Serum uric acid and the risk of cardiovascular and renal disease.

Review

Serum uric acid and the risk of cardiovascular and renal disease Claudio Borghi a, Enrico Agabiti Rosei b, Thomas Bardin c,d,e, Jesse Dawson f, Anna Dominiczak f, Jan T. Kielstein g, Athanasios J. Manolis h, Fernando Perez-Ruiz i, and Giuseppe Mancia j

Substantial evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, chronic kidney disease (CKD) and cardiovascular diseases. This highlights the need for greater attention to serum uric acid levels when profiling patients, and suggests that the threshold above which uricemia is considered abnormal is 6 mg/dl, in light of the available evidence. Another important question is whether lowering serum uric acid can improve cardiovascular and renal outcomes, and what therapeutic mechanism of action could provide more clinical benefits to patients; the available literature shows a trend toward improvement associated with administration of urate-lowering drugs, in particular for the xanthine oxidase inhibitors. The demonstrated efficacy of urate-lowering therapy on outcomes other than gout flares leads to the consideration that treatment may be beneficial even in the absence of overt gout when hyperuricemia accompanies other clinical conditions, such as urate deposition, advanced CKD or cardiovascular risk factors. Keywords: cardiovascular disease, hyperuricemia, renal disease, serum uric acid Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; GFR, glomerular filtration rate; sUA, serum uric acid; XO, xanthine oxidase

INTRODUCTION

U

ric acid has long been considered an inert endproduct of purine catabolism; however, a substantial and increasing body of evidence suggests that chronic hyperuricemia, in addition to causing deposition of urate crystals in the body, is an independent risk factor for the development of hypertension, as well as for the risk of metabolic syndrome, chronic kidney disease (CKD) and cardiovascular diseases. The average levels of serum uric acid (sUA) in the general population are increasing over time [1]. This is mainly attributable to dietary changes, increasing BMI and improved life expectancy both in the general population and in patients with CKD and congestive heart failure. Hyperuricemia, and the associated range of pathological conditions, is thus becoming a highly prevalent condition. These considerations point to the need for greater attention to sUA levels when profiling patients, not

Journal of Hypertension

only from a rheumatologic standpoint, but also in terms of cardiovascular and renal risk. The threshold above which uricemia becomes ‘abnormal’ is still disputed: a statistical approach assesses the reference range of sUA and its variation among healthy individuals; a pathophysiological approach uses the super saturation concentration of uric acid, 6.8 mg/dl at 378C, as a cut-off value. The therapeutic target of 6 mg/dl (360 mmol/l) indicated by guidelines for management of gout [2] seems to be the most appropriate for this purpose. However, the clinically relevant sUA concentration needs to be revised in light of recent findings. This article presents considerations on the appropriate sUA value to serve as the threshold for defining clinical hyperuricemia. The consensus-building process was conducted by a board of European investigators of different aspects of uric acid-dependent diseases.

BIOCHEMISTRY OF URIC ACID Hominids have lost expression of the gene encoding uricase, the enzyme that converts uric acid to the more soluble molecule, allantoin in other mammals. Whereas this may have been advantageous as a means to favor the formation of adipose tissue from fructose [3], the increased availability of nutrients in modern societies may be responsible for raising sUA levels [4], and predisposing to excessive fat storage, insulin resistance and hypertension [3]. Uric acid is the end-product of purine metabolism. Purines are generated through two pathways: de novo Journal of Hypertension 2015, 33:1729–1741 a

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy, Department of Clinical and Experimental Sciences, University of Brescia, Department of Medicine, Spedali Civili, Brescia, Italy, cAssistance Publique Hoˆpitaux de Paris, Hoˆpital Lariboisie`re, dUniversite´ Paris Diderot, Sorbonne Paris Cite´, eINSERM, UMR 1132, Paris, France, fInstitute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK, g Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany, hCardiology Department, Asklepeion Hospital, Athens, Greece, i Rheumatology Division, Hospital Universitario Cruces and Biocruces Health Research Institute, Vizcaya, Spain and jUniversita` Milano-Bicocca, IRCCS Istituto Auxologico Italiano, Milan, Italy b

Correspondence to Giuseppe Mancia, Universita` Milano-Bicocca, IRCCS Istituto Auxologico Italiano, Milan, Italy, P.za dei Daini, 4, 20126 Milan, Italy. Tel: +39 039 233 3357; fax: +39 039 322274; e-mail: [email protected] Received 10 February 2015 Revised 11 June 2015 Accepted 11 June 2015 J Hypertens 33:1729–1741 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000701

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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synthesis from nonpurine compounds, regulated by phosphoribosyl-pyrophosphate synthetase, and the purine salvage pathway, regulated by hypoxanthine-xanthine phosphoribosyl-transferase. Dietary factors and endogenous processes with high cell turnover may increase sUA levels. Uric acid has been described as an oxygen radical scavenger [5]. In contrast to this proposed beneficial role of uric acid, an increased risk of total and cardiovascular mortality in subjects with elevated serum uric acid levels is well documented. This dual role has been described as the ‘uric acid paradox,’ whereby this substance would act as antioxidant or pro-oxidant depending on the intracellular or extracellular localization, and interactions with other factors. Catabolism of purines is regulated mainly by xanthine-oxidoreductase, which converts hypoxanthine to xanthine, and xanthine to uric acid. Xanthine-oxidoreductase exists in two interconvertible isoforms: xanthine dehydrogenase and xanthine oxidase. Xanthine oxidase uses molecular oxygen as an electron acceptor, thus generating superoxide anion and other reactive oxygen species as by-products. Xanthine oxidase is over-expressed in inflamed and ischemic tissues [6]. This mechanism, together with the pro-oxidant effect of urate described previously, could explain the negative impact of elevated sUA on cardiovascular events. Uric acid is eliminated through both renal and intestinal excretion. The relevant renal and intestinal transporters of uric acid have been characterized over the last decade [7]. Inefficient renal excretion of uric acid is the main cause of both primary and secondary hyperuricemia in patients with gout [8]. Reduced intestinal excretion of uric acid associated to polymorphisms of the ABCG2 gene appears to contribute to a ‘pseudo-overproduction’ phenotype [9].

