia can, in theory, lead to CH. However, a meta-analysis found that uricemia is not a good predictor of maternal-fetal complications in the context of preeclampsia.
In one study, 89% of 125 children aged 6 to 18 years, with primary arterial hypertension, had serum uric acid concentrations > 5.5 mg/dl, while these levels were found only in 30% of children with secondary arterial hypertension and in 0% of children with normal blood pressure. Therefore, HC is also correlated with hypertension in children.
| Hyperuricemia and metabolic disease |
> Prevalence of hyperuricemia in metabolic diseases
CH is also associated with metabolic syndrome (MS) and type 2 diabetes.
Epidemiological studies identified a positive correlation between uricemia and the prevalence of MS. Between 1988 and 1994, this prevalence showed a gradual increase, from 18.9% in individuals with uricemia <6 mg/dl to 70.7% in those with levels ≥10 mg/dl. This association was independent of sex, age, alcohol consumption, body mass index, and the presence of hypertension and diabetes.
On the other hand, the prevalence of the individual components of MS (HC, hypertriglyceridemia, low HDL-cholesterol, hypertension) also increased with increasing serum uric acid levels, except for abdominal obesity, which decreased slightly in individuals with very high HC. . (≥10 mg/dl). In prospective observational studies, HC was found to predict the risk of developing SM and its individual components.
Several studies have examined the effect of sex on the association between HC and SM. It was found that the higher the levels of GH, the greater the risk of MS. In a meta-analysis of 7 prospective cohort studies (n = 23,081 men; 12,195 women), the incidence of MS increased by almost 5% in men and 9% in women, for every 1 mg/dl increase in uric acid.
For an equivalent increase in uric acid concentrations, the risk of developing MS was greater in women <52 years of age than in men or older women. In an analysis of 10,649 men and 12,696 women, an association was found between uricemia and the risk of MS, which was significantly stronger in women.
The link between uric acid levels and SM has been proven in children . In adolescents, this relationship is more complex. In another trial, HC was predictive of the development of SM in men, but not in women, all older adults.
> Hyperuricemia as a risk factor for metabolic diseases
It was found that CH is associated with insulin resistance in women and obese individuals, while this association was not proven in non-obese, non-diabetic, and non-CVD men).
Several studies have reported increased risk of type 2 diabetes in people with HC. On the other hand, the individual components of MS, except dyslipidemia, are more common in individuals with CH and type 2 diabetes. Several meta-analyses have concluded that there would be a dose-response relationship.
In a meta-analysis of 11 observational cohort studies, with a total of 42,834 participants, it was concluded that the risk of developing type 2 diabetes increases 17% for every 1 mg/dl increase in serum uric acid. However, in a subsequent meta-analysis of 8 prospective cohort studies and 32,016 participants, which used a more rigorous methodology, the risk of developing type 2 diabetes increased 6% for each 1 mg/dl increase in serum uric acid.
The association between uric acid levels and type 2 diabetes was independent of the serum components of MS. On the other hand, a European analysis concluded that the risk of developing type 2 diabetes increases by 20% for every 1 mg/dl increase in uric acid concentration. However, the results of an instrumental multivariate analysis did not confirm this finding, calling into question the existence of a causal relationship between the two conditions.
> Hyperuricemia and cardiovascular disease
The most modern studies found a significant association between CH and several CVDs. That association remained even after adjustments for possible confounding factors. Serum uric acid levels are significantly associated with the presence and severity of coronary artery disease, left ventricular hypertrophy, and atrial fibrillation in both healthy and hypertensive individuals.
CH is a risk factor for myocardial infarction, cerebrovascular accident (CVA) and heart failure.
The Brisighella heart study also reported a significant correlation between HC levels, hypertension, and atherosclerosis (including increases in carotid intima-media thickness, and pulse wave velocity).
Results from a meta-analysis reported that CH conferred a modest but statistically significant risk of stroke and stroke death in both men and women and was an independent risk factor for heart failure and adverse outcomes in patients with heart failure. existing. HC also predicted 1-year mortality in patients with acute heart failure and adverse effects, as well as death in patients with acute myocardial infarction.
