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
only from a rheumatologic standpoint, but also in terms of

Substantial evidence suggests that chronic hyperuricemia is cardiovascular and renal risk.
an independent risk factor for hypertension, metabolic The threshold above which uricemia becomes ‘abnor-
syndrome, chronic kidney disease (CKD) and cardiovascular mal’ is still disputed: a statistical approach assesses the
diseases. This highlights the need for greater attention to reference range of sUA and its variation among healthy
serum uric acid levels when profiling patients, and individuals; a pathophysiological approach uses the super
suggests that the threshold above which uricemia is saturation concentration of uric acid, 6.8 mg/dl at 378C, as a
considered abnormal is 6 mg/dl, in light of the available cut-off value. The therapeutic target of 6 mg/dl (360 mmol/l)
evidence. Another important question is whether lowering indicated by guidelines for management of gout [2] seems to
serum uric acid can improve cardiovascular and renal be the most appropriate for this purpose. However, the
outcomes, and what therapeutic mechanism of action clinically relevant sUA concentration needs to be revised in
could provide more clinical benefits to patients; the light of recent findings.
available literature shows a trend toward improvement This article presents considerations on the appropriate
associated with administration of urate-lowering drugs, in sUA value to serve as the threshold for defining clinical
particular for the xanthine oxidase inhibitors. The hyperuricemia. The consensus-building process was con-
demonstrated efficacy of urate-lowering therapy on ducted by a board of European investigators of different
outcomes other than gout flares leads to the consideration aspects of uric acid-dependent diseases.
that treatment may be beneficial even in the absence of
overt gout when hyperuricemia accompanies other clinical
BIOCHEMISTRY OF URIC ACID
conditions, such as urate deposition, advanced CKD or
cardiovascular risk factors. Hominids have lost expression of the gene encoding uri-
Keywords: cardiovascular disease, hyperuricemia, renal case, the enzyme that converts uric acid to the more soluble
disease, serum uric acid molecule, allantoin in other mammals. Whereas this may
have been advantageous as a means to favor the formation
Abbreviations: CAD, coronary artery disease; CKD, of adipose tissue from fructose [3], the increased availability
chronic kidney disease; GFR, glomerular filtration rate; of nutrients in modern societies may be responsible for
sUA, serum uric acid; XO, xanthine oxidase raising sUA levels [4], and predisposing to excessive fat
storage, insulin resistance and hypertension [3].
Uric acid is the end-product of purine metabolism.
INTRODUCTION Purines are generated through two pathways: de novo
U
ric acid has long been considered an inert end-
product of purine catabolism; however, a substan-
Journal of Hypertension 2015, 33:1729–1741
tial and increasing body of evidence suggests that
a
chronic hyperuricemia, in addition to causing deposition of Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,
b
Department of Clinical and Experimental Sciences, University of Brescia, Department
urate crystals in the body, is an independent risk factor for of Medicine, Spedali Civili, Brescia, Italy, cAssistance Publique Hôpitaux de Paris,
the development of hypertension, as well as for the risk of Hôpital Lariboisière, dUniversité Paris Diderot, Sorbonne Paris Cité, eINSERM, UMR
metabolic syndrome, chronic kidney disease (CKD) and 1132, Paris, France, fInstitute of Cardiovascular and Medical Sciences, College
of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK,
cardiovascular diseases. g
Department of Nephrology and Hypertension, Hannover Medical School,
The average levels of serum uric acid (sUA) in the Hannover, Germany, hCardiology Department, Asklepeion Hospital, Athens, Greece,
i
Rheumatology Division, Hospital Universitario Cruces and Biocruces Health Research
general population are increasing over time [1]. This is Institute, Vizcaya, Spain and jUniversità Milano-Bicocca, IRCCS Istituto Auxologico
mainly attributable to dietary changes, increasing BMI Italiano, Milan, Italy
and improved life expectancy both in the general popu- Correspondence to Giuseppe Mancia, Università Milano-Bicocca, IRCCS Istituto
lation and in patients with CKD and congestive heart fail- Auxologico Italiano, Milan, Italy, P.za dei Daini, 4, 20126 Milan, Italy. Tel: +39 039
233 3357; fax: +39 039 322274; e-mail: giuseppe.mancia@unimib.it
ure. Hyperuricemia, and the associated range of
Received 10 February 2015 Revised 11 June 2015 Accepted 11 June 2015
pathological conditions, is thus becoming a highly preva-
J Hypertens 33:1729–1741 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights
lent condition. These considerations point to the need for reserved.
greater attention to sUA levels when profiling patients, not DOI:10.1097/HJH.0000000000000701
Journal of Hypertension www.jhypertension.com 1729
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Borghi et al.
synthesis from nonpurine compounds, regulated by phos- In Mendelian randomization studies, a genotype associ-
phoribosyl-pyrophosphate synthetase, and the purine ated with the risk factor of interest is used as an instrumental
salvage pathway, regulated by hypoxanthine-xanthine variable. This approach accounts for potential confounders
phosphoribosyl-transferase. Dietary factors and endogenous and reverse causality. A study by Palmer et al. [12] found no
processes with high cell turnover may increase sUA levels. association between a single nucleotide polymorphism
Uric acid has been described as an oxygen radical (SNP) in the SLC2A9 gene that accounted for approximately
scavenger [5]. In contrast to this proposed beneficial role 2% of the variability in sUA levels and ischemic heart
of uric acid, an increased risk of total and cardiovascular disease or blood pressure (BP) level in two large Danish
mortality in subjects with elevated serum uric acid levels is cohorts. Further, a study by Oikonen et al. [13] found no
well documented. This dual role has been described as the association between a different SNP in the SLC2A9 gene and
‘uric acid paradox,’ whereby this substance would act as carotid intima-media thickness. These findings are in con-
antioxidant or pro-oxidant depending on the intracellular trast to a study by Kleber et al. [14] wherein a genetic risk
or extracellular localization, and interactions with other score for high uric acid including eight gene variants was
factors. Catabolism of purines is regulated mainly by xan- related with cardiovascular death. Moreover, in a study by
thine-oxidoreductase, which converts hypoxanthine to Mallamaci et al. [15], a different SNP in the SLC2A9 gene was
xanthine, and xanthine to uric acid. Xanthine-oxidoreduc- associated with higher serum uric acid and higher SBP. This
tase exists in two interconvertible isoforms: xanthine was in agreement with a careful analysis of an Amish cohort
dehydrogenase and xanthine oxidase. Xanthine oxidase that revealed an association between a variant of the
uses molecular oxygen as an electron acceptor, thus gen- SLC2A9 gene and hypertension [16]. In a study by Hughes
erating superoxide anion and other reactive oxygen species et al. [17], a uric acid genetic risk score was associated with
as by-products. Xanthine oxidase is over-expressed in improved renal function. However, in a further genetic risk