GENETIC AND ENVIRONMENTAL FACTORS ASSOCIATED WITH SERUM URIC ACID LEVEL A small number of monogenic disorders are associated with hyperuricemia and deposition of mono sodium urate crystals. These include activating mutations in the phosphoribosyl pyrophosphate synthetase gene, inactivating mutations in the hypoxanthine guanine phosphoribosyl transferase gene (Lesch-Nyhan syndrome) and mutations in the uromodulin gene. Numerous candidate genes have been reported to be involved in regulation of sUA levels via genome-wide association studies. In these studies to date, 26 were identified and replicated via genome-wide association analysis and a further two via pathway analysis [10]. An association with four additional candidate genes has been reported in other studies [11] (Table 1). The proportion of variance in sUA explained by these genes is approximately 5–7%. Candidate genes encode either urate transporters, proteins involved in glucose metabolism and insulin response, proteins that interact with urate transporters, transcription factors or growth factors or gene products of unknown or poorly described function with an unclear relationship with uric acid regulation. Mendelian randomization and genetic risk score studies have given conflicting results regarding the causality of uric acid in cardiovascular disease. 1730


In Mendelian randomization studies, a genotype associated with the risk factor of interest is used as an instrumental variable. This approach accounts for potential confounders and reverse causality. A study by Palmer et al. [12] found no association between a single nucleotide polymorphism (SNP) in the SLC2A9 gene that accounted for approximately 2% of the variability in sUA levels and ischemic heart disease or blood pressure (BP) level in two large Danish cohorts. Further, a study by Oikonen et al. [13] found no association between a different SNP in the SLC2A9 gene and carotid intima-media thickness. These findings are in contrast to a study by Kleber et al. [14] wherein a genetic risk score for high uric acid including eight gene variants was related with cardiovascular death. Moreover, in a study by Mallamaci et al. [15], a different SNP in the SLC2A9 gene was associated with higher serum uric acid and higher SBP. This was in agreement with a careful analysis of an Amish cohort that revealed an association between a variant of the SLC2A9 gene and hypertension [16]. In a study by Hughes et al. [17], a uric acid genetic risk score was associated with improved renal function. However, in a further genetic risk score study, Sedaghat et al. [18] found 30 gene variants that were associated with increased serum uric acid but with lower blood pressure. In that study, the results were sensitive to diuretic therapy, and there was no relationship between a SLC2A9 SNP and BP in patients not treated with diuretics. However, each of the involved genes has a modest effect on sAU variance and results must be taken with some caution, as studies may be underpowered unless very large cohorts are examined. These genetic studies suggest that the relationship between uric acid and cardiovascular disease is complex, potentially confounded, and modified by other treatments for cardiovascular disease and may differ across the spectrum of cardiovascular disease. This highlights the need for rigorous well designed studies exploring the effect of uric acid reduction in defined groups, with attention to concurrent treatments. Environmental factors associated with uric acid levels include diet and prescribed drugs, and levels are associated with numerous cardiovascular risk factors. Several drugs lower sUA levels, in particular in patients with hyperuricemia that is accompanied by deposition. These include uricosuric drugs such as probenecid, benzbromarone and sulfinpyrazone and the xanthine oxidase inhibitors allopurinol and febuxostat. Numerous other drugs have secondary effects on sUA levels. These include antihypertensive drugs, cholesterol-lowering drugs, steroid medication, some nonsteroidal anti-inflammatory drugs and some antibiotics (Table 2). Dietary factors known to increase sUA levels include higher intake of meat, seafood, fructose, alcohol and sodium. Factors associated with lower sUA levels are increasing ascorbic acid intake and consumption of coffee and dairy products.

EPIDEMIOLOGICAL ASPECTS The prevalence of hyperuricemia As already mentioned, the definition of hyperuricemia varies among studies, making comparisons between them Volume 33 Number 9 September 2015


Serum uric acid and cardiovascular risk TABLE 1. Candidate genes reportedly involved in the regulation of serum uric acid levels Gene a

A1CF ABCG2a ARNTa ATXN2a BAZ1Ba BCAS3a GCKRa HLFa HNF4Ga IGF1Ra INHBBa INHBEa LRRC16Ab MAFa NFAT5a NRXN2b ORC4La OVOL1a PDZK1a PKD2b PRKAG2a QRICH2a RREB1a SFMBT1a SLC16A9a SLC17A1b SLC17A3a SLC22A11a SLC22A12a SLC22A7a SLC2A9a STC1a TMEM171a TRIM46a UBE2Q2a VEGFAa