In patients with chronic heart failure, CH was significantly associated with diastolic dysfunction. In particular, the prognostic value of elevated serum uric acid concentration is associated with brain natriuretic peptide values, a common biomarker in patients with left ventricular dysfunction.
The prognostic values of serum urate and brain natriuretic peptide appear to be independent, but the combined elevation of both biomarkers in the same subject is associated with a worse prognosis, and can be used to monitor the clinical course in patients with acute heart failure.
CH is also associated with the development of cardiac hypertrophy. On the other hand, the results of a study carried out in 173 patients with normal uricemia, CH and gouty arthritis show that gout is associated with diastolic dysfunction of the left ventricle, but CH is not.
In addition to major CVD, CH has been associated with microvascular and peripheral artery diseases.
His suspected coronary microvascular disease was due to the absence of “myocardial rubus” on coronary angiography. Greater 1-year mortality is associated with CH after percutaneous treatment of ST-segment elevation myocardial infarction, compared to coronary artery disease, in which myocardial “blush” is present on coronary angiography. Prasad et al. studied coronary microcirculation abnormalities in postmenopausal women and found an association with CH and inflammation.
In patients with high calcium scores, an increase in serum urate has been demonstrated with an independent link between asymptomatic CH and coronary artery calcification, in the absence of overt CVD. In patients with an increased calcium index in the coronary arteries, an association with CH and asymptomatic joint urate deposits was also found, which could explain the higher risk of CVD in patients with “asymptomatic gout.”
Finally, a longitudinal association between CH and peripheral atherosclerosis has also been described , including the intra- and extracranial vascular system and CVD and peripheral vascular disease. It should be taken into account that treatment with diuretics directly affects HC, a point that must be taken into account in the management of CVD.
| Hyperuricemia and chronic kidney disease |
There is much evidence linking CH with the development of chronic kidney disease (CKD).
Studies in the general population have shown that CH is an independent risk factor for the development of CKD. Similarly, studies conducted in patients with type 1 and type 2 diabetes have shown that, in these populations, CH predicts the development of new-onset CKD. However, not all studies have shown this association.
Several large-scale trials, carried out in the general population, have confirmed that CH predicts the development of end-stage renal failure and that its presence during the first year after kidney transplant predicts graft loss.
Recent evidence also assigns a role to perioperative CH in the pathogenesis of acute kidney disease in patients undergoing cardiovascular surgery. On the other hand, evidence continues to accumulate that even mild CH correlates with early kidney damage, as shown by albuminuria and abnormalities on renal ultrasound.
| Hyperuricemia and heart failure |
Heart failure is one of the most important issues supporting the role of serum uric acid in CVD. The abundant information published describes the increased incidence and worse prognosis in patients with heart failure and CH.
In particular, the negative effects of serum uric acid are independent of the decrease in glomerular filtration rate (GFR), since at least 3 studies have shown a worse clinical outcome (mortality and hospitalization) in patients with heart failure and normal renal function. .
This evidence is supported by the finding of a significant overexpression of xanthine oxidase in patients with heart failure, which causes an increase in oxidative stress, which would be responsible for a further deterioration of left ventricular function, largely proportional to the levels circulating uric acid.
The prognostic role of uricemia is only partially supported by clinical trial results. The OPT-CHF study shows a significant improvement of the main results. in patients with CH treated with oxipurinol, while the results of the EXACT-HF study, with allopurinol, did not confirm this.
The discrepancy in the results of the 2 trials is probably due to the drugs used, the sample size of the studies and the lack of baseline stratification of the patients, considering that not all respond equally to the inhibition of xanthine oxidase.
| Uric acid-lowering drugs |
> Uric acid-lowering therapy in clinical practice
Current European guidelines recommend starting uric acid-lowering treatment with a low dose and increasing it until the desired serum uric acid level is reached.
First, the authors recommend reviewing the medications the patient is taking that may cause CH, such as thiazides and loop diuretics , to change them if there are no contraindications.
Second, in subjects receiving modulators of the renin-angiotensin system, the authors would consider switching to drugs capable of lowering serum uric acid independently of their involvement in angiotensin blockade.