inflamed and ischemic tissues [6]. This mechanism, together score study, Sedaghat et al. [18] found 30 gene variants that
with the pro-oxidant effect of urate described previously, were associated with increased serum uric acid but with
could explain the negative impact of elevated sUA on lower blood pressure. In that study, the results were sensi-
cardiovascular events. tive to diuretic therapy, and there was no relationship
Uric acid is eliminated through both renal and intestinal between a SLC2A9 SNP and BP in patients not treated with
excretion. The relevant renal and intestinal transporters of diuretics. However, each of the involved genes has a
uric acid have been characterized over the last decade [7]. modest effect on sAU variance and results must be taken
Inefficient renal excretion of uric acid is the main cause of with some caution, as studies may be underpowered unless
both primary and secondary hyperuricemia in patients with very large cohorts are examined.
gout [8]. Reduced intestinal excretion of uric acid associated These genetic studies suggest that the relationship
to polymorphisms of the ABCG2 gene appears to contribute between uric acid and cardiovascular disease is complex,
to a ‘pseudo-overproduction’ phenotype [9]. potentially confounded, and modified by other treatments
for cardiovascular disease and may differ across the spec-
GENETIC AND ENVIRONMENTAL trum of cardiovascular disease. This highlights the need for
rigorous well designed studies exploring the effect of uric
FACTORS ASSOCIATED WITH SERUM acid reduction in defined groups, with attention to
URIC ACID LEVEL concurrent treatments.
A small number of monogenic disorders are associated with Environmental factors associated with uric acid levels
hyperuricemia and deposition of mono sodium urate crys- include diet and prescribed drugs, and levels are associated
tals. These include activating mutations in the phosphor- with numerous cardiovascular risk factors. Several drugs
ibosyl pyrophosphate synthetase gene, inactivating lower sUA levels, in particular in patients with hyperurice-
mutations in the hypoxanthine guanine phosphoribosyl mia that is accompanied by deposition. These include
transferase gene (Lesch-Nyhan syndrome) and mutations uricosuric drugs such as probenecid, benzbromarone
in the uromodulin gene. Numerous candidate genes have and sulfinpyrazone and the xanthine oxidase inhibitors
been reported to be involved in regulation of sUA levels via allopurinol and febuxostat. Numerous other drugs have
genome-wide association studies. In these studies to date, secondary effects on sUA levels. These include antihyper-
26 were identified and replicated via genome-wide associ- tensive drugs, cholesterol-lowering drugs, steroid medi-
ation analysis and a further two via pathway analysis [10]. cation, some nonsteroidal anti-inflammatory drugs and
An association with four additional candidate genes has some antibiotics (Table 2).
been reported in other studies [11] (Table 1). The pro- Dietary factors known to increase sUA levels include
portion of variance in sUA explained by these genes is higher intake of meat, seafood, fructose, alcohol and
approximately 5–7%. Candidate genes encode either urate sodium. Factors associated with lower sUA levels are
transporters, proteins involved in glucose metabolism and increasing ascorbic acid intake and consumption of coffee
insulin response, proteins that interact with urate trans- and dairy products.
porters, transcription factors or growth factors or gene
products of unknown or poorly described function with EPIDEMIOLOGICAL ASPECTS
an unclear relationship with uric acid regulation. Mendelian
randomization and genetic risk score studies have given The prevalence of hyperuricemia
conflicting results regarding the causality of uric acid in As already mentioned, the definition of hyperuricemia
cardiovascular disease. varies among studies, making comparisons between them
1730 www.jhypertension.com 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 Gene Product Putative role in regulation of urate level
a
A1CF APOBEC1 complementation factor Unknown
ABCG2a ATP Binding Cassette B member 2 Urate transporter
ARNTa Aryl hydrocarbon receptor nuclear translocator Unknown, interacts with transcription factors
ATXN2a Ataxin 2 protein Unknown
BAZ1Ba Bromodomain protein Unknown
BCAS3a Unknown Unknown
GCKRa Glucokinase regulatory (inhibitory) protein Unknown, role in glucose metabolism
HLFa Proline and acidic rich transcriptor factor family Unknown, transcription factor
HNF4Ga Hepatocyte nuclear factor 4 Growth factor
IGF1Ra Insulin like growth factor 1 receptor Unknown, role in glucose metabolism
INHBBa Activin B Unknown
INHBEa Beta chain of inhibin Unclear, TGF-B superfamily
LRRC16Ab Leucine rich repeat containing 16A Unknown
MAFa MAF protein Unknown, transcription factor
NFAT5a Nuclear factor of activated T cells 5 Unknown, role in glucose metabolism
NRXN2b Neurexin family protein Unknown, cellular adhesion molecule
ORC4La Origin recognition complex subunit 4 Unknown
OVOL1a OVOL 1 protein Unknown, putative trabscription factor
PDZK1a PDZ domain containing 1 protein (scaffolding protein) May interact with urate transporters
PKD2b Polycystin 2 Unknown
PRKAG2a 5’AMP activated protein kinase subunit gamma 2 Unknown, role in glucose metabolism
QRICH2a Glutamine rich protein 2 Unknown
RREB1a Ras responsive element binding protein Unknown, transcription factor
SFMBT1a SCM-like protein with four MBT domains Unknown
SLC16A9a Monocarboxylic acid transporter 9 Unknown, role in glucose metabolism
SLC17A1b NPT1 (renal sodium phosphate transporter protein 1) Urate transporter
SLC17A3a NPT4 (renal sodium phosphate transporter protein 1) Urate transporter
SLC22A11a Solute carrier family 11 r (related to URAT1) Urate transporter
SLC22A12a URAT1 Urate transporter
SLC22A7a Organic anion transporter 2 (OAT2)
SLC2A9a GLUT 9 Urate transporter
STC1a Stanniocalcin 1 Unknown
TMEM171a Transmembrane protein Unknown, putative growth factor
TRIM46a TRIM46 Protein Unknown, Incorporates a motif associated with microtubule binding.
UBE2Q2a Ubiquitin conjugating enzyme member 2 Unknown
VEGFAa VEGFA 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 than non-African Americans (25.7 vs 22.1%) [1]. A clear
has been reported in certain aboriginal populations of the signal of increasing prevalence of hyperuricemia was
pacific regions, with highest values (41.4 and 11.7% respect- recently reported in an Italian survey, where the pro-
ively) found in Taiwanese aboriginals [19]. The estimated portion, using a cut-off of 6 mg/dl (360 mmol/l), was
prevalence of hyperuricemia from the US National Health 8.5% in 2005 and had increased to 11.9% in 2009 [20]. This
and Nutrition Examination Survey (NHANES) 2007–2008 is has important implications because hyperuricemia is
approximately 23%, somewhat higher in African Americans strongly associated with a number of cardiovascular risk
TABLE 2. Drugs that influence serum uric acid levels

Drug Name Effect on serum uric acid Magnitude of effect Mechanism of effect
Losartan # 20–25% # Uricosuric effect
Diuretics " 6–19% " " Uric acid reabsorption in proximal tubule
Beta-blockers " 6–9% " Unclear
ACE inhibitors $(but attenuates rise caused by diuretics) – Uricosuric effect
Calcium channel blockers # 3–10% # Uricosuric effect
Alpha blockers $ – –
HmG CoA reductase inhibitorsa # 3.6–12% # Uricosuric effect
Fenofibrate # 20% # Presumed inhibition of URAT 1 transporter
Acetylsalicylic acid " at low doses, #at higher doses 6% " with low doses 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.