Gene Product

Putative role in regulation of urate level

APOBEC1 complementation factor ATP Binding Cassette B member 2 Aryl hydrocarbon receptor nuclear translocator Ataxin 2 protein Bromodomain protein Unknown Glucokinase regulatory (inhibitory) protein Proline and acidic rich transcriptor factor family Hepatocyte nuclear factor 4 Insulin like growth factor 1 receptor Activin B Beta chain of inhibin Leucine rich repeat containing 16A MAF protein Nuclear factor of activated T cells 5 Neurexin family protein Origin recognition complex subunit 4 OVOL 1 protein PDZ domain containing 1 protein (scaffolding protein) Polycystin 2 5’AMP activated protein kinase subunit gamma 2 Glutamine rich protein 2 Ras responsive element binding protein SCM-like protein with four MBT domains Monocarboxylic acid transporter 9 NPT1 (renal sodium phosphate transporter protein 1) NPT4 (renal sodium phosphate transporter protein 1) Solute carrier family 11 r (related to URAT1) URAT1 Organic anion transporter 2 (OAT2) GLUT 9 Stanniocalcin 1 Transmembrane protein TRIM46 Protein Ubiquitin conjugating enzyme member 2 VEGFA

Unknown Urate transporter Unknown, interacts with transcription factors Unknown Unknown Unknown Unknown, role in glucose metabolism Unknown, transcription factor Growth factor Unknown, role in glucose metabolism Unknown Unclear, TGF-B superfamily Unknown Unknown, transcription factor Unknown, role in glucose metabolism Unknown, cellular adhesion molecule Unknown Unknown, putative trabscription factor May interact with urate transporters Unknown Unknown, role in glucose metabolism Unknown Unknown, transcription factor Unknown Unknown, role in glucose metabolism Urate transporter Urate transporter Urate transporter Urate transporter Urate transporter Unknown Unknown, putative growth factor Unknown, Incorporates a motif associated with microtubule binding. Unknown Unknown, growth factor

GLUT, glucose transporter; MAF, musculoaponeurotic fibrosarcoma; MBT, malignant brain tumour; OVOL 1, ovo-like zinc finger 1, SCM, sex comb on midleg; TGF-B, transforming growth factor beta, VEGFA, vascular endothelial growth factor A. a Identified and replicated in the study by Kottgen et al. [10] (ARNT and SLC22A7 were identified and replicated using pathway analysis). b Association reported in the study by Kolz et al. [11] (and others) but not by Kottgen et al. [10].

difficult. A very high prevalence of hyperuricemia and gout has been reported in certain aboriginal populations of the pacific regions, with highest values (41.4 and 11.7% respectively) found in Taiwanese aboriginals [19]. The estimated prevalence of hyperuricemia from the US National Health and Nutrition Examination Survey (NHANES) 2007–2008 is approximately 23%, somewhat higher in African Americans

than non-African Americans (25.7 vs 22.1%) [1]. A clear signal of increasing prevalence of hyperuricemia was recently reported in an Italian survey, where the proportion, using a cut-off of 6 mg/dl (360 mmol/l), was 8.5% in 2005 and had increased to 11.9% in 2009 [20]. This has important implications because hyperuricemia is strongly associated with a number of cardiovascular risk

TABLE 2. Drugs that influence serum uric acid levels Drug Name

Effect on serum uric acid

Losartan Diuretics Beta-blockers ACE inhibitors Calcium channel blockers Alpha blockers HmG CoA reductase inhibitorsa Fenofibrate Acetylsalicylic acid

# " " $(but attenuates rise caused by diuretics) # $ # # " at low doses, #at higher doses

Magnitude of effect 20–25% # 6–19% " 6–9% " – 3–10% # – 3.6–12% # 20% # 6% " with low doses

Mechanism of effect Uricosuric effect " Uric acid reabsorption in proximal tubule Unclear Uricosuric effect Uricosuric effect – Uricosuric effect Presumed inhibition of URAT 1 transporter High doses are uricosuric, low dose causes uric acid retention

ACE, angiotensin-converting enzyme; URAT 1, urate transporter 1. A class effect is assumed, except for where individual drug names are given. a Strongest evidence for atorvastatin but also supports mild effect of simvastatin and rosuvastatin.




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factors including the components of the metabolic syndrome, of which it was formerly a part. These associations are evident at sUA levels well below the saturation concentration of monosodium urate.

Hyperuricemia and new onset of hypertension Epidemiological evidence supporting an association between sUA and the incidence of hypertension is consistent. A large number of observational studies have revealed an increase in the relative risk of hypertension with increasing levels of sUA, and this association is clearly independent of traditional risk factors (major studies are summarized in Table 3) [21,22,24–31]. Grayson et al. [21] have conducted a meta-analysis of 18 prospective cohort studies of subjects who were normotensive at baseline (n ¼ 55 607). The pooled adjusted relative risk for incident hypertension in subjects with hyperuricemia was 1.41 [95% confidence interval (CI) 1.23–1.58] and further data later showed hyperuricemia to be independently predictive of new-onset hypertension as diagnosed by ambulatory and home BP, that is BP elevations with a greater adverse prognostic value than office values [22]. Analysis of age and sex strata showed a stronger association in younger subjects and in women, the stronger association in younger subjects possibly resulting from the presence of fewer confounding risk factors in this population. An early effect of hyperuricemia in the development of hypertension is also suggested by the results of a study of 125 children (mean age 13.4 3.3 years) with untreated newly diagnosed hypertension and normal renal function [23]. sUA was directly correlated with SBP and DBP (r ¼ 0.80, P ¼ 0.0002 and r ¼ 0.66, P ¼ 0.0006, respectively). The mean sUA in children with primary hypertension (n ¼ 63) was 6.7 mg/dl, whereas that for children with white coat hypertension confirmed with ambulatory monitoring (n ¼ 22) was 3.5 mg/dl, and comparable with normal control children (n ¼ 40) 3.6 mg/dl. Longitudinal data from the Bogalusa Heart Study indicate that hyperuricemia in childhood is associated with hypertension in both childhood [SBP (r ¼ 0.31; P 0.0001); DBP (r ¼ 0.20; P 0.0001)] as

well as adult life [SBP (r ¼ 0.29; P 0.0001) and DBP (r ¼ 0.28; P 0.0001)] [32]. Thus, hyperuricemia is clearly associated with the onset of hypertension, a major cardiovascular risk factor. Further studies are needed to establish the mechanism and markers through which uric acid influences the pathogenesis of hypertension, thereby indirectly effecting cardiovascular risk.

