Allopurinol Is an Independent Determinant of Improved Arterial Stiffness in Chronic Kidney Disease: A Cross-Sectional Study
et al. (2014) Allopurinol Is an Independent Determinant of Improved Arterial Stiffness in Chronic Kidney
Disease: A Cross-Sectional Study. PLoS ONE 9(3): e91961. doi:10.1371/journal.pone.0091961
Allopurinol Is an Independent Determinant of Improved Arterial Stiffness in Chronic Kidney Disease: A Cross- Sectional Study
Khai P. Ng 0
Stephanie J. Stringer 0
Mark D. Jesky 0
Punit Yadav 0
Rajbir Athwal 0
Mary Dutton 0
Charles J. Ferro 0
Paul Cockwell 0
Jose Vina, University of Valencia, Spain
0 1 Department of Renal Medicine, Queen Elizabeth Hospital Birmingham , Birmingham , United Kingdom , 2 School of Immunity and Infection, University of Birmingham , Birmingham , United Kingdom
Background: Arterial stiffness is increased in patients with CKD and is a powerful predictor of cardiovascular morbidity and mortality. Use of the xanthine oxidase inhibitor allopurinol has been shown to improve endothelial function, reduce left ventricular hypertrophy and possibly improve cardiovascular outcome. We explored the relationship between use of allopurinol and arterial stiffness in patients with chronic kidney disease (CKD). Methods: Cross-sectional observational study of 422 patients with CKD with evidence of, or at high risk of, renal disease progression. Arterial stiffness was determined by carotid-femoral pulse wave velocity (PWV). Results: The mean age was 63616 years, median estimated glomerular filtration rate was 25 (interquartile range: 19-31) ml/ min/1.73 m2 and mean PWV was 10.262.4 m/s. Seventy-seven patients (18%) were receiving regular allopurinol, 61% at a dose of 100 mg/day (range: 50-400 mg/day). Patients receiving allopurinol had significantly lower peripheral pulse pressure, central pulse pressure, central systolic blood pressure, serum uric acid level tissue advanced glycation end product levels but comparable high-sensitivity C-reactive protein levels. Use of allopurinol was associated with lower PWV. After adjusting for age, gender, ethnicity, tissue advanced glycation end product level, peripheral pulse pressure, smoking pack years, presence of diabetes mellitus and use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, the use of allopurinol remained a significant independent determinant of PWV (mean difference: 20.63 m/s; 95% CI, 20.09 to 21.17 m/s, p = 0.02). Conclusion: In patients with CKD, use of allopurinol is independently associated with lower arterial stiffness. This study provides further justification for a large definitive randomised controlled trial examining the therapeutic potential of allopurinol to reduce cardiovascular risk in people with CKD.
Funding: The study is supported by JABBS foundation (Birmingham, United Kingdom) (URL: http://opencharities.org/charities/1128402), University Hospital
Birmingham Charities (URL: http://qehb.org/) and the British Renal Society (URL: http://www.britishrenal.org/). CJF is supported through a National Institute for
Health Research Fellowship (URL: http://www.nihrtcc.nhs.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have read the journals policy and have the following conflicts: PC has received an honorarium for a lecture and research
funding for investigator led studies from the Binding Site. CJF has received lecture fees and advisory board fees from Genzyme Corp. The other authors have
declared no competing interests exist. This does not alter their adherence to PLOS ONE policies on sharing data and materials.
Asymptomatic hyperuricaemia is associated with increased
cardiovascular (CV) and all-cause mortality in the general
population  and in patients with chronic kidney disease
(CKD) . Use of the xanthine oxidase inhibitor allopurinol in
patients with CKD is associated with improvements in surrogate
markers for CV disease (CVD) including endothelial function
[13,14] and left ventricular hypertrophy . Furthermore,
allopurinol use is associated with a slower progression of renal
dysfunction  and a reduction in CV events [15,16] in CKD
Arterial stiffness is increased in patients with CKD and is a
powerful predictor of mortality in this patient group .
Arterial stiffness is associated with endothelial dysfunction and
increased left ventricular mass and is thought to be a key initiating
factor contributing to the elevated CV risk observed in patients
with CKD . Carotid-femoral pulse wave velocity (PWV) is
considered to be the current gold-standard measurement of
arterial stiffness . Although allopurinol has been shown to
improve endothelial function, lower central aortic pressure and
regress left ventricular hypertrophy in patients with CKD, its
effects on PWV remain unclear . We therefore examined the
relationship between allopurinol use and carotid-femoral PWV in
patients with CKD recruited into the Renal Impairment In
Secondary Care (RIISC) cohort study.