Borghi et al.
factors including the components of the metabolic syn- well as adult life [SBP (r ¼ 0.29; P 0.0001) and DBP
drome, of which it was formerly a part. These associations (r ¼ 0.28; P 0.0001)] [32].
are evident at sUA levels well below the saturation con- Thus, hyperuricemia is clearly associated with the onset
centration of monosodium urate. 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
Hyperuricemia and new onset of hypertension hypertension, thereby indirectly effecting cardiovascular
Epidemiological evidence supporting an association risk.
between sUA and the incidence of hypertension is consist-
ent. A large number of observational studies have revealed Hyperuricemia and cardiovascular disease
an increase in the relative risk of hypertension with increas- Hyperuricemia correlates strongly with cardiovascular risk.
ing levels of sUA, and this association is clearly independent Higher levels are associated with the incidence and pro-
of traditional risk factors (major studies are summarized in gression of a wide variety of microvascular and macro-
Table 3) [21,22,24–31]. vascular diseases. Recently, a study conducted in 15 773
Grayson et al. [21] have conducted a meta-analysis of 18 participants in the Third National Health and Nutrition
prospective cohort studies of subjects who were normo- Examination Survey (NHANES) revealed an increased risk
tensive at baseline (n ¼ 55 607). The pooled adjusted of total mortality and cardiac mortality with increasing sUA
relative risk for incident hypertension in subjects with levels. The increase in hazard ratio (95% CI) per 59.5 mmol/l
hyperuricemia was 1.41 [95% confidence interval (CI) of sUA was 1.32 (1.25–1.38), and remained 1.15 (1.08–1.21)
1.23–1.58] and further data later showed hyperuricemia even after extensive adjustment for demographic factors,
to be independently predictive of new-onset hypertension comorbidities and other risk factors [33]. This is reflected
as diagnosed by ambulatory and home BP, that is BP also in cardiovascular and total mortality associated with
elevations with a greater adverse prognostic value than uric acid deposition (Fig. 1). However, establishing
office values [22]. Analysis of age and sex strata showed a whether sUA is an independent risk factor has been com-
stronger association in younger subjects and in women, the plicated by interactions between sUA levels and kidney
stronger association in younger subjects possibly resulting function.
from the presence of fewer confounding risk factors in this Analysis published in 1999 of data from 6763 subjects in
population. An early effect of hyperuricemia in the devel- the Framingham Heart Study cohort did not reveal a sig-
opment of hypertension is also suggested by the results of a nificant association between uric acid levels and the inci-
study of 125 children (mean age 13.4 3.3 years) with dence of CHD or cardiovascular mortality after adjustment
untreated newly diagnosed hypertension and normal renal for cardiovascular risk factors [34]. The authors indicated
function [23]. sUA was directly correlated with SBP and DBP that the observed lack of association between uric acid and
(r ¼ 0.80, P ¼ 0.0002 and r ¼ 0.66, P ¼ 0.0006, respectively). cardiovascular endpoints was likely because of the close
The mean sUA in children with primary hypertension association between uric acid and known risk factors. In
(n ¼ 63) was 6.7 mg/dl, whereas that for children with white particular, decreased glomerular filtration rate (GFR), the
coat hypertension confirmed with ambulatory monitoring use of diuretics and insulin resistance are known to increase
(n ¼ 22) was 3.5 mg/dl, and comparable with normal con- uric acid levels, and were implicated as major confounding
trol children (n ¼ 40) 3.6 mg/dl. Longitudinal data from the factors.
Bogalusa Heart Study indicate that hyperuricemia in child- Subsequently, a better understanding of the biological
hood is associated with hypertension in both childhood effects of uric acid and results obtained in experimental
[SBP (r ¼ 0.31; P 0.0001); DBP (r ¼ 0.20; P 0.0001)] as 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] 3073 Normotensive men, >7.0 mg/dl 6 years HR 1.81 (95% CI, 1.59–2.07)
age 35–57 yrs, nondiabetic,
without metabolic syndrome
Grayson et al., 2011 [21] 55 607 Meta-analysis 1 SD higher serum uric acid 3 to 21.5 years RR 1.13 (95% CI, 1.06–1.20)
Perlstein et al., 2006 [25] 2062 Healthy men >7.0 mg/dl 21.5 years RR 1.1 (95% CI, 1.06–1.15)
Forman et al., 2009 [26] 1496 Healthy women >4.6 mg/dl 8 years OR 1.89 (95% CI, 1.26–2.82).
aged 32–52 yrs
Mellen et al., 2006 [27] 9104 Healthy, mean (range) >7.0 mg/dl 9 years HR 1.1 (95% CI, 1.04–1.15)
age 53.3 (45–64) yrs
Zhang et al., 2009 [28] 7220 General population 5.7 (men) 4 years RR 1.55 (95% CI, 1.10–2.19) for men
4.8 (women) RR 1.91 (95% CI, 1.12–3.25) for women
Shankar et al., 2006 [29] 2520 General population 6.6 mg/dl 10 years RR 1.65 (95% CI, 1.41–1.93)
Sundström et al., 2005 [30] 3329 General population 1 SD increase in serum uric acid 4 years OR 1.17 (95% CI, 1.02–1.33)
Bombelli et al., 2014 [22] 2051 General population 1-mg/dl increase in serum uric acid 16 years HR 1.34 (95% CI 1.06–1.70)
home hypertension
HR 1.29 (95% CI 1.05–1,70)
ambulatory hypertension
CI, confidence interval; HR, hazard ratio; NC, not calculated; OR, odds ratio; RR, relative risk.

