The pathophysiology of hyperuricaemia and its
possible relationship to cardiovascular disease,
morbidity and mortality
David Gustafsson1*and Robert Unwin2
Uric acid is the end product of purine metabolism in humans. High levels are causative in gout and urolithiasis.
Hyperuricaemia has also been implicated in the pathophysiology of hypertension, chronic kidney disease (CKD),
congestive heart failure (CHF), the metabolic syndrome, type 2 diabetes mellitus (T2DM), and atherosclerosis, with
or without cardiovascular events. This article briefly reviews uric acid metabolism and summarizes the current
literature on hyperuricaemia in cardiovascular disease and related co-morbidities, and emerging treatment options.
Keywords: Uric acid, Urate, Hypertension, Chronic kidney disease, Congestive heart failure, Type 2 diabetes mellitus,
Metabolic syndrome, Cardiovascular events, Atherosclerosis
Physiology and pharmacology
Uric acid largely exists as urate (the ionized form, pKa is
5.8) at neutral pH. It is the end product of purine metabol-
ism in humans. High serum levels of urate (hyperuricaemia)
are causative in gout and urolithiasis, due to the formation
and deposition of monosodium urate crystals. Urate is sin-
gly charged at neutral pH and at a concentration of 6.8 mg/
dL (0.40 mmol/L) in human serum, crystals can form spon-
taneously. The solubility of urate decreases with increasing
local sodium concentration, and decreasing temperature
and pH . The latter is an important factor in urate stone-
formation in patients with acidic urine. The serum level of
urate in man considered to be ‘normal’ varies among la-
boratories and in publications, but a range of 3.5 mg/dL
(0.2 mmol/L) to 7.0 mg/dL (0.4 mmol/L) is often quoted.
Serum urate is usually 0.5-1 mg/dL (0.03-0.06 mmol/L)
lower in women compared with men. Serum urate levels in
men have increased gradually from 3.5 mg/dl (0.2 mmol/L)
in the 1920s to 6.0 mg/dL (0.35 mmol/L) in the 1970s .
However, no explanation for this observation has been
given, but it is probably related to changes in diet, e.g., in-
creased intake of fructose.
The serum urate level depends on dietary purines, the
degradation of endogenous purines, and the renal and in-
testinal excretion of urate. The dominating factor contrib-
uting to hyperuricaemia is under-excretion of urate .
High ingestion of purine sources (animal protein - meat
and seafood - and beer) and alcohol increase the demands
on purine elimination, while coffee and vitamin C reduce
demand. Also, high intake of fructose increases serum
urate, a relationship that has been ascribed to fructose
phosphorylation in the liver with subsequent ATP deple-
tion and regeneration [1,3].
Increased cell turnover (e.g., haemolysis, tumour growth
and large tumour necrosis) leads to increased production
of adenosine, inosine and guanosine. These are degraded
to hypoxantine and xanthine, which are the substrates for
the widely distributed xanthine oxidase (XO) in the for-
mation of uric acid (Figure 1). Allopurinol and febuxostat
are inhibitors of XO and reduce uric acid formation. In
man and some higher primates, uric acid is the end-
product of purine metabolism. However, most mammals
can degrade uric acid further to water-soluble allantoin by
the enzyme uricase and as a result serum urate levels are
about 1/10 of human values . Pegloticase is a pegylated
* Correspondence: firstname.lastname@example.org
1Bioscience, CVMD iMED, AstraZeneca R&D Mölndal, Mölndal, Sweden
Full list of author information is available at the end of the article
© 2013 Gustafsson and Unwin; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Gustafsson and Unwin BMC Nephrology 2013, 14:164
uricase that reduces urate levels by increasing its metabol-
ism and it can be used therapeutically in man .
Urinary excretion accounts for two-thirds of total elimin-
ation of uric acid and the remainder is excreted in faeces.
Urate is not protein bound and is freely filtered at the
glomerulus, but up to 90% of filtered urate is reabsorbed
(Figure 1). The main transporters responsible for tubular
reabsorption are SLC22A12 (URAT1 - dominant expres-
sion is in the kidney and apical in tubular cells) and
SLC2A9 (GLUT9 – widely expressed, but most likely
basolateral in tubular cells), while SLC22A11 (OAT4 - ap-
ical) is less important and the evidence is weaker .