The study was approved by the South Birmingham Local
Research Ethics committee (reference: 10/H1207/6) and all
participants gave informed and written consent. The study was
conducted in accordance with the Declaration of Helsinki.
(Clinical Trials Registration Number: NCT01722383; Date of
Registration: November 11, 2012)
Study Design and Participants
The RIISC study is a prospective, observational cohort study of
patients with CKD with evidence of, or at high risk of, renal
disease progression. The inclusion and exclusion criteria have
previously been reported in detail . In brief, patients were
included if they had stage 3 CKD with a declining estimated
glomerular filtration rate (eGFR) of $5 ml/min/year or $10 ml/
min/5years or a urine albumin creatinine ratio (uACR) $70 mg/
mmol on three consecutive occasions, or stage 4/5 CKD. GFR
was estimated (eGFR) using the four-variable Modification of Diet
in Renal Disease (MDRD) equation with serum creatinine
recalibrated to be traceable to an isotope derived mass
spectroscopy method . Patients with established renal failure receiving
dialysis treatment and patients receiving immunosuppressive
medication were excluded from the study. From October 2010
to November 2012, 437 out-patients under regular follow-up were
recruited from renal clinics at two large teaching hospitals in the
Baseline clinical information on participants demographics,
renal diagnosis, diagnosis of diabetes mellitus (DM), CV history,
past medication history, family history, concomitant medication,
smoking and alcohol consumption history were recorded. Presence
of CVD was defined by history or other evidence of angina,
previous myocardial infarction, previous stroke or transient
ischaemic attack, peripheral vascular disease, a previous
revascularisation procedure or heart failure. Presence of DM was defined
as receiving treatment for DM or a confirmed clinical diagnosis of
diet-controlled DM. Smoking history and pack years were
determined by participant self-reporting. An allopurinol user was
defined as a participant who was receiving any dosage of
allopurinol on recruitment. We contacted the primary care
physician of all allopurinol users to obtain further details on the
reason for prescription, presence of side effect related to
allopurinol in the initial 3 months of treatment and start date of
allopurinol to determine the duration of exposure.
Peripheral blood pressure (BP) was measured in the dominant
arm using a British Hypertension Society approved automated
oscillometric sphygmomanometer (BPM-100, BpTRUTM), which
obtained a series of six BP readings at 1-minute intervals after
5 minutes of rest . Mean peripheral BP was derived from the
average of the 2nd to 6th BP readings. Carotid-femoral PWV was
measured non-invasively using the Vicorder system (Skidmore
Medical, Bristol, UK) as previously described . This is an
operator independent and highly reproducible technique with low
within-subject variation . After 5 minutes of lying supine,
PWV measurements were obtained in duplicate; the mean of the
measurements was used in data analyses. Central pressure
waveforms were derived and analysed using pulse wave analysis
as previously described . The central pressure waveform was
analysed to determine the augmentation index (AIx) and central
aortic pressures. AIx represents the difference between the second
and first peaks of the central pressure waveform in systole,
expressed as a percentage of the pulse pressure. Given the known
effects of heart rate, AIx was corrected to a heart rate of 75 beats
per minute (AIx75) .
Routine laboratory testing included blood haematological
(Beckman Coulter Haematology Analyzer) and biochemical
profiles and urinary albumin creatinine ratios (ACR) (Roche
Hitachi 702 Analyser). Additional samples were centrifuged and
serum was aliquoted and stored at 280uC and subsequently batch
analysed for high sensitivity C-reactive protein (hsCRP) using a
commercially available assay (SpaPlus assay, Binding Site). Tissue
advanced glycation end product (AGE) level was determined by
skin autofluorescence (SAF) using a validated AGE ReaderTM
(DiagnOptics BV, Groningen, The Netherlands).
Statistical analysis was performed using SPSS version 19.0
(SPSS Inc, Chicago, IL). Numerical values are expressed as mean
6 standard deviation for parametric data or median (interquartile
range) for non-parametric data. Normality of the distribution of
data was assessed by visual inspection of histogram and normal
probability plot . Non-parametric variables were log
transformed prior to analysis to achieve normal distribution. If normal
distribution was not achieved after transformation,
non-parametric tests were used. Parametric continuous data were compared
using student t-tests and non-parametric using Mann-Whitney
tests. Pearson or Spearmans bivariate correlation analysis was
used to examine the relationship between parametric and
nonparametric numerical variables, respectively. Correlation
coefficient factors were expressed as r for Pearson correlation analyses
and rho for Spearmans analysis. Categorical data were
compared by x2 tests. As age is strongly correlated with arterial
stiffness, we divided the studied population into 4 age quartiles.