(a)
2.00
**
*
1.50
**
Hazard ratios
1.00
0.50
0.00
<256 256 to <309 309 to <357 >357
With gout 0.93 1.57 1.64* 1.77**
No gout 1.00 0.99 1.09 1.37**
Serum uric acid (quartiles)
(b)
2.50
**
2.00
*
Hazard ratios
1.50
*
1.00
0.50
0.00
<256 256 to <309 309 to <357 >357
With gout 0.82 2.00 1.80* 2.09**
No gout 1.00 0.92 1.09 1.33*
Serum uric acid (quartiles)

FIGURE 1 Associations of serum uric acid and gout with total mortality (a) and cardiovascular mortality (b) in the general population. P < 0.05, P < 0.01 for comparisons
with a reference group (uric acid <256 mmol/l and no gout). Data are adjusted for age, sex, race, comorbid conditions and BMI. (Redrawn with permission from [33]).
role of uric acid in hypertension and cardiovascular disease diuretic use, metabolic syndrome and other established
[35]. Numerous epidemiological studies have now inves- cardiovascular risk factors [44]. Importantly, this association
tigated the link between hyperuricemia and the incidence was still observed in the subgroup not receiving diuretics.
of major cardiovascular endpoints. A majority of those Bos et al. [45] monitored for incident myocardial infarc-
studies support an independent association between both tion or stroke in 4385 middle-aged participants in the
sUA and hypertension, as well as between sUA and car- Rotterdam Study without history of myocardial infarction
diovascular disease. It is also clear that these associations or stroke at baseline. After a mean follow-up of 8.4 years,
are stronger in women and appears to be stronger also in incident CVD, myocardial infarction and stroke were found
younger patients and those with fewer cardiovascular risk to be independently associated with sUA. A much larger
factors. Larger studies are summarized in Table 4 cohort study conducted in Taiwan assessed cardiovascular
[22,33,34,36,38–50]. A meta-analysis has shown that studies mortality among 354 110 patients without gout who had
adjusting for more factors show less or no significant data on sUA levels at baseline [50]. After 7 years of follow-
association [36]. In fact, the issue of adjustment should up, hazard ratios for mortality were estimated in predefined
be reassessed in light of new understanding of the potential sUA strata. The adjusted incidence of mortality was higher
role of sUA as a causal agent in cardiovascular disease and in both low sUA and high sUA strata, assuming a U-shaped
its strong interaction, for example, with components of the curve. Using the third stratum as a reference [relative risk
metabolic syndrome. (RR) 1.00], the incidence of coronary heart disease and heart
Krishnan et al. analyzed data on the incidence of myo- failure was significantly higher in the highest stratum,
cardial infarction in 12 866 men in the Multiple Risk Factor hazard ratio (HR) 2.56 (95% CI, 2.12–3.10) and HR 3.52
Intervention Trial, and found a modest association with (95% CI, 2.47–5.01) respectively. The biphasic association
hyperuricemia and gout after adjustment for renal function, may indicate that uric acid plays an important role as an

1734
TABLE 4. Studies assessing relationship of hyperuricemia and morbidity and/or mortality
Borghi et al.
Author Patients (n) Cut-off point Follow up Outcome Adjusted risk ratio
Wong et al., 2002 [37] 354 Stroke survivors >5.76 mg/dl 2.8 years Cardiac mortality RR 3.2
Høieggen et al., 2004 [38] 9193 Hypertension Per 10-mmol/l increase 4.8 years CV events HR 1.009 (0.998–1.019), P ¼ NS (population)
in serum uric acid
HR 1.006 (0.998–1.014), P ¼ NS (men)
HR 1.013 (1–1.025), P ¼ 0.0457 (women)
Fang and Alderman, 2000 [39] 5926 General population Per 59.48-mmol/l increase 16.4 years CV mortality HR 1.09 (95% CI, 1.02–1.18) (men)
in serum uric acid
HR 1.26 (95% CI, 1.16–1.36) (women)
Meisinger et al., 2008 [40] 3604 General population >6.6 mg/dl 11.7 years CV mortality HR 1.44 (95% CI, 1.04 to 2.0)
www.jhypertension.com
Skak-Nielsen et al., 2013 [41] 9742 Obese or overweight >432 mmol/l (men) 4.2 years CV events HR 1.59 (95% CI, 1.20–2.10) (Women only).
with diabetes and/or CVD Not significant after adjustment for CV risk factors
>395 mmol/l (women)
Holme et al., 2009 [42] 417 734 general population >362 mmol/l (men) 11.8 years Stroke HR 1.39 (men)
>327 mmol/l (women) Heart failure HR 1.59 (women)
AMI HR 1.86 (men)
HR 1.70 (women)
HR 1.44 (men)
HR 1.90 (women)
Choi and Curhan, 2007 [43] 51 297 Prospective cohort History of gout 12 years CV mortality RR 1.38 (95% CI, 1.15–1.66)
of male health professionals
Krishnan et al. 2006 [44] 12 866 Framingham Hyperuricemia 7.0 mg/dl 6.5 years AMI OR 1.26 (95% CI, 1.14–1.40) (hyperuricemia)
CV risk in upper 15%
Gout OR 1.11 (95% CI, 1.08–1.15, P < 0.001) (gout)
Bos et al., 2006 [45] 4385 No history of stroke or CHD 476 mmol/l (men) 8.4 years CVD HR 1.68 (95% CI, 1.24–2.27) (CVD, n ¼ 515)
453 mmol/l (women) MI HR 1.87 (95% CI, 1.12–3.13) (MI, n ¼ 194)
Stroke HR 1.57 (95% CI, 1.11 to 2.22) (stroke, n ¼ 381)
Kuo 2010 [46] 61 527 General population History of gout, or 6 years CV mortality HR 1.97 (95% CI 1.08–3.59; P ¼ 0.027) for gout
Hyperuricemia (>7.7 mg/dl, HR 1.08 (95% CI 0.78–1.51; P ¼ NS) for hyperuricemia
men; >6.6 mg/dl, women)
Stack 2013 [33] 15 773 General population For each 59.5 mmol/l 10 years CV mortality HR 1.16 (CI 1.10–1.22)
(1 mg/dl) increase
Latif et al., 2011 [47] 5827 Chronic hemodialysis <8.2 mg/dl 23 months CV mortality HR 1.54 (95% CI: 1.15 to 2.07)
Note: higher uric acid levels associated with lower mortality.
Wheeler 2005 [36] 9458 Meta-analyses >339 mmol/l (men) 12 years CHD OR 1.12 (CI, 1.07–1.20) for all 16 studies
>280 mmol/l (women) OR 1.02 (CI, 0.91–1.14; P ¼ NS) for the eight studies
with the most adjustment for confounders (8–9 factors).
Ndrepepa et al., 2013 [48] 13 273 History of CAD >7.0 mg/dl (men) 1-year All cause mortality HR 1.17 (95% CI, 1.03–1.31) in men
>5.7 mg/dl (women) HR 1.25 (95% CI, 1.06–1.48) in women
Alderman et al., 1999 [49] 7978 Mild-to-moderate hypertension >0.447 mmol/l 6.6 years CVD HR 1.22 (95% CI, 1.11–1.35), after adjustment for
diuretics and CV risk factors
Kuo et al., 2013 [50] 354 110 No history of gout 0.66 mmol/l 7 years CV mortality 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
Bombelli et al. 2014 [22] 2051 General population 1-mg/dl increase in uricemia 16 years CV mortality 1.22 (1.02–1.46)
All-cause mortality 1.12 (1.01–1.25)
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.
Volume 33 Number 9 September 2015