There also seems to be tubular secretion of urate with
some evidence existing for ABCG2, SLC17A1, SLC17A3
(apical) and SLC22A6 (OAT1) and SLC22A8 (OAT3)
(both basolateral) . Probenecid, benzbromarone and
lesinurad all inhibit URAT1, thereby reducing serum urate
levels. Non-renal elimination of urate is poorly under-
stood: a recent publication suggests that uric acid is also
secreted directly into the intestinal lumen, but not via the
bile ; studies in Caco2 cells indicate that ABCG2 is im-
portant for this route of urate elimination.
Genome-wide association studies (GWAS) have impli-
cated a number of genes associated with serum urate and
gout. Hereditary renal hypouricaemia type 1 is due to loss
of function mutations in URAT1 (SLC22A12) and is rela-
tively common in Japan, and can be complicated by neph-
rolithiasis or exercise-induced acute renal failure .
URAT1 has been genetically associated with urate levels,
though no genetic association has been demonstrated for
URAT1 and gout [8,9]. SLC2A9 (GLUT9) is responsible
for approximately 4% of the variance in serum urate levels
and has an association with gout [8,9]. It is a glucose, fruc-
tose, and uric acid transporter, although its greatest affinity
is for uric acid. It reabsorbs urate from the proximal renal
tubule and may also be expressed in the distal nephron
(and the liver and intestine); a homozygous loss-of-function
mutation causes severe hereditary renal hypouricaemia type
2 . ABCG2 is a renal and extra-renal urate exporter re-
sponsible for <1% of the variance of serum urate, although
it has also been associated with gout [8,9]. Recently a large
GWAS (>140,000 individuals) was published . Of loci
described previously 10 were confirmed and 18 new loci
were identified. However, none of the new loci seemed to
be candidates for urate transport but were instead related
to glycolysis, glucose, insulin and pyruvate, indicat-
ing an importance in de novo purine synthesis and
thereby uric acid production . It was also found that
alleles associated with increased serum urate concentra-
tions were associated with increased risk of gout. Fi-
nally, the rare autosomal dominant diseases collectively
known as uromodulin-associated kidney diseas (UAKD)
should also be mentioned. These are characterized by
hyperuricaemia, gout, and finally end stage renal disease.
They are caused by mutations in the renal specific gene
UMOD . This suggests a coupling between urate
transport and the UMOD gene product uromodulin, also
known as Tamm Horsfall protein, although the details are
still unclear. Uromodulin is produced by the epithelial
cells of the thick ascending limb of the loop of Henle and
is secreted into the urine. It is possible that uromodulin
might regulate sodium transport in the thick ascending
*=Not in man and high primates
Inhibitor of purine
Figure 1 Schematic representation of uric acid formation and elimination showing the drugs that can affect both.
Gustafsson and Unwin BMC Nephrology 2013, 14:164
Page 2 of 9
limb and that hyperuricaemia in UAKD is secondary to
hypovolaemia and increased reabsorption of urate along
the proximal tubule.
Treatment of gout
Gout is the result of monosodium urate crystals in joints,
which trigger the NALP3 (cryopyrin) inflammasome and
release of pro-inflammatory cytokines, especially IL-1β.
Gouty arthritis is often intermittent, but can be chronic,
joint destructive and deforming, and persistently painful.
Tophi (large crystal deposits) can form in longstanding
disease. Gout affects 1–4% of adults (it is more common
in the USA) and its prevalence is increasing, probably due
to changes in diet, increases in CKD (gout has a higher
prevalence in CKD ), obesity, and a longer lifespan.
Subjects with serum urate between 7 and 8 mg/dL (0.40-
0.48 mmol/L) have an accumulated risk of developing
gout of 3%, while those above 9 mg/dL (>0.54 mmol/L)
have an accumulated risk of 22%. The American College
of Rheumatology guidelines recommend a serum urate
target level of <6 mg/dL (<0.35 mmol/L) in all gout cases
and <5 mg/dL (<0.3 mmol/L) in gout with tophi . The
recommendation in Japan also includes reducing hyper-
uricaemia, even in the absence of gout, with lifestyle guid-
ance or drugs if >8 mg/dL (>0.48 mmol/L) and certain
conditions apply . Gout is costly to Society, since those
affected are often absent from work .