Hyperuricemia and cardiovascular disease Hyperuricemia correlates strongly with cardiovascular risk. Higher levels are associated with the incidence and progression of a wide variety of microvascular and macrovascular diseases. Recently, a study conducted in 15 773 participants in the Third National Health and Nutrition Examination Survey (NHANES) revealed an increased risk of total mortality and cardiac mortality with increasing sUA levels. The increase in hazard ratio (95% CI) per 59.5 mmol/l of sUA was 1.32 (1.25–1.38), and remained 1.15 (1.08–1.21) even after extensive adjustment for demographic factors, comorbidities and other risk factors [33]. This is reflected also in cardiovascular and total mortality associated with uric acid deposition (Fig. 1). However, establishing whether sUA is an independent risk factor has been complicated by interactions between sUA levels and kidney function. Analysis published in 1999 of data from 6763 subjects in the Framingham Heart Study cohort did not reveal a significant association between uric acid levels and the incidence of CHD or cardiovascular mortality after adjustment for cardiovascular risk factors [34]. The authors indicated that the observed lack of association between uric acid and cardiovascular endpoints was likely because of the close association between uric acid and known risk factors. In particular, decreased glomerular filtration rate (GFR), the use of diuretics and insulin resistance are known to increase uric acid levels, and were implicated as major confounding factors. Subsequently, a better understanding of the biological effects of uric acid and results obtained in experimental models have prompted further research into a causative

TABLE 3. Studies assessing the relationship between hyperuricemia and the risk of new onset hypertension Author

Patients (n)

Cut-off point

Follow-up

Adjusted risk ratio

Krishnan et al., 2007 [24]

>7.0 mg/dl

6 years

HR 1.81 (95% CI, 1.59–2.07)

1 SD higher serum uric acid >7.0 mg/dl >4.6 mg/dl

3 to 21.5 years 21.5 years 8 years

RR 1.13 (95% CI, 1.06–1.20) RR 1.1 (95% CI, 1.06–1.15) OR 1.89 (95% CI, 1.26–2.82).

>7.0 mg/dl

9 years

HR 1.1 (95% CI, 1.04–1.15)

Zhang et al., 2009 [28]

3073 Normotensive men, age 35–57 yrs, nondiabetic, without metabolic syndrome 55 607 Meta-analysis 2062 Healthy men 1496 Healthy women aged 32–52 yrs 9104 Healthy, mean (range) age 53.3 (45–64) yrs 7220 General population

4 years

Shankar et al., 2006 [29] Sundstro¨m et al., 2005 [30] Bombelli et al., 2014 [22]

2520 General population 3329 General population 2051 General population

5.7 (men) 4.8 (women) 6.6 mg/dl 1 SD increase in serum uric acid 1-mg/dl increase in serum uric acid

RR 1.55 (95% CI, 1.10–2.19) for men RR 1.91 (95% CI, 1.12–3.25) for women RR 1.65 (95% CI, 1.41–1.93) OR 1.17 (95% CI, 1.02–1.33) HR 1.34 (95% CI 1.06–1.70) home hypertension HR 1.29 (95% CI 1.05–1,70) ambulatory hypertension

Grayson et al., 2011 [21] Perlstein et al., 2006 [25] Forman et al., 2009 [26] Mellen et al., 2006 [27]

10 years 4 years 16 years

CI, confidence interval; HR, hazard ratio; NC, not calculated; OR, odds ratio; RR, relative risk.

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Serum uric acid and cardiovascular risk (a) 2.00 ** *

Hazard ratios

1.50

**

1.00

0.50

0.00

280 mmol/l (women)

16 years

7 years

6.6 years

1-year

12 years

23 months

10 years

6 years

8.4 years

Gout 476 mmol/l (men) 453 mmol/l (women) History of gout, or Hyperuricemia (>7.7 mg/dl, men; >6.6 mg/dl, women) For each 59.5 mmol/l (1 mg/dl) increase 395 mmol/l (women) >362 mmol/l (men) >327 mmol/l (women)

History of gout

11.7 years 4.2 years

16.4 years

2.8 years 4.8 years

Follow up

>6.6 mg/dl >432 mmol/l (men)

Per 59.48-mmol/l increase in serum uric acid

>5.76 mg/dl Per 10-mmol/l increase in serum uric acid

Cut-off point

CV mortality All-cause mortality

CV mortality

CVD

All cause mortality

CHD

CV mortality

CV mortality

CVD MI Stroke CV mortality

AMI

CV mortality

Stroke Heart failure AMI

CV mortality CV events

CV mortality

Cardiac mortality CV events

Outcome

HR 1.54 (95% CI: 1.15 to 2.07) Note: higher uric acid levels associated with lower mortality. OR 1.12 (CI, 1.07–1.20) for all 16 studies OR 1.02 (CI, 0.91–1.14; P ¼ NS) for the eight studies with the most adjustment for confounders (8–9 factors). HR 1.17 (95% CI, 1.03–1.31) in men HR 1.25 (95% CI, 1.06–1.48) in women HR 1.22 (95% CI, 1.11–1.35), after adjustment for diuretics and CV risk factors HR 2.56 (95% CI, 2.12 -3.10) for CHD HR 1.22 (95% CI, 0.97–1.54) for ischemic stroke(P ¼ NS) HR 3.52 (95% CI, 2.47–5.01) for HF 1.22 (1.02–1.46) 1.12 (1.01–1.25)