antioxidant, in addition to promoting endothelial dysfunc- Uric acid also stimulates proliferation of vascular smooth
tion at higher levels [50]. muscle cells through the renin-angiotensin system [61]. This
Thus, epidemiological data collected in recent years effect appears to be facilitated by the presence of a func-
clearly support the association between sUA and the risk tional urate transporter on vascular smooth muscle cells
of cardiovascular disease. [62]. In addition, activation of the tissue RAS system leads to
further activation of the xanthine oxidase and NADPH
PATHOPHYSIOLOGICAL ASPECTS systems through a shift from the xanthine-dehydrogenase
form to the xanthine oxidase form [63]. This phenomenon
Crystallization of uric acid leads to the formation of urate can impair arterial function and cause arterial stiffening,
deposits in the body; however, hyperuricemia is associated a risk factor for hypertension and cardiovascular and
with a number of effects on the vascular endothelium, cerebrovascular events.
vessel walls and kidney parenchyma even in absence of Hyperuricemia is associated also with elevated markers
crystallization and deposition. As previously pointed out, of systemic inflammation, including C-reactive protein and
uric acid can exert, along with the extracellular antioxidant tumor necrosis factor-a [64–66], as well as higher levels of
activity, an intracellular pro-oxidant effect. As a con- serum chemokine ligand 2 and CD14þ blood monocytes
sequence, hyperuricemia has a detrimental effect on the [66]. In several small controlled studies, lowering sUA
vascular endothelium. It promotes endothelial dysfunction reduced systemic inflammation [67–72]; however, larger
that is ameliorated by administration of xanthine oxidase trials are needed to confirm these results.
inhibitors, but not uricosuric drugs [51]. This would appear
to indicate that the effect is mediated not only by uric acid URIC ACID AND THE KIDNEY
but also by oxidative stress generated by xanthine oxidase
activity. Lowering BP with thiazide diuretics reduces car- About 14% of the adult population in industrialized
diovascular risk, in spite of raising sUA levels through countries suffers from CKD. Two-thirds of the population
reduced clearance of uric acid. Likewise, hyperuricemia over the age of 80 years have a reduced glomerular filtration
predicts poor outcomes in patients with heart failure only if rate (GFR), defined as estimated GFR less than 60 ml/min
it is not associated with CKD, suggesting that the poor per 1.73m2 [73]. But CKD can be present also with normal
outcomes are associated with xanthine oxidase activity GFR, identified solely by the presence of proteinuria. The
[52,53]. Oxidative stress generated by xanthine oxidase 2013 KDIGO Clinical Practice Guidelines for the Evaluation
activity may have an important role in the negative effect and Management of Chronic Kidney Disease [74] show that
of uric acid on the cardiovascular system [52,54]. Recent decreased GFR and increased albuminuria are both com-
findings from the Brisighella Heart Study reveal an associ- ponents of CKD that can potentiate cardiovascular risk.
ation between sUA and LDL oxidation, which might explain Moreover, a guidance document produced by the American
the relationship with atherosclerotic disease [55]. Thus, uric Heart Association in 2006 recommends measurement of
acid may serve as an important index of impaired oxidative both estimated GFR and proteinuria when determining the
metabolism, which at least partially mediates vascular dys- contribution of CKD to cardiovascular risk [75].
function and promotes cardiovascular diseases. The association between hyperuricemia and renal dis-
Oxidative stress from xanthine oxidase activity could be ease has been known for a long time. Although early
involved also in the association between hyperuricemia observations suggested a possible causative role for uric
and hypertension. The underlying pathophysiological acid in the pathogenesis of CKD, this theory was regarded
mechanisms responsible for the association between as outdated in the 1970s and 1980s, when hyperuricemia
hyperuricemia and hypertension have been investigated came to be considered a marker of CKD rather than a risk
in animal models. Hyperuricemia can be induced in rats factor or pathophysiological factor causing it. Indeed, large
through inhibition of urate oxidase with oxonic acid [56], or studies like the National Health and Nutrition Examination
through fructose overfeeding, which depletes hepatocyte Survey (NHANES) [76] and the German Chronic Kidney
ATP and raises sUA by increasing the flux of adenosine Disease (GCKD) study [77] show an increase in the inci-
nucleotides toward purine disposal [57]. Increasing sUA dence of hyperuricemia, with and without deposition, in
causes a proportional rise in BP that can be prevented or parallel with the decline in GFR. The former study also
reversed with uricosuric drugs or xanthine oxidase inhibi- showed that hyperuricemia with and without deposition is
tors [58]. This finding is confirmed by recent results directly related to the degree of albuminuria. In addition to
obtained in enterocyte-specific Glut 9-deficient mice, these cross-sectional studies, data from 18 prospective
which developed hyperuricemia and hypertension that cohort studies in 431 000 patients revealed that hyperur-
were reversible on treatment with allopurinol [59]. icemia predicts the occurrence of CKD as well as the rate of
Data from these models clearly establish a temporal decline in renal function [78].
relationship between hyperuricemia and the onset of hy- Studies on the role of sUA in CKD are hampered by
pertension in the rat model, and suggest that hyperuricemia confounding factors such as hypertension. Hypertension
causes hypertension through a two-stage process. Initially, can cause CKD, and the resulting reduction in GFR can
hyperuricemia promotes reversible, salt-insensitive hyper- subsequently lead to hyperuricemia. Moreover, pharmaco-
tension through activation of the renin-angiotensin system therapy with diuretics for the treatment of hypertension can
and reduction of nitric oxide synthesis; subsequent micro- increase sUA levels. However, this problem has been
vascular damage to afferent arterioles leads to permanent addressed in several recent studies that investigated the
sodium-sensitive hypertension [60]. association of sUA with the onset of kidney disease in