Standard treatment consists of acute anti-inflammatory
drugs for gouty flares, followed by the long-term urate-
lowering therapy. Anti-inflammatory treatment aims at re-
ducing the pain and swelling. Established treatments are
NSAIDs and sometimes corticosteroids. Colchicine can be
used as gout prophylaxis, especially when urate-lowering
therapy is first introduced, but it is also used for acute
gout. Drugs targeting IL-1β  are also effective in acute
gout (e.g. rilonacept and canakinumab).
Primary urate-lowering therapy (Figure 1) is often initi-
ated with a XO inhibitor such as allopurinol or febuxostat,
but the number of patients achieving serum urate
levels <6 mg/dL (<0.35 mmol/L) is in the range of 20-
40% for allopurinol and 45–67% for febuxostat (Phase
III data ), indicating the need for additional therap-
ies. Moreover, allopurinol can have both dose-related
(e.g., gastrointestinal intolerance, rashes) and idiosyn-
cratic side effects, which can be life-threatening and
may by more frequent in Asians [16,18]. Examples of
non-specific uricosuric drugs are the older URAT1 in-
hibitors probenecid (which also inhibits OAT1 and 3),
which is still available in some countries, and benz-
bromarone, which has largely been withdrawn because
of liver toxicity. Uricosuric drugs in clinical development
are mainly URAT1 inhibitors, i.e., lesinurad (Phase III),
arhalofenate (Phase II and also in development for dia-
betes), levotofisopam (Phase II and the S-enantiomer of
RS-tofisopam, an anxiolytic agent used in some countries)
and RDEA3170 (Phase I) [4,19,20]. Lesinurad can achieve
target serum urate levels when given with allopurinol or
febuxostat in 60-100% of the patients, according to avail-
able Phase II data . Use of the non-absorbable phos-
phate binder sevelamer can also decrease serum urate in
haemodialysis patients, most likely the result of increased
gastrointestinal elimination . BCX4208, an inhibitor of
purine nucleotide phosphorylase (an enzyme ‘higher up’
in the purine metabolic pathway), is in Phase II trial .
There are two pegylated uricase derivatives: pegloticase is
approved for patients refractory to conventional treatments
(mainly used in severe tophaceous gout) and pegadricase
has been in Phase I trial and may still be in development
. These emerging therapies are aiming to improve effi-
cacy and reduce side effects [4,16].
Pathophysiology of hyperuricaemia-associated conditions
The initial trigger of the ‘inflammasome’ is from the ef-
fect of monosodium urate crystals on cells of the mono-
cyte/macrophage lineage . This leads (via the NALP3
inflammasome) to secretion of IL-1β, which then acts to
recruit more inflammatory cells. The detailed mechan-
ism underlying the secretion of IL-1β is not known, but
cell damage leading to ATP release and activation of the
P2X7 receptor may be involved. Potassium efflux may
also be important, as well as generation of reactive oxy-
gen species (ROS). Released IL-1β recruits other inflam-
matory cells and so amplifies the inflammatory reaction.
The result is a burst of inflammatory mediator release.
The inflammation spontaneously resolves, perhaps medi-
ated by release of the anti-inflammatory cytokine TGF-β.
The inflammasome is considered to be essential in gout
and other crystalopathies, but its role in any associated
pathology is less clear. It is also unclear if hyperuricaemia
alone can initiate other pathological processes. What in-
formation is available, will be included with the discussion
of various diseases associated with hyperuricaemia.
Multivariate analysis has been used to assess if serum
urate is an independent risk factor for disease. A positive
association has been found between urate levels and a num-
ber of important disorders, including hypertension, CKD,
CHF, the metabolic syndrome, T2DM, endothelial cell
dysfunction, cardiovascular events, and fatty liver disease.
The strength of these associations will be discussed below.
There are also a few intervention studies, mostly with allo-
purinol, but these are small and may not be representative
of the effects of lowering urate by different mechanisms.