HR 1.16 (CI 1.10–1.22)

OR 1.11 (95% CI, 1.08–1.15, P < 0.001) (gout) HR 1.68 (95% CI, 1.24–2.27) (CVD, n ¼ 515) HR 1.87 (95% CI, 1.12–3.13) (MI, n ¼ 194) HR 1.57 (95% CI, 1.11 to 2.22) (stroke, n ¼ 381) HR 1.97 (95% CI 1.08–3.59; P ¼ 0.027) for gout HR 1.08 (95% CI 0.78–1.51; P ¼ NS) for hyperuricemia

OR 1.26 (95% CI, 1.14–1.40) (hyperuricemia)

HR 1.39 (men) HR 1.59 (women) HR 1.86 (men) HR 1.70 (women) HR 1.44 (men) HR 1.90 (women) RR 1.38 (95% CI, 1.15–1.66)

HR 1.26 (95% CI, 1.16–1.36) (women) HR 1.44 (95% CI, 1.04 to 2.0) HR 1.59 (95% CI, 1.20–2.10) (Women only). Not significant after adjustment for CV risk factors

HR 1.006 (0.998–1.014), P ¼ NS (men) HR 1.013 (1–1.025), P ¼ 0.0457 (women) HR 1.09 (95% CI, 1.02–1.18) (men)

RR 3.2 HR 1.009 (0.998–1.019), P ¼ NS (population)

Adjusted risk ratio

AMI, acute myocardial infarction; CAD, coronary artery disease; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; OR, odds ratio; RR, relative risk.

13 273 History of CAD

Ndrepepa et al., 2013 [48]

Krishnan et al. 2006 [44]

Patients (n)

Author

TABLE 4. Studies assessing relationship of hyperuricemia and morbidity and/or mortality

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Serum uric acid and cardiovascular risk

antioxidant, in addition to promoting endothelial dysfunction at higher levels [50]. Thus, epidemiological data collected in recent years clearly support the association between sUA and the risk of cardiovascular disease.

PATHOPHYSIOLOGICAL ASPECTS Crystallization of uric acid leads to the formation of urate deposits in the body; however, hyperuricemia is associated with a number of effects on the vascular endothelium, vessel walls and kidney parenchyma even in absence of crystallization and deposition. As previously pointed out, uric acid can exert, along with the extracellular antioxidant activity, an intracellular pro-oxidant effect. As a consequence, hyperuricemia has a detrimental effect on the vascular endothelium. It promotes endothelial dysfunction that is ameliorated by administration of xanthine oxidase inhibitors, but not uricosuric drugs [51]. This would appear to indicate that the effect is mediated not only by uric acid but also by oxidative stress generated by xanthine oxidase activity. Lowering BP with thiazide diuretics reduces cardiovascular risk, in spite of raising sUA levels through reduced clearance of uric acid. Likewise, hyperuricemia predicts poor outcomes in patients with heart failure only if it is not associated with CKD, suggesting that the poor outcomes are associated with xanthine oxidase activity [52,53]. Oxidative stress generated by xanthine oxidase activity may have an important role in the negative effect of uric acid on the cardiovascular system [52,54]. Recent findings from the Brisighella Heart Study reveal an association between sUA and LDL oxidation, which might explain the relationship with atherosclerotic disease [55]. Thus, uric acid may serve as an important index of impaired oxidative metabolism, which at least partially mediates vascular dysfunction and promotes cardiovascular diseases. Oxidative stress from xanthine oxidase activity could be involved also in the association between hyperuricemia and hypertension. The underlying pathophysiological mechanisms responsible for the association between hyperuricemia and hypertension have been investigated in animal models. Hyperuricemia can be induced in rats through inhibition of urate oxidase with oxonic acid [56], or through fructose overfeeding, which depletes hepatocyte ATP and raises sUA by increasing the flux of adenosine nucleotides toward purine disposal [57]. Increasing sUA causes a proportional rise in BP that can be prevented or reversed with uricosuric drugs or xanthine oxidase inhibitors [58]. This finding is confirmed by recent results obtained in enterocyte-specific Glut 9-deficient mice, which developed hyperuricemia and hypertension that were reversible on treatment with allopurinol [59]. Data from these models clearly establish a temporal relationship between hyperuricemia and the onset of hypertension in the rat model, and suggest that hyperuricemia causes hypertension through a two-stage process. Initially, hyperuricemia promotes reversible, salt-insensitive hypertension through activation of the renin-angiotensin system and reduction of nitric oxide synthesis; subsequent microvascular damage to afferent arterioles leads to permanent sodium-sensitive hypertension [60]. Journal of Hypertension

Uric acid also stimulates proliferation of vascular smooth muscle cells through the renin-angiotensin system [61]. This effect appears to be facilitated by the presence of a functional urate transporter on vascular smooth muscle cells [62]. In addition, activation of the tissue RAS system leads to further activation of the xanthine oxidase and NADPH systems through a shift from the xanthine-dehydrogenase form to the xanthine oxidase form [63]. This phenomenon can impair arterial function and cause arterial stiffening, a risk factor for hypertension and cardiovascular and cerebrovascular events. Hyperuricemia is associated also with elevated markers of systemic inflammation, including C-reactive protein and tumor necrosis factor-a [64–66], as well as higher levels of serum chemokine ligand 2 and CD14þ blood monocytes [66]. In several small controlled studies, lowering sUA reduced systemic inflammation [67–72]; however, larger trials are needed to confirm these results.