Two-way analysis of variance (ANOVA) was performed to
examine the interaction between age and the use of allopurinol
as well as their individual effect on PWV. In addition, multiple
linear regression was performed to explore the relationship
between PWV and independent variables. Missing data was
excluded by cases pairwise during analyses. Statistical significance
is defined as a two-tailed p value ,0.05.
Four hundred and thirty-seven patients were recruited; of whom
14 did not have PWV measured for technical reasons and were
therefore excluded from the study. One patient who was receiving
febuxostat was excluded. Therefore 422 patients were included in
the analyses. The numbers of individuals at each stage of study are
detailed in Figure 1. The baseline demographic and biochemical
characteristics of the study population are shown in Table 1. The
mean age was 63616 years with 60% of male gender and 71% of
white ethnicity. Use of antihypertensive agents was common and
67% were receiving either an angiotensin converting enzyme
inhibitor (ACEI) or angiotensin II receptor blocker (ARB). A small
number (5%) were on both an ACEI and an ARB. There was a
high prevalence of hyperuricaemia; 84% had a serum uric acid
concentration greater than 360 mmol/L. The frequencies of
different stages of CKD were: stage 1, 0.2%; stage 2, 1%; stage
3a, 5.3%; stage 3b, 23.1%; stage 4, 61.7%; stage 5, 8.7%.
Seventyseven patients (18%) were receiving regular allopurinol, 61% as a
dose of 100 mg/day (range: 50400 mg/day). Haemodynamic
parameters are presented in Table 2.
and 1 complained of increased thirst. The mean duration of
allopurinol use at recruitment was 74 months (SD: 54 months).
Use of allopurinol
The demographic, clinical and biochemical characteristics of
the cohort and a comparison between allopurinol users and
nonallopurinol users is shown in Table 1. There was a significantly
higher proportion of patients of male gender and white ethnicity
and a significantly lower proportion of patients who were current
smokers among allopurinol users. Allopurinol users had a higher
body mass index (BMI) than non-allopurinol users. There was no
significant difference in age, prevalence of DM, prevalence of
CVD, percentage of ex-smokers, smoking pack years, total
number of antihypertensive agents used and use of ACEI/ARB
between the groups. Allopurinol users had significantly lower
serum uric acid concentrations and lower SAF level compared to
non-allopurinol users. Other biochemical variables, including
kidney function, albuminuria, lipid and bone profiles and hsCRP
levels were not different between the groups. Allopurinol users had
significantly lower peripheral and central pulse pressures (PP),
central systolic BP (SBP) and PWV (Table 2). There were no
differences in heart rate, peripheral SBP, AIx and AIx75 between
allopurinol and non-allopurinol users.
Among the 77 allopurinol users, details regarding allopurinol
prescription were available from their primary care physician on
59 patients. Ninety four per cent were commenced on allopurinol
for gout and 6% for asymptomatic hyperuricaemia. Side effects
were reported in 12% during the first 3 months of allopurinol
treatment: 3 had acute gout, 2 had a skin rash, 1 had diarrhoea
Use of allopurinol and pulse wave velocity
Univariate correlations with PWV are shown in Table 3.
Although BMI positively correlated with serum uric acid level
(r = 0.178, p,0.001), there was no significant correlation between
BMI and PWV. Uric acid levels, kidney function and hsCRP also
did not correlate with PWV. In participants who were not
receiving ACEI/ARB (n = 141), there was no correlation between
uric acid and PWV (p = 0.66). Six per cent of participants were
receiving a thiazide, use of this drug did not correlate with levels of
uric acid (p = 0.58) or PWV (p = 0.66).
Pulse wave velocity positively correlated with increasing age,
white ethnicity, SAF, peripheral and central SBP and PP.
Exsmokers and smoking pack years had a significant positive
correlation with PWV whilst current smoking did not. Use of
allopurinol (mean difference: 20.8 m/s; 95% CI, 20.2 to
21.4 m/s, p = 0.006), use of ACEI/ARB and Afro-Caribbean
ethnicity were also associated with lower PWV. Neither the dose of
allopurinol or duration of use of allopurinol had a significant
correlation with PWV. Fifty-one per cent (n = 39) of the
allopurinol users had a uric acid level below 416 mmol/L. Among
allopurinol users, there was no difference in PWV between those
with a uric acid below or above this threshold (p = 0.92).