It is important to mention that urate also plays an essen-
tial function in humans. The loss of uricase in higher pri-
mates parallels the similar loss of our ability to synthesize
ascorbic acid, an important anti-oxidant, leading to the
suggestion that urate may partially substitute for ascorbate
in humans [1,5,23]. Both uric acid and ascorbic acid are
Gustafsson and Unwin BMC Nephrology 2013, 14:164
Page 3 of 9
strong reducing agents (electron donors) and potent anti-
oxidants. In humans, the major extracellular antioxidant
capacity of blood comes from urate, but urate can also be
pro-oxidant depending on the conditions [5,23] (see also
below under the metabolic syndrome). Epidemiological
data suggest that urate may be important in neuropro-
tection. The brain is vulnerable to oxidative stress due to its
high metabolic rate and high levels of unsaturated fatty
acids. Thus, increased lipid peroxidation could be one ex-
planation for the association found between reduced serum
urate levels and CNS disorders such as multiple sclerosis
(MS), AML, Parkinson’s, Alzheimer’s and Huntington’s dis-
eases. Patients with MS have significantly lower serum
urate levels and there seem to be no reported cases of pa-
tients suffering from both MS and gout .
Animal models have shown that acute elevations of serum
urate (e.g., by inhibition of uricase) induce a prompt rise in
blood pressure and that chronic urate elevation maintains
the rise in pressure and induces irreversible vascular dam-
age and glomerular changes, and results in a form of salt-
sensitive hypertension [25,26]. The mechanisms suggested
are a renin-angiotensin-aldosterone-dependent arteriolop-
athy, inhibition of neuronal nitric oxide synthase, and
interstitial fibrosis and glomerulosclerosis with albumin-
uria. A meta-analysis of 11 studies showed that hyper-
uricaemia is associated with an increased risk of incident
hypertension, independent of traditional risk factors. This
risk appears more pronounced in younger individuals
(with pre-hypertension) and in women . In adults with
essential hypertension an association with hyperuricaemia
is very common.
Feig and Johnson found that about 90% of adolescent
hypertension is associated with hyperuricaemia . The
threshold for hypertension could be as low as 5.0-5.5 mg/
dL (0.30-0.33 mmol/L), clearly below the supersaturation
value of 6.8 mg/dL (0.4 mmol/L). Thus, it should be inde-
pendent of the formation of monosodium crystals. They
also showed an effect of allopurinol, where two thirds
of subjects tested normalized their blood pressure .
Recently, a second study published a comparison of al-
lopurinol with probenecid, a randomized, double-blind,
placebo-controlled study, in pre-hypertensive obese ado-
lescents. The urate-lowering effect was in the same range
of 6.3 to 4.1 mg/dL (0.38 to 0.24 mmol/L). Both treat-
ments were effective, with reductions of 10 and 9 mmHg
in systolic and diastolic blood pressures, respectively,
suggesting that decreased urate was responsible for the
effects and not decreased XO activity . A systematic
meta-analysis of 10 longitudinal studies (738 patients) that
assessed the effect of allopurinol on blood pressure showed
significant 3.3 and 1.3 mmHg decreases in systolic and dia-
stolic blood pressures, respectively . However, a recent
Cochrane review only found one study fulfilling their strict
criteria  and concluded that the data are insufficient to
recommend this treatment . Finally, it should be men-
tioned that losartan and some calcium channel blockers
are uricosuric and reduce the risk of gout. Data also sug-
gest that these agents may have a greater blood pressure-
lowering effect, because their uricosuric property .
Chronic kidney disease (CKD)
Animal studies with experimental hyperuricaemia (e.g.,
through inhibition of uricase) suggest a causative role
for urate in renal disease models , especially if there
is pre-existing renal impairment as in the 5/6 nephrec-
tomy model . In humans the situation is more com-
plicated. A number of cross-sectional studies have found
an association of urate levels with decreased eGFR or
microalbuminuria, but the interpretation is difficult, be-
cause CKD can elevate urate levels and hyperuricaemia
might cause or aggravate CKD. When it comes to inci-
dent CKD, most studies show an independent associ-
ation with serum urate levels. However, the analysis of
the progression of CKD 3–4 and its relationship to urate
levels show conflicting results, most studies finding no
independent association with hyperuricaemia. This could
indicate that urate is more a risk factor for the onset of
CKD than its progression. When it comes to kidney
transplant graft loss or reduction in graft function, data
are also conflicting with most studies showing no inde-
pendent association with serum urate levels . How-
ever, a recent review is supportive of urate as risk factor
for CKD .
There are at least four randomized interventional
studies using allopurinol in renal disease. Siu et al. ran-
domized 54 patients with CKD 3-4 to allopurinol or pla-
cebo for 12 months. Allopurinol decreased systolic blood
pressure (from 140 to 127 mmHg; control unchanged at
135 mmHg) and slowed CKD progression (defined as >40%
rise in serum creatinine; 12 versus 42% of patients) .