URIC ACID AND THE KIDNEY About 14% of the adult population in industrialized countries suffers from CKD. Two-thirds of the population over the age of 80 years have a reduced glomerular filtration rate (GFR), defined as estimated GFR less than 60 ml/min per 1.73m2 [73]. But CKD can be present also with normal GFR, identified solely by the presence of proteinuria. The 2013 KDIGO Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease [74] show that decreased GFR and increased albuminuria are both components of CKD that can potentiate cardiovascular risk. Moreover, a guidance document produced by the American Heart Association in 2006 recommends measurement of both estimated GFR and proteinuria when determining the contribution of CKD to cardiovascular risk [75]. The association between hyperuricemia and renal disease has been known for a long time. Although early observations suggested a possible causative role for uric acid in the pathogenesis of CKD, this theory was regarded as outdated in the 1970s and 1980s, when hyperuricemia came to be considered a marker of CKD rather than a risk factor or pathophysiological factor causing it. Indeed, large studies like the National Health and Nutrition Examination Survey (NHANES) [76] and the German Chronic Kidney Disease (GCKD) study [77] show an increase in the incidence of hyperuricemia, with and without deposition, in parallel with the decline in GFR. The former study also showed that hyperuricemia with and without deposition is directly related to the degree of albuminuria. In addition to these cross-sectional studies, data from 18 prospective cohort studies in 431 000 patients revealed that hyperuricemia predicts the occurrence of CKD as well as the rate of decline in renal function [78]. Studies on the role of sUA in CKD are hampered by confounding factors such as hypertension. Hypertension can cause CKD, and the resulting reduction in GFR can subsequently lead to hyperuricemia. Moreover, pharmacotherapy with diuretics for the treatment of hypertension can increase sUA levels. However, this problem has been addressed in several recent studies that investigated the association of sUA with the onset of kidney disease in www.jhypertension.com


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healthy populations. In a 7-year prospective study of 21 475 healthy volunteers, sUA was associated with incident kidney disease (estimated GFR 30% decrease in GFR or requirement for dialysis) (HR 0.63, 95% CI, 0.5–0.78; P < 0.0001). An ongoing Japanese prospective study will test the effect of febuxostat on the slope of GFR over a 2-year period in 400 patients with stage 3 CKD and hyperuricemia without deposition [88]. Thus, hyperuricemia is common in CKD and increases in parallel with the decline in GFR and the increase in proteinuria. Data from observational studies show that increased levels of sUA predict the development and progression of CKD. Results from several interventional studies suggest that effective pharmacological treatment of hyperuricemia in patients with CKD may slow the progression of CKD, thus delaying or even preventing the need for dialysis.

INTERVENTION STUDIES Hypertension and cardiovascular disease Several interventional studies have been conducted in preclinical and clinical settings to examine the relationship between sUA and BP. Fructose feeding increases sUA levels and BP in rats, and both of these are prevented by xanthine oxidase inhibition [56]. In a randomized placebo-controlled trial of 74 healthy subjects given fructose, simultaneous administration of allopurinol, but not placebo, significantly reduced sUA levels and prevented the increase in mean arterial BP after 2 weeks [89]. Thus, this effect appears to be reproduced in humans, raising the question of whether early hypertension in humans is associated with hyperuricemia, and if so, whether this is also reversible. Feig et al. [90] have investigated the effect of sUA-lowering therapy on blood pressure in hyperuricemic adolescents with newly diagnosed, untreated mild hypertension in a small randomized controlled cross-over trial. In this proof of principle trial, allopurinol 200 mg twice daily for 4 weeks significantly reduced daytime and mean 24-h ambulatory BP compared with placebo, with 20 of 30 patients achieving normal BP, including 19 of 22 patients whose sUA was below 5.0 mg/dl after treatment with allopurinol. Exploratory endpoints of renin activity and systemic vascular resistance were also significantly decreased. This demonstrated that xanthine oxidase inhibition is associated with reduction in sUA and BP; however, questions remained about the relative roles of sUA and reactive oxygen species produced by xanthine oxidase activity, the latter being implicated as a cause of endothelial dysfunction [51]. This point was addressed in a second controlled trial in which obese adolescents with hyperuricemia and Volume 33 Number 9 September 2015



prehypertension were randomly assigned to inhibition of xanthine oxidase (allopurinol), inhibition of uric acid reabsorption (probenecid) or placebo [91]. Reduction of sUA through either mechanism resulted in similar BP responses after 7 weeks, confirming a causal link between sUA levels and BP in this young population that is independent of xanthine oxidase activity. Agarwal et al. conducted a meta-analysis of 10 studies that had assessed the effect of allopurinol on SBP and DBP (n ¼ 738) [92]. SBP decreased by 3.3 mmHg (95% CI, 1.4– 5.3; P ¼ .001) and DBP decreased by 1.3 mmHg (95% CI, 0.1–2.5; P ¼ .03) in patients treated with allopurinol compared with the control group. This finding is statistically significant, but much smaller that the results obtained in hypertensive adolescents [90]. This discrepancy is most likely because of the differences in age and in the number and duration of comorbidities between the study populations.