Borghi et al.
healthy populations. In a 7-year prospective study of 21 475 enrolled in the open-label Febuxostat/Allopurinol Com-
healthy volunteers, sUA was associated with incident kid- parative Extension Long-Term (EXCEL) study [86]. Sus-
ney disease (estimated GFR <40 ml/min per 1.73 m2) [79]. tained reduction of sUA was associated with a slower
For sUA levels between 7.0 and 8.9 mg/dl, the OR was 1.74 decline in renal function (P < 0.001). The study data pre-
(95% CI, 1.45–2.09), whereas with sUA levels 9.0 mg/dl or dicted that every 1 mg/dl of sustained reduction in sUA
higher, the OR was 3.12 (95% CI, 2.29–4.25). Analysis of would correlate with preservation of 1.15 ml/min of
data from 656 108 patients followed for a mean of 8.0 years estimated GFR.
in Taiwan revealed that uric acid deposition was associated The results of this small prospective trial are supported
with an increase in the incidence of end-stage CKD [HR 1.57 by a retrospective analysis of nearly 17 000 patients in a
(95%CI, 1.38–1.79); P < 0.001] [80]. Kaiser Permanente database [87]. In that cohort, reduction
It took the seminal article by Kang et al. [81] to convince of uric acid below 6 mg/dl was associated with a 37%
the nephrology community that hyperuricemia can accel- reduction in renal endpoints (>30% decrease in GFR or
erate the progression of renal disease, at least in a preclin- requirement for dialysis) (HR 0.63, 95% CI, 0.5–0.78;
ical model. Kang et al. used the 5/6 nephrectomy model P < 0.0001).
and a series of superbly planned experiments to show that An ongoing Japanese prospective study will test the
hyperuricemia is linked to hypertension and also leads to effect of febuxostat on the slope of GFR over a 2-year
COX-2-mediated, thromboxane-induced vascular disease period in 400 patients with stage 3 CKD and hyperuricemia
with the associated changes in renal histology. Moreover, without deposition [88].
this research indicated that lowering uric acid could slow Thus, hyperuricemia is common in CKD and increases in
the progression of renal disease. These preclinical data parallel with the decline in GFR and the increase in pro-
were in line with the newer epidemiological data. teinuria. Data from observational studies show that
Five-year follow-up of a prospective cohort of 900 increased levels of sUA predict the development and pro-
healthy, normotensive subjects with normal kidney func- gression of CKD. Results from several interventional studies
tion revealed an association between sUA levels and the suggest that effective pharmacological treatment of hyper-
likelihood of a decrease in estimated GFR [HR 1.13 (95% CI, uricemia in patients with CKD may slow the progression
1.04–1.39) for each 1-mg/dl increase in sUA] [82]. An effect of CKD, thus delaying or even preventing the need for
was apparent at a sUA concentration of 5.5 mg/dl (5.0 mg/dl dialysis.
in women). Likewise, in patients with type 1 diabetes who
do not have proteinuria, there is a clear linear relationship INTERVENTION STUDIES
between sUA and the risk of reduction in GFR that extends
across the range of sUA concentrations, with an OR of 1.4 Hypertension and cardiovascular disease
(95% CI, 1.1–1.8) for every 1-mg/dl increase in sUA [83]. Several interventional studies have been conducted in
This relationship was linear also at physiological sUA levels. preclinical and clinical settings to examine the relationship
This finding is supported by the results of a 5-year obser- between sUA and BP. Fructose feeding increases sUA levels
vational study in 1449 patients with type 2 diabetes and and BP in rats, and both of these are prevented by xanthine
normal kidney function [84]. The incidence of CKD was oxidase inhibition [56]. In a randomized placebo-controlled
significantly higher in hyperuricemic patients (OR 2.55, 95% trial of 74 healthy subjects given fructose, simultaneous
CI, 1.71–3.85, P < 0.001). These data indicate that the cut- administration of allopurinol, but not placebo, significantly
off for hyperuricemia, which is loosely based on the sol- reduced sUA levels and prevented the increase in mean
ubility of uric acid under physiological conditions, may arterial BP after 2 weeks [89]. Thus, this effect appears to be
need to be reconsidered. reproduced in humans, raising the question of whether
Can these preclinical and newer epidemiological data be early hypertension in humans is associated with hyper-
translated into the therapeutic formula ‘effective lowering uricemia, and if so, whether this is also reversible.
of uric acid slows the progression of CKD and decreases Feig et al. [90] have investigated the effect of sUA-low-
proteinuria’? One small prospective trial suggests that this ering therapy on blood pressure in hyperuricemic adoles-
may be the case. Goicoechea et al. [70] randomized 113 cents with newly diagnosed, untreated mild hypertension
patients with CKD and an estimated GFR near 40 ml/min in a small randomized controlled cross-over trial. In this
per 1.73 m2 to receive either placebo or xanthine oxidase- proof of principle trial, allopurinol 200 mg twice daily for 4
inhibitor treatment for 2 years. As in the animal experiment weeks significantly reduced daytime and mean 24-h ambu-
by Kang et al., this therapeutic approach slowed pro- latory BP compared with placebo, with 20 of 30 patients
gression of CKD in the treatment group, whereas the achieving normal BP, including 19 of 22 patients whose sUA
placebo group lost nearly 10% of the initial renal function. was below 5.0 mg/dl after treatment with allopurinol.
In addition to the improvement in GFR, the rate of protei- Exploratory endpoints of renin activity and systemic vas-
nuria decreased. Siu et al. [85] investigated the effect of cular resistance were also significantly decreased.
allopurinol on renal disease progression in a 12-month This demonstrated that xanthine oxidase inhibition is
prospective, randomized, controlled trial of 54 hyperurice- associated with reduction in sUA and BP; however, ques-
mic patients with CKD. Treated patients had a significant tions remained about the relative roles of sUA and reactive
decrease in sUA and preservation of renal function over 12 oxygen species produced by xanthine oxidase activity, the
months. The effect of xanthine oxidase inhibition on renal latter being implicated as a cause of endothelial dysfunction
function was determined using data from 551 subjects with [51]. This point was addressed in a second controlled trial in
gout who received febuxostat for up to 4 years while which obese adolescents with hyperuricemia and