Goicoechea et al. randomized 113 patients with eGFR <60
mL/min/1.73m2to allopurinol or usual treatment for 24
months. There was an effect on eGFR decline (defined as a
decrease of >0.2 mL/min/1.73 m2; adjusted HR 0.53) and
hs-CRP (from 4.4 to 3.0 versus 3.4-3.2 mg/l) favouring allo-
purinol treatment, and a beneficial effect on cardiovascular
endpoints (7/57 versus 15/56), but no effect on blood pres-
sure . Momeni et al. randomized 40 patients with type
2 diabetes mellitus and diabetic nephropathy to allopurinol
or placebo, with a reduction in proteinuria (from 1.8 to 1.0
versus 1.7 to 1.6 g per 24 h) in the allopurinol-treated group
. Shi et al. randomized 40 IgA nephropathy patients to
allopurinol or usual treatment for 6 months. There was in-
direct evidence for a reduction in blood pressure on allo-
purinol (the antihypertensive drug doses were reduced in
7/9 cases with hypertension on allopurinol versus 0/9 in the
Gustafsson and Unwin BMC Nephrology 2013, 14:164
Page 4 of 9
control group), but no difference in eGFR . In a post-
hoc analysis of the RENAAL trial, losartan reduced urate
levels by 0.16 mg/dL (0.01 mmol/L) from 6.7 mg/dL (0.4
mmol/L) during the first 6 months; adjustment for the
urate effect indicated that 1/5 of losartan's renoprotective
effect could be attributed to this reduction in urate .
However, it is difficult to draw any firm or generalizable
conclusion for CKD, although there could be an effect of
allopurinol on blood pressure and possibly an effect on
Congestive heart failure (CHF)
Gout is associated with CHF, subclinical measures of
systolic dysfunction and mortality according to an ana-
lysis of the Framingham Offspring Study . However,
there also seems to be increased XO activity in the fail-
ing myocardium, perhaps due to hypoxia and apoptosis,
resulting in accumulation of uric acid precursors (hypo-
xanthine and xanathine) and XO-induced production of
ROS, causing a vicious cycle of damage . There are
several studies showing an association between increased
serum urate levels in CHF and morbidity and mortality
[43-45]. Gotsman et al.  in an Israeli heart failure
register-based study found that treatment with allopur-
inol in CHF was associated with improved survival.
A group evaluating data from the Beta-Blocker Evalu-
ation of Survival Trial took a different approach .
They assumed that hyperuricaemia without CKD is pri-
marily due to increased production of uric acid from the
failing heart, while hyperuricaemia in patients with CKD
is in large part due to impaired renal excretion of urate.
The conclusion was that hyperuricaemia is associated
with a poor outcome in CHF without CKD, but not in
those with CHF and CKD. This suggests that hyperuri-
caemia in CHF without CKD might be ascribed to in-
creased XO activity. Although the role of XO in CHF is
not clearly established, it appears that its inhibition (inde-
pendent of urate-lowering) in patients with hyperuricaemia
may have a beneficial effect on endothelial cell function,
myocardial function and ejection fraction, while in con-
trast, reducing urate levels with probenecid or benz-
bromarone does not improve endothelial cell function or
haemodynamic impairment, despite a significant decrease
in serum urate level [for references see 47-50]. These data
suggest that increased XO activity, rather than the serum
urate level per se, is involved in CHF pathophysiology.
The metabolic syndrome, T2DM and obesity
The patient with metabolic syndrome should have at least
three of the following five clinical features: abdominal obe-
sity, impaired fasting glucose, hypertriglyceridaemia, low
HDL-cholesterol, and elevated blood pressure. An elevated
serum urate concentration is commonly associated with
the metabolic syndrome ; while the increase in serum
urate has often been considered to be secondary, recent
studies suggest that it may have an important contributory
role . First, elevated serum urate levels commonly
precede insulin resistance, T2DM [52,53], and obesity ,
which is consistent with hyperuricaemia as a tentative
causal factor; second, studies in cell culture and animal
models have suggested a causative role for urate in models
of the metabolic syndrome. Two mechanisms are sug-
gested [2,23,55]: 1) hyperuricaemia-induced endothelial
dysfunction, leading to reduced insulin-stimulated nitric
oxide-induced vasodilatation in skeletal muscle, and as a
consequence reduced glucose uptake in skeletal muscle; 2)
inflammatory and oxidative changes induced by intracellu-
lar urate levels in adipocytes. For example, mice lacking
XO (producing uric acid from xanthine) only have half
the adipocyte mass of their wild-type littermates. A recent
review  suggests a bidirectional and causal relationship
between hyperuricaemia and hyperinsulinaemia, the former
reducing nitric oxide bioavailability and the latter decreas-
ing the renal excretion of urate. The renal clearance of
urate has been found to be inversely related to insulin re-
sistance , which is supported by experimental studies in
healthy volunteers and hypertensive patients [58,59].