For most subjects, the medications of choice for lowering uric acid are xanthine oxidase inhibitors (IXOs), such as allopurinol ( 100 and 900 mg/day in adults; children: up to 400 mg/day using 10 to 20 mg/kg/day) and febuxostat (80 mg/day, increased to 120 mg/day). These drugs are indicated when the deposit has already occurred.
Its use in children is rarely recommended. In patients with renal or hepatic insufficiency, lower doses are recommended. In patients with mild hepatic impairment, 80 mg/day is indicated, with no adjustment needed in patients with mild to moderate renal impairment.
In the US, the approved starting dose of febuxostat is 40 mg/day, increasing to 80 mg/day in those who do not achieve a serum uric acid level <6 mg/dL; in patients with severe renal dysfunction (i.e. CKD) the maximum daily dose should be limited to 40 mg/day.
Of the uric acid-lowering medications, those considered to have the greatest comparative effectiveness are IXOs, while uricosuric agents are not universally available and are mainly recommended, combined with IXOs or, as a sole treatment in patients in whom IXOs are not used. tolerated or are contraindicated.
Febuxostat has been reported to be superior to allopurinol in patients with gout, in terms of reducing serum urate and the percentage of patients achieving the target uricemia proposed by the guidelines.
Regarding cardiovascular prevention, the evidence is still a matter of debate, but it supports a certain degree of cardiovascular prevention in patients treated with urate-lowering drugs, mainly IXO, with some differences between the different drugs. The risk/benefit profile of uric acid-lowering therapy is an important aspect that should be taken into account in the treatment of asymptomatic patients.
Serious adverse reactions to allopurinol range from mild dermatitis to Stevens-Johnson syndrome.
Sudden cardiac death has been reported among patients treated with febuxostat (CARES trial and post-marketing experience). After the review, it has been concluded that, to date, there is no conclusive evidence supporting the use of IXO for the prevention and treatment of asymptomatic and non-severe CH.
> In arterial hypertension
Several studies suggest that uric acid-lowering treatment can lower blood pressure in hypertensive people with CH, especially if they are young, have not had a long history of hypertension, and have relatively preserved kidney function.
Other studies have shown that allopurinol significantly reduces systolic and diastolic blood pressure in children and adolescents with newly diagnosed essential hypertension.
The decrease occurs in systolic and diastolic pressures. On the other hand, studies suggest that if blood pressure is in the normal range (<140/90 mm Hg), treatment may not lower blood pressure.
In other studies of hypertensive patients with CH, febuxostat no m showed significant differences with placebo in terms of mean 24-hour ambulatory systolic blood pressure. Same result for diastolic blood pressure. However, analysis of a planned subgroup of patients with normal renal function revealed that systolic blood pressure was significantly reduced after 6 weeks of treatment with febuxostat.
In a recent study in patients with stage 3 CKD, febuxostat at a dose of 40 mg/day had no effect on blood pressure over 2 years of treatment. A meta-analysis of prospective and retrospective studies evaluating the effects of allopurinol treatment on blood pressure over 4 weeks showed that opurinol significantly reduced systolic and diastolic pressures compared to the control group. This effect was smaller than in other studies; but the age of the population was different. However, it is worth noting the good quality of the meta-analyses and their studies.
Most of the studies included in the meta-analysis were not designed to measure the effect of allopurinol on blood pressure and, consequently, many of the studies had patients with relatively well-controlled blood pressure.
In another more recent meta-analysis on the effect of uric acid lowering therapy on blood pressure, allopurinol was found to decrease both systolic and diastolic blood pressure in patients with CH.
> In metabolic disease
The adverse effects of HC can be prevented in part by reducing serum uric acid levels. Allopurinol (300 mg per day) was shown to reduce uric acid, and improve insulin resistance and systemic inflammation. Similarly, febuxostat decreased uric acid levels and improved insulin resistance in patients with gout.
Another study in which 200 g of fructose was administered for 2 weeks, allopurinol prevented increases in blood pressure, and the incidence of newly diagnosed MS, compared to men who did not receive allopurinol. At the same time, no effect was observed on homeostatic model assessment (HOMA) indices or fasting.