prehypertension were randomly assigned to inhibition of forearm venous occlusion plethysmography (93 67%
xanthine oxidase (allopurinol), inhibition of uric acid reab- vs. 145 106%, P ¼ 0.006), flow-mediated dilation
sorption (probenecid) or placebo [91]. Reduction of sUA (4.2 1.8% vs. 5.4 1.7%, P < 0.001) and pulse wave
through either mechanism resulted in similar BP responses analysis (2.6 7.0%, P < 0.001). Vascular oxidative stress,
after 7 weeks, confirming a causal link between sUA levels assessed by infusion of acetylcholine with and without
and BP in this young population that is independent of vitamin C, was still present in these optimally treated
xanthine oxidase activity. patients after receiving placebo but not after receiving
Agarwal et al. conducted a meta-analysis of 10 studies allopurinol treatment. Thus, even patients receiving
that had assessed the effect of allopurinol on SBP and DBP optimal treatment for CAD have residual oxidative stress
(n ¼ 738) [92]. SBP decreased by 3.3 mmHg (95% CI, 1.4– and endothelial dysfunction that is resolved by xanthine
5.3; P ¼ .001) and DBP decreased by 1.3 mmHg (95% CI, oxidase inhibition. A small study conducted in patients with
0.1–2.5; P ¼ .03) in patients treated with allopurinol com- severe tophaceous gout directly comparing the effects of
pared with the control group. This finding is statistically allopurinol and febuxostat on carotid pulse wave velocity
significant, but much smaller that the results obtained in showed that, with equivalent sUA reduction, only febuxo-
hypertensive adolescents [90]. This discrepancy is most stat was able to prevent worsening of this marker of arterial
likely because of the differences in age and in the number stiffness [96].
and duration of comorbidities between the study popu- The effect of allopurinol on exercise capacity in patients
lations. with confirmed CAD and chronic stable angina was inves-
tigated in a double-blind, placebo-controlled cross-over
Surrogate cardiovascular endpoints study in which 65 patients (mean SD age 64.6 9.3 y)
The role of hyperuricemia in the progression of hyperten- were randomly assigned to receive allopurinol 600 mg/day,
sion to cardiovascular disease requires clarification because or placebo for 6 weeks [97]. This allopurinol dosage was
the clinical data available to date are limited to surrogate higher than the recommended dosage for the renal function
endpoints. Recently, Higgins et al. [93] conducted a meta- of the patients [98]. Significant improvements compared
analysis evaluating the evidence for an effect of xanthine with placebo were recorded for the time to ST depression
oxidase inhibition on markers of cardiovascular function in (43 s; 95% CI, 31–58; primary endpoint) time to chest pain
studies reported up to June 2010. Most of the studies were (38 s; 95% CI, 17–55) and total exercise time (58 s; 95% CI,
small and heterogeneous in terms of design and outcomes. 45–77). The 26 patients with 1 or more angina episode per
Meta-analysis of a subset of comparable studies for two week had a trend toward reduction in episodes and nitrate
measures of endothelial function (brachial artery flow- use while receiving allopurinol (P ¼ 0.053 and P ¼ 0.064
mediated dilatation and forearm blood flow responses to respectively).
acetylcholine) and circulating markers of oxidative stress Inhibition of xanthine oxidase with febuxostat or allo-
showed significant favorable results for treatment with purinol was compared in a randomized study of 141 hyper-
allopurinol. uricemic patients undergoing cardiac surgery [99]. Both
Subsequently, a number of controlled trials have groups had a substantial reduction in sUA, but only the
addressed the effect of xanthine oxidase inhibition on febuxostat group had significant reductions in serum crea-
cardiovascular markers. Xanthine oxidase -generated reac- tinine, urinary albumin, cystatin-C and oxidized low-
tive oxygen species have been implicated as a cause of density lipoprotein, SBP, pulse wave velocity and left
vascular oxidative stress and endothelial dysfunction, rep- ventricular mass index.
resenting another mechanism through which this pathway
may influence cardiovascular risk. Randomized controlled Left ventricular hypertrophy
trials (RCTs) have shown that xanthine oxidase inhibitors Left ventricular hypertrophy is a strong predictor of cardi-
improve endothelial function. Asymptomatic hyperurice- ovascular and cerebrovascular outcomes and is highly
mic patients with normal renal function and no evidence of prevalent in a number of conditions, including CKD, hy-
diabetes, hypertension or cardiovascular disease were ran- pertension, diabetes and CAD. Recently, the group of
domly assigned to receive allopurinol 300 mg/day (n ¼ 30, Struthers have conducted a series of randomized double-
mean sUA 8.3 1.1 mg/dl) or no treatment (n ¼ 37) [94]. A blind, placebo-controlled, parallel group studies investi-
normouricemic control group (n ¼ 30) was also included. gating the effect of allopurinol on endothelial function and
Assessments included sUA, 24-h ambulatory blood pres- left ventricular hypertrophy in patients with stage 3 CKD
sure, endothelial function and estimated GFR at baseline [100], type 2 diabetes [101] and CAD [102]. In each of these
and after 4 months of treatment. Allopurinol treatment studies, 66 or 67 patients were enrolled and treatment lasted
significantly decreased sUA and BP, while improving endo- 9 months. The primary outcome was change in left ven-
thelial function and estimated GFR in these healthy subjects tricular mass measured by cardiac magnetic resonance
(P < 0.05 for all parameters). imaging; other outcomes included endothelial function
The effect of allopurinol on endothelial function has evaluated by brachial artery flow-mediated dilatation and
been tested also in patients with optimally treated stable arterial stiffness assessed by pulse-wave analysis. Small but
coronary artery disease (CAD) [95]. Allopurinol 600 mg/day statistically significant regression of left ventricular mass
was compared with placebo in a randomized, double- index was recorded in all three treated populations after 9
blind, crossover study with 8-week treatment periods con- months: (CDK, allopurinol 1.42 4.67 g/m2 vs. placebo
ducted in 80 patients. Endothelial function improved sig- þ1.28 4.45 g/m2, P ¼ 0.036; type 2 diabetes, allopurinol
nificantly after allopurinol treatment when assessed by 1.32 2.84 g/m2 vs. placebo group þ0.65 3.07 g/m2,