Polymorphisms in the uric acid transporter SLC2A9
(GLUT9) are associated with elevated serum urate and
the risk of gout, but SLC2A9 polymorphisms are not asso-
ciated with obesity or the metabolic syndrome phenotype.
However, SLC2A9 exports urate out of cells [60,61], in
contrast to the transporter URAT1 (SLC22A12), which
mediates entry (uptake) of urate into cells. URAT1 is lo-
cated on adipocytes [62,63] and URAT1 transporter gene
polymorphisms in hypertensive subjects are associated
with body mass index (BMI), waist circumference, HDL
cholesterol, and the metabolic syndrome; - they accounted
for 7% of the variation of BMI in Caucasians. However,
there was no such association in African Americans .
In support of an involvement of adipocytes is a study in
obese mice with the metabolic syndrome . These mice
are hyperuricaemic and lowering urate levels with allopur-
inol improves their pro-inflammatory phenotype in adi-
pose tissue, with decreased macrophage infiltration and
reduced insulin resistance.
A recent clinical trial studied urate-lowering with benz-
bromarone in patients with CHF . While there was no
effect on the altered haemodynamics in these CHF pa-
tients, lowering urate did improve insulin resistance. How-
ever, it cannot be excluded that it may have been a
secondary pharmacological effect of benzbromarone re-
lated to its PPAR agonist activity. In a small Polish study,
28 patients with CKD were switched from a regular fruc-
tose diet to a low fructose diet for 6 weeks, and then back
again. There were significant reductions in fasting serum
insulin and inflammatory biomarkers, and a trend toward
reductions in serum urate and blood pressure .
Gustafsson and Unwin BMC Nephrology 2013, 14:164
Page 5 of 9
Hyperuricaemia could be a risk factor for T2DM, but
a causal link remains controversial. Thus, there are stud-
ies concluding an association, no association, and even
an inverse association, and have been reviewed recently
by Li et al. . Obesity is associated with reduced life-
expectancy, largely because of the increased risk of car-
diovascular disease. However, approximately a third of
obese individuals do not develop cardiovascular disease.
This group is generally referred to as the ‘metabolically
healthy obese’. In a recent study, serum urate was the
best predictor of ‘metabolically unhealthy obesity’ (defined
as having features of the metabolic syndrome), with in-
creased cardiovascular risk in adolescents and adults .
Some studies also suggest an independent association be-
tween non-alcoholic fatty liver disease (NAFLD) and hy-
peruricaemia . Hyperuricaemia is also independently
associated with the severity of steatosis and a poor re-
sponse to therapy in patients with chronic hepatitis C in-
It should also be mentioned that there is an increased
incidence and prevalence of nephrolithiasis in patients
with T2DM, and it is possible that treatment with a
URAT1 inhibitor might, as a side effect, increase the risk
of forming urate stones. With insulin resistance, although
urinary urate levels are usually not increased (because of
increased renal tubular reabsorption of urate), urinary am-
monium excretion is reduced and urine pH is more acid,
which increases the risk of urate crystallization .
Atherosclerosis and cardiovascular events
The Framingham Heart Study reported that urate was
not a risk factor for cardiovascular events, because urate
was not independent of hypertension . A systematic
review and meta-analysis determined the risk of coron-
ary heart disease (CHD) associated with hyperuricaemia
in 26 studies with 402,997 adults. It was found that
hyperuricaemia may modestly increase the risk of CHD
events independently of traditional CHD risk factors.
Women were found to have a more pronounced in-
crease in risk for CHD mortality than for men . A
similar meta-analysis was performed for hyperuricaemia
and stroke (16 studies, 238,449 adults), showing that
hyperuricaemia modestly increased the risk of stroke in-
cidence and mortality, independent of known risk fac-
tors, but without gender difference .