Surrogate cardiovascular endpoints The role of hyperuricemia in the progression of hypertension to cardiovascular disease requires clarification because the clinical data available to date are limited to surrogate endpoints. Recently, Higgins et al. [93] conducted a metaanalysis evaluating the evidence for an effect of xanthine oxidase inhibition on markers of cardiovascular function in studies reported up to June 2010. Most of the studies were small and heterogeneous in terms of design and outcomes. Meta-analysis of a subset of comparable studies for two measures of endothelial function (brachial artery flowmediated dilatation and forearm blood flow responses to acetylcholine) and circulating markers of oxidative stress showed significant favorable results for treatment with allopurinol. Subsequently, a number of controlled trials have addressed the effect of xanthine oxidase inhibition on cardiovascular markers. Xanthine oxidase -generated reactive oxygen species have been implicated as a cause of vascular oxidative stress and endothelial dysfunction, representing another mechanism through which this pathway may influence cardiovascular risk. Randomized controlled trials (RCTs) have shown that xanthine oxidase inhibitors improve endothelial function. Asymptomatic hyperuricemic patients with normal renal function and no evidence of diabetes, hypertension or cardiovascular disease were randomly assigned to receive allopurinol 300 mg/day (n ¼ 30, mean sUA 8.3 1.1 mg/dl) or no treatment (n ¼ 37) [94]. A normouricemic control group (n ¼ 30) was also included. Assessments included sUA, 24-h ambulatory blood pressure, endothelial function and estimated GFR at baseline and after 4 months of treatment. Allopurinol treatment significantly decreased sUA and BP, while improving endothelial function and estimated GFR in these healthy subjects (P < 0.05 for all parameters). The effect of allopurinol on endothelial function has been tested also in patients with optimally treated stable coronary artery disease (CAD) [95]. Allopurinol 600 mg/day was compared with placebo in a randomized, doubleblind, crossover study with 8-week treatment periods conducted in 80 patients. Endothelial function improved significantly after allopurinol treatment when assessed by Journal of Hypertension

forearm venous occlusion plethysmography (93 67% vs. 145 106%, P ¼ 0.006), flow-mediated dilation (4.2 1.8% vs. 5.4 1.7%, P < 0.001) and pulse wave analysis (2.6 7.0%, P < 0.001). Vascular oxidative stress, assessed by infusion of acetylcholine with and without vitamin C, was still present in these optimally treated patients after receiving placebo but not after receiving allopurinol treatment. Thus, even patients receiving optimal treatment for CAD have residual oxidative stress and endothelial dysfunction that is resolved by xanthine oxidase inhibition. A small study conducted in patients with severe tophaceous gout directly comparing the effects of allopurinol and febuxostat on carotid pulse wave velocity showed that, with equivalent sUA reduction, only febuxostat was able to prevent worsening of this marker of arterial stiffness [96]. The effect of allopurinol on exercise capacity in patients with confirmed CAD and chronic stable angina was investigated in a double-blind, placebo-controlled cross-over study in which 65 patients (mean SD age 64.6 9.3 y) were randomly assigned to receive allopurinol 600 mg/day, or placebo for 6 weeks [97]. This allopurinol dosage was higher than the recommended dosage for the renal function of the patients [98]. Significant improvements compared with placebo were recorded for the time to ST depression (43 s; 95% CI, 31–58; primary endpoint) time to chest pain (38 s; 95% CI, 17–55) and total exercise time (58 s; 95% CI, 45–77). The 26 patients with 1 or more angina episode per week had a trend toward reduction in episodes and nitrate use while receiving allopurinol (P ¼ 0.053 and P ¼ 0.064 respectively). Inhibition of xanthine oxidase with febuxostat or allopurinol was compared in a randomized study of 141 hyperuricemic patients undergoing cardiac surgery [99]. Both groups had a substantial reduction in sUA, but only the febuxostat group had significant reductions in serum creatinine, urinary albumin, cystatin-C and oxidized lowdensity lipoprotein, SBP, pulse wave velocity and left ventricular mass index.

Left ventricular hypertrophy Left ventricular hypertrophy is a strong predictor of cardiovascular and cerebrovascular outcomes and is highly prevalent in a number of conditions, including CKD, hypertension, diabetes and CAD. Recently, the group of Struthers have conducted a series of randomized doubleblind, placebo-controlled, parallel group studies investigating the effect of allopurinol on endothelial function and left ventricular hypertrophy in patients with stage 3 CKD [100], type 2 diabetes [101] and CAD [102]. In each of these studies, 66 or 67 patients were enrolled and treatment lasted 9 months. The primary outcome was change in left ventricular mass measured by cardiac magnetic resonance imaging; other outcomes included endothelial function evaluated by brachial artery flow-mediated dilatation and arterial stiffness assessed by pulse-wave analysis. Small but statistically significant regression of left ventricular mass index was recorded in all three treated populations after 9 months: (CDK, allopurinol 1.42 4.67 g/m2 vs. placebo þ1.28 4.45 g/m2, P ¼ 0.036; type 2 diabetes, allopurinol 1.32 2.84 g/m2 vs. placebo group þ0.65 3.07 g/m2, www.jhypertension.com


1737

Borghi et al.

P ¼ 0.017; CAD, allopurinol 2.2 2.78 g/m2 vs. placebo 0.53 2.5 g/m2, P ¼ 0.023). Significant improvements in endothelial function and arterial stiffness were only recorded in the CKD and CAD studies. The reported regression of left ventricular mass was smaller than has been seen in trials of hypertensive drugs.