Plasma levels of triglycerides could be detected. Furthermore, in patients with non-alcoholic fatty liver disease, which is part of the MS complex, allopurinol administered for 3 months significantly improved serum levels of alanine and aspartate transaminases, cholesterol, and triglycerides, compared with placebo.
> In cardiovascular disease
Controlling uric acid levels with appropriate medications may be beneficial for patients with CVD.
A retrospective study of allopurinol reported a decreased incidence of stroke and cardiovascular events in adult patients. This treatment improved blood flow and peripheral vasodilatory capacity in patients with chronic heart failure.
Another randomized controlled study of allopurinol compared with placebo reported improvement in endothelial dysfunction in patients with chronic heart failure. Another study showed that high doses of allopurinol could reduce mortality in patients with coronary artery disease, by reducing vascular oxidative stress and improving endothelial dysfunction.
Furthermore, a systematic review and meta-analysis reported that IXO treatment of patients at risk for CVD improved endothelial function and markers of circulating oxidative stress. However, the authors have found several limitations to these studies. With allopurinol, there appears to be a gradual reduction in the risk of heart attack and stroke. Longer therapy, in older subjects, may provide optimal benefit.
On the other hand, one study showed that benzbromarone, a uricosuric not affected by xanthine oxidase, does not improve hemodynamic parameters, including left ventricular ejection fraction, heart rate, and blood pressure. However, benzbromarone treatment significantly reduced serum uric acid concentrations and improved fasting insulinemia and the insulin resistance index.
The superiority of IXOs can be explained by their multiple mechanisms of action, which involve a reduction in serum levels of uric acid and vascular oxidative stress, associated with a decrease in intracellular levels of uric acid. This is not the case with uricosuric agents (probenecid, benzbromarone and lesinurad) which only affect urate transport, without any effect on the pro-oxidative system.
The FREED trial revealed that in older adults with CH, “interestingly,” febuxostat reduced cerebral, cardiovascular, and renal events by 25%. A recent population-based cohort study found a modest decreased risk of heart failure exacerbation in patients with gout treated with febuxostat compared with those treated with allopurinol.
Furthermore, results from the FEATHER (febuxosta) study in patients with CKD stage 3 reported fewer major CVD adverse events.
Both studies were performed with low doses of febuxostat, thus supporting a favorable interaction between serum urate reduction and the selectivity of IXOs for CVD prevention. A prospective study (LEAF-CHF) of febuxostat is ongoing, investigating a possible additional benefit in heart failure.
> In kidney disease
Treatment with allopurinol or febuxostat is effective in reducing uric acid in patients with CKD. In asymptomatic CH, allopurinol significantly improved endothelial function and estimated GFR (eGFR) compared to placebo.
Similarly, patients with hypertension and asymptomatic CH, treated with febuxostat, experienced a more pronounced improvement in eGFR and greater suppression of the renin-angiotensin-aldosterone system than controls.
In studies of patients with CKD, allopurinol slowed disease progression, reduced the likelihood of kidney failure (with higher doses of allopurinol), and improved measures of cardiovascular risk. It was also observed that it achieved the target uricemia (<6 mg/dl) and reduced the risk of nephropathy progression by 37%. Treatment with febuxostat has been shown to reduce the progression of eGFR deterioration in patients with CKD.
Although some trials have not been able to demonstrate kidney protection, it could be because the control group did not present progression of kidney disease during the time the trial lasted.
So far, the largest prospective randomized trial, with patients with stage 3 CKD, showed that, compared with placebo, febuxostat mitigated the decline in renal function, due to the decrease in asymptomatic CH, but only in patients without proteinuria and with a fairly high eGFR (52 ml/min). The kidney protective effect provided by febuxostat was further confirmed in the FREED study and other major trials.
However, there are studies in which it has been shown that reducing uric acid does not provide any benefit for the progression of CKD in hyperuricemic subjects. But, in many of these trials, the control group failed to show progression of their kidney disease over the course of the trial.
In fact, in studies in which there was significant progression in the control group, the use of IXO was uniformly protective. This justifies therapeutic intervention aimed at reducing uric acid in individuals with CH and CKD in stage 3 or higher, who have signs of progression of renal activity. In any case, the authors warn about the need for more research.
Conclusions
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