The potential relationship between hyperuricaemia and
cardiovascular events could be through hypertension, but
it may also involve a direct relationship due to disturbed
endothelial function as a consequence of reduced nitric
oxide production. Endothelial dysfunction is believed to
play a key role in the early development of atheroscle-
rosis and precedes plaque formation . Endothelial-
dependent flow-mediated vasodilatation of the brachial
artery can assess, among other things, nitric oxide-induced
vasodilatation. A recent review and meta-analysis  of
XO inhibitors evaluated three outcome parameters and
showed favourable changes in each one following XO in-
hibition: brachial artery flow-mediated dilatation (5 stud-
ies: XO inhibition n = 75, control n = 69) increased by
2.5% (95% CI, 0.15–4.84); forearm blood flow responses to
acetylcholine infusion (5 studies: XO inhibition n = 74,
control n = 74) increased by 68.8% (95% CI, 18.7–118.9; a
percent change relative to the non-infused control arm);
circulating markers of oxidative stress (malondialdehyde,
6 studies: XO inhibition n = 78, control n = 68) decreased
by 0.56 nmol/mL (95% CI, 0.26–0.87). Three additional
studies have been published following this review, two are
positive [76,77] and one is negative . However, it is
noteworthy that short-term lowering of serum urate by
intravenous uricase had no effect on forearm blood flow
responses to acetylcholine and L-NMMA (n = 10 patients
and n = 10 healthy subjects ).
The present review of the available literature shows that
there is an association between serum urate levels and
hypertension, CKD, heart failure, the metabolic syn-
drome, obesity and cardiovascular events. However, as is
often the case in the published literature, support is not
unanimous. Understanding in the field is hampered by
the difference in urate metabolism between laboratory
animals and man, which makes animal studies difficult
to interpret. Thus, there is limited evidence for a causal
relationship. The interventional studies in man can be
considered more as hypothesis-generating, since design
quality, duration, and sample size are often insufficient
to clarify the role of urate in cardiovascular disease. In
addition, most interventional studies are with allopur-
inol, which is lowering urate via inhibition of XO, lead-
ing to decreased production of ROS, which may have
contributed to any apparent beneficial effect. A definitive
answer to the question of whether urate-lowering therapy
can reduce cardiovascular morbidity and mortality will, in
the end, require large interventional trials, but it is doubt-
ful that the safety profile of allopurinol is sufficient for
such large-scale studies. The recently approved and emer-
ging novel urate-lowering agents may have a better safety
profile for these much needed larger and longer-term
studies. Ideally, these studies would compare cardiovascu-
lar endpoints in patients treated with placebo versus XO
and/or URAT1 inhibition, to establish both the benefits
and mechanisms of treating hyperuricaemia.
A very recent online publication has used mendelian
randomization to investigate the association of plasma uric
acid (SLC2A9) with ischaemic heart disease and hyperten-
sion (Palmer et al, BMJ 2013;347:f4262 doi: 10.1136/bmj.
f4262) and concluded that there is no strong evidence for
Gustafsson and Unwin BMC Nephrology 2013, 14:164
Page 6 of 9
a causal association, and that the apparent link is con-
founded by body weight.
BMI: Body mass index; CHD: Coronary heart disease; CHF: Congestive heart
failure; CKD: Chronic kidney disease; GWAS: Genome-wide association studies;
MS: Multiple sclerosis; NAFLD: Non-alcoholic fatty liver, disease; ROS: Reactive
oxygen species; T2DM: Type 2 diabetes mellitus; XO: Xanthine oxidase.
DG is an employee of AstraZeneca and RU is consulting with AstraZeneca.
DG drafted the manuscript and both DG and RU revised it and approved the
final manuscript. Both authors have read and approved the final manuscript.
The authors would like to thank Peter Morsing for initiating this work and
James Mackay and his team for valuable input on the manuscript.
1Bioscience, CVMD iMED, AstraZeneca R&D Mölndal, Mölndal, Sweden.
2University College London, UCL Centre for Nephrology, Royal Free Campus,
Received: 14 May 2013 Accepted: 19 July 2013
Published: 29 July 2013
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Cite this article as: Gustafsson and Unwin: The pathophysiology of
hyperuricaemia and its possible relationship to cardiovascular disease,
morbidity and mortality. BMC Nephrology 2013 14:164.
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