Heart failure Hyperuricemia is associated with increased risk of all-cause mortality in patients with heart failure [103]. A retrospective case–control analysis of patients with symptomatic heart failure (14 327 events consisting of heart failure, readmission or all cause mortality) revealed that hyperuricemia was significantly associated with increased events, whereas allopurinol use was associated with a reduction in events (adjusted RR, 0.69; 95% CI, 0.60–0.79) and the association between gout and events was no longer significant among patient receiving allopurinol [104]. Thus, xanthine oxidase inhibition may be associated with better heart failure outcomes in hyperuricemic patients. Indeed, several small controlled interventional studies have shown an improvement in peripheral endothelial function in patients with heart failure receiving allopurinol [105,106]. However, lowering uric acid with the uricosuric benzbromarone in patients with heart failure was not effective at improving hemodynamic impairment [71].

IMPORTANT QUESTIONS Is hyperuricemia an independent risk factor for cardiovascular disease? Data supporting sUA as an independent risk factor are now very strong. Hyperuricemia may account for at least part of the excess risk not explained by traditional risk factors. In fact, the increase in cardiovascular risk associated with sUA is clinically relevant, for example in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, the impact was greater than that of age or BP [22]. sUA predicts also a number of conditions themselves associated with high cardiovascular risk, including hypertension, hyperinsulinemia, organ damage and obesity.

What threshold should be adopted to define hyperuricemia? The official definition of hyperuricemia is still disputed. The 2013 ESH/ESC Hypertension guidelines [107] recommend routine measurement of sUA in profiling patients; however, this parameter is not considered in the algorithm for assessing total cardiovascular risk, and a cut-off value has not been indicated. It is the opinion of the members of this Board of Experts that this lack represents a source of misunderstanding for all Healthcare Professionals (clinical and laboratory physicians primarily) and a potential danger for patients. Our analysis of the available data on this topic points to 6 mg/dl as the most clinically meaningful cut-off, above which there is a substantial increase in cardiovascular and renal risk; however, receiver-operating characteristic analysis of data from the PAMELA study identified an even lower sUA value, in the range of 5 mg/dl (somewhat lower for women) [22]. 1738


Can we improve cardiovascular and renal outcomes by lowering sUA levels? Uncontrolled studies have shown a reduction in cardiovascular risk associated with uric acid-lowering therapy [108]. An interesting retrospective study conducted on 200 Korean patients with a mean follow-up of 7.6 years showed a significant reduction in incident hypertension, type II diabetes and cardiovascular disease in patients with hyperuricemia with deposition that had been properly treated to a cut-off value of 6 mg/dl [109]. The available literature suggest that the best therapeutic approach to obtaining cardiovascular and renal benefits through sUA lowering is through xanthine oxidase inhibition, rather than uricosuric drugs, probably because of the concomitant inhibition of reactive oxygen species production and consequent antioxidant effect of these compounds. In this light, allopurinol and febuxostat can be considered the most appropriate choices.

When should urate-lowering therapy be started? Currently, there is no evidence from RCTs to support treatment of asymptomatic hyperuricemics, even though both xanthine oxidase inhibitors are indicated in this setting in some countries [110]. In Europe, no urate-lowering drug has been approved for the management of asymptomatic hyperuricemia; however, the increasing body of data suggesting efficacy of urate-lowering therapy on outcomes other than gout flares may lead to considering treatment even in the absence of overt gout when hyperuricemia accompanies other cardiovascular risk factors. Large controlled studies are needed to formally establish the effect of sUA lowering on hard cardiovascular and renal endpoints. The ongoing Febuxostat for Cerebral and caRdiorenovascular Events prEvEntion stuDy (FREED; ClinicalTrials.gov Identifier: NCT01984749) is investigating the effect of xanthine oxidase inhibition on cardiovascular and renal endpoints in elderly hyperuricemic patients. Results are expected in late 2017. Meanwhile, studies conducted with surrogate endpoints could provide useful information and resolve some of these questions. Clinically validated intermediate endpoints that provide reproducible, short-term treatment-related effects should be considered. Examples could include carotid-femoral pulse wave velocity [96] or blood pressure [90,91] and protective effects on renal parameters [86,87].

ACKNOWLEDGEMENTS We wish to thank Richard Vernell, an independent medical writer acting on behalf of Springer Healthcare Communications, for medical writing assistance. This assistance was supported by A.menarini Farmaceutica Internazionale sri.

Conflicts of interest C.B. has received speaking fees from Novartis, Amgen, Servier, Stroder, Ely-Lilly and is a member of advisory boards for Amgen, Sanofi, Takeda, Menarini, Servier and Novartis. Volume 33 Number 9 September 2015



E.A.R. has received speaking fees from Menarini, Recordati, Stroder, Servier and has received research funds from Novartis, Recordati, Stroder. T.B. is a consultant or speaker for AstraZeneca, Ipsen Pharma, Menarini, Novartis, Swedish Orphan Biovitrum and Takeda A.D. has received speaking fees from Servier and Menarini. J.T.K. has received speaking fees from Berlin-Chemie. F.P.R. is a consultant or speaker for AstraZeneca, Menarini, Pfizer, Novartis, and Swedish Orphan Biovitrum. G.M. is a consultant for Boehringer Ingelheim, and has received speaking fees from Bayer AG, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Menarini, Merck & Co, Novartis, Recordati, Servier, and Takeda. The other authors report no conflicts of interest.

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Reviewer’s Summary Evaluation Reviewer 2 This is a timely and interesting review on the role of sUA for associations with hypertension, metabolic syndrome and markers of cardiovascular disease. The problem, however,


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is that we lack data from randomized controlled trials when sUA is targeted with drug interventions. Before this is available, there is doubt about the causality of sUA for the observed associations. Furthermore, genetic studies based on Mendelian randomization methods have not been supportive of a casual role for sUA in the pathogenesis of cardiovascular disease.



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