Borghi et al.
P ¼ 0.017; CAD, allopurinol 2.2 2.78 g/m2 vs. placebo Can we improve cardiovascular and renal
0.53 2.5 g/m2, P ¼ 0.023). Significant improvements in outcomes by lowering sUA levels?
endothelial function and arterial stiffness were only Uncontrolled studies have shown a reduction in cardiovas-
recorded in the CKD and CAD studies. The reported cular risk associated with uric acid-lowering therapy [108].
regression of left ventricular mass was smaller than has An interesting retrospective study conducted on 200 Korean
been seen in trials of hypertensive drugs. patients with a mean follow-up of 7.6 years showed a
significant reduction in incident hypertension, type II dia-
Heart failure betes and cardiovascular disease in patients with hyper-
Hyperuricemia is associated with increased risk of all-cause uricemia with deposition that had been properly treated to
mortality in patients with heart failure [103]. A retrospective a cut-off value of 6 mg/dl [109].
case–control analysis of patients with symptomatic heart The available literature suggest that the best therapeutic
failure (14 327 events consisting of heart failure, readmis- approach to obtaining cardiovascular and renal benefits
sion or all cause mortality) revealed that hyperuricemia was through sUA lowering is through xanthine oxidase inhi-
significantly associated with increased events, whereas bition, rather than uricosuric drugs, probably because of the
allopurinol use was associated with a reduction in events concomitant inhibition of reactive oxygen species pro-
(adjusted RR, 0.69; 95% CI, 0.60–0.79) and the association duction and consequent antioxidant effect of these com-
between gout and events was no longer significant among pounds. In this light, allopurinol and febuxostat can be
patient receiving allopurinol [104]. Thus, xanthine oxidase considered the most appropriate choices.
inhibition may be associated with better heart failure out-
comes in hyperuricemic patients. Indeed, several small
When should urate-lowering therapy be
controlled interventional studies have shown an improve-
ment in peripheral endothelial function in patients with started?
heart failure receiving allopurinol [105,106]. However, low- Currently, there is no evidence from RCTs to support treat-
ering uric acid with the uricosuric benzbromarone in ment of asymptomatic hyperuricemics, even though both
patients with heart failure was not effective at improving xanthine oxidase inhibitors are indicated in this setting in
hemodynamic impairment [71]. some countries [110]. In Europe, no urate-lowering drug
has been approved for the management of asymptomatic
hyperuricemia; however, the increasing body of data
IMPORTANT QUESTIONS suggesting efficacy of urate-lowering therapy on outcomes
Is hyperuricemia an independent risk factor for other than gout flares may lead to considering treatment
even in the absence of overt gout when hyperuricemia
cardiovascular disease? accompanies other cardiovascular risk factors.
Data supporting sUA as an independent risk factor are now
Large controlled studies are needed to formally establish
very strong. Hyperuricemia may account for at least part of
the effect of sUA lowering on hard cardiovascular and renal
the excess risk not explained by traditional risk factors. In
endpoints. The ongoing Febuxostat for Cerebral and caR-
fact, the increase in cardiovascular risk associated with sUA
diorenovascular Events prEvEntion stuDy (FREED; Clinical-
is clinically relevant, for example in the Pressioni Arteriose
Trials.gov Identifier: NCT01984749) is investigating the
Monitorate E Loro Associazioni (PAMELA) study, the impact
effect of xanthine oxidase inhibition on cardiovascular
was greater than that of age or BP [22]. sUA predicts also a
and renal endpoints in elderly hyperuricemic patients.
number of conditions themselves associated with high
Results are expected in late 2017. Meanwhile, studies con-
cardiovascular risk, including hypertension, hyperinsuline-
ducted with surrogate endpoints could provide useful
mia, organ damage and obesity.
information and resolve some of these questions. Clinically
validated intermediate endpoints that provide reproduci-
What threshold should be adopted to define ble, short-term treatment-related effects should be con-
hyperuricemia? sidered. Examples could include carotid-femoral pulse
The official definition of hyperuricemia is still disputed. The wave velocity [96] or blood pressure [90,91] and protective
2013 ESH/ESC Hypertension guidelines [107] recommend effects on renal parameters [86,87].
routine measurement of sUA in profiling patients; however,
this parameter is not considered in the algorithm for assess-
ing total cardiovascular risk, and a cut-off value has not ACKNOWLEDGEMENTS
been indicated. It is the opinion of the members of this We wish to thank Richard Vernell, an independent medical
Board of Experts that this lack represents a source of writer acting on behalf of Springer Healthcare Communi-
misunderstanding for all Healthcare Professionals (clinical cations, for medical writing assistance. This assistance was
and laboratory physicians primarily) and a potential danger supported by A.menarini Farmaceutica Internazionale sri.
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 cardiovas- Conflicts of interest
cular and renal risk; however, receiver-operating charac- C.B. has received speaking fees from Novartis, Amgen,
teristic analysis of data from the PAMELA study identified an Servier, Stroder, Ely-Lilly and is a member of advisory
even lower sUA value, in the range of 5 mg/dl (somewhat boards for Amgen, Sanofi, Takeda, Menarini, Servier
lower for women) [22]. and Novartis.

E.A.R. has received speaking fees from Menarini, 15. Mallamaci F, Testa A, Leonardis D, Tripepi R, Pisano A, Spoto B, et al.
A polymorphism in the major gene regulating serum uric acid associ-
Recordati, Stroder, Servier and has received research funds ates with clinic SBP and the white-coat effect in a family-based study. J
from Novartis, Recordati, Stroder. Hypertens 2014; 32:1621–1628.
T.B. is a consultant or speaker for AstraZeneca, Ipsen 16. Parsa A, Brown E, Weir MR, Fink JC, Shuldiner AR, Mitchell BD, et al.
Pharma, Menarini, Novartis, Swedish Orphan Biovitrum Genotype-based changes in serum uric acid affect blood pressure.
and Takeda Kidney Int 2012; 81:502–507.
17. Hughes K, Flynn T, de Zoysa J, Dalbeth N, Merriman TR. Mendelian
A.D. has received speaking fees from Servier and randomization analysis associates increased serum urate, due to
Menarini. genetic variation in uric acid transporters, with improved renal
J.T.K. has received speaking fees from Berlin-Chemie. function. Kidney Int 2014; 85:344–351.
F.P.R. is a consultant or speaker for AstraZeneca, Menar- 18. Sedaghat S, Pazoki R, Uitterlinden AG, Hofman A, Stricker BH, Ikram
ini, Pfizer, Novartis, and Swedish Orphan Biovitrum. MA, et al. Association of uric acid genetic risk score with blood
pressure: the Rotterdam study. Hypertension 2014; 64:1061–1066.
G.M. is a consultant for Boehringer Ingelheim, and has 19. Chou CT, Lai JS. The epidemiology of hyperuricaemia and gout in
received speaking fees from Bayer AG, Boehringer Ingel- Taiwan aborigines. Br J Rheumatol 1998; 37:258–262.
heim, CVRx, Daiichi Sankyo, Menarini, Merck & Co, Novar- 20. Trifirò G, Morabito P, Cavagna L, Ferrajolo C, Pecchioli S, Simonetti M,
tis, Recordati, Servier, and Takeda. et al. Epidemiology of gout and hyperuricaemia in Italy during the
years 2005-2009: a nationwide population-based study. Ann Rheum
The other authors report no conflicts of interest. Dis 2013; 72:694–700.
21. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and
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Reviewer’s Summary Evaluation is that we lack data from randomized controlled trials when
sUA is targeted with drug interventions. Before this is available,
Reviewer 2 there is doubt about the causality of sUA for the observed
This is a timely and interesting review on the role of sUA for associations. Furthermore, genetic studies based on Mendelian
associations with hypertension, metabolic syndrome and randomization methods have not been supportive of a casual
markers of cardiovascular disease. The problem, however, role for sUA in the pathogenesis of cardiovascular disease.


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Review

Serum uric acid and the risk of cardiovascular and

only from a rheumatologic standpoint, but also in terms of

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TABLE 2. Drugs that influence serum uric acid levels

ACE, angiotensin-converting enzyme; URAT 1, urate transporter 1.

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With gout 0.93 1.57 1.64* 1.77**

No gout 1.00 0.99 1.09 1.37**

Serum uric acid (quartiles)

With gout 0.82 2.00 1.80* 2.09**

No gout 1.00 0.92 1.09 1.33*

Serum uric acid (quartiles)

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Volume 33 Number 9 September 2015

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