Two-way ANOVA was used to explore the impact of age and
use of allopurinol on PWV. Participants were divided into
quartiles of age (1950, 5165, 6676 and 7792 years). Pulse
wave velocity increased with age and was significantly lower in
All participants (n = 422) Allopurinol user (n = 77) (n = 345)
Body Mass Index (kg/m2) 29.866.8
Data are presented as frequency (percentage), mean 6 standard deviation or *median (interquartile range).
Parametric data was analysed using unpaired two-tailed t-test or Pearsons x2 unless otherwise specified.
1Log-transformed prior to analyses.
11Analysed using Mann-Whiteney U test.
Abbreviations: ACR = albumin creatinine ratio; bpm = beats per minutes; CVD = cardiovascular disease; ACEI = angiotensin converting enzyme inhibitor; ARB = Angiotensin II
receptor blocker; eGFR = estimate glomerular filtration rate, hsCRP = high sensitivity C-reactive protein; SAF = skin autofluorescence.
Abbreviations: AIx: augmentation index; AIx75 = augmentation index adjusted to heart rate of 75 bpm; bpm = beats per minute; DBP = diastolic blood pressure; SBP = systolic
blood pressure; PP = pulse pressure; PWV = pulse wave velocity.
Body Mass Index (kg/m2)
Presence of diabetes mellitus
Presence of cardiovascular disease
Smoking Pack Years**
BpTRU Peripheral SBP (mmHg)
BpTRU Peripheral DBP (mmHg)
Peripheral PP (mmHg)
Central SBP (mmHg)
Central PP (mmHg)
Serum creatinine* (mmol/L)
eGFR (ml/min/1.73 m2)*
Urine ACR (mg/mmol)*
Serum uric acid (mmol/L)
Corrected calcium (mmol/L)
Dose of allopurinol (mg)
Duration of allopurinol exposure (months) 20.019
Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ACR = albumin
creatinine ratio; AIx: augmentation index; AIx75 = augmentation index adjusted to
heart rate of 75 bpm; ARB = angiotensin II receptor blocker; SBP = systolic blood
pressure; DBP = diastolic blood pressure; PP = pulse pressure; SAF = skin
Parametric data was analysed using Pearson correlation unless otherwise
*Natural Log transformed prior to analyses.
**Non-parametric data was analysed using Spearmans bivariate correlation
non-allopurinol users (Figure 2). There was no interaction between
age and use of allopurinol (p = 0.27). There were significant main
effects for both age and use of allopurinol, with age having a large
effect size (partial eta squared = 0.201, p,0.001) and use of
allopurinol having a small albeit significant effect size (partial eta
squared = 0.011, p = 0.03).
A linear regression model was created with PWV as the
dependent variable. Variables which correlated with PWV at a p
value ,0.1 were included in a standard regression model. As there
was strong co-linearity among the BP measures, peripheral PP was
selected from these parameters for incorporation in the regression
model as it had the strongest correlation (r = 0.45, p,0.001) with
PWV. Similarly, smoking pack years was selected to adjust for the
relationship between smoking history and PWV in the regression
model. Preliminary analyses were performed to ensure no
violation of the assumptions of normality, linearity and
multicollinearity. Factors entered into the model were age, gender,
ethnicity, smoking pack years, diagnosis of DM, SAF level,
peripheral PP, use of ACEI/ARB and use of allopurinol. Age,
peripheral PP and use of allopurinol were significant independent
determinants of PWV (Table 4). In the regression model, the use of
allopurinol was associated with a mean reduction of PWV of
0.63 m/s (95% CI, 20.09 to 21.17 m/s, p = 0.02). The model
explained 35% of the variance in PWV. Substituting peripheral
SBP, central SBP or central PP, for peripheral PP and substituting
smoking pack years for current or previous smoking status made
no appreciable difference to the model.
This observational study in a prospectively recruited CKD
cohort suggests that the use of allopurinol was associated with
reduced arterial stiffness as measured by carotid-femoral PWV, the
current gold-standard measurement of arterial stiffness ; this
association was independent of age and BP. Arterial stiffness,
which is a hallmark of CKD, is a well-recognised, powerful
prognostic marker of CV morbidity and mortality in both the
general and CKD population . Increased arterial stiffness
results in higher systolic pressures, greater pressure fluctuations
and leads to ventricular-arterial uncoupling, myocardial
hypertrophy and fibrosis. Alterations in the extracellular matrix and
endothelial dysfunction promoted by chronic inflammation,
increase oxidative stress and accumulation of advanced glycation
end products, vascular calcification, and activation of
reninangiotensin-aldosterone system (RAAS) have been postulated to
contribute to increased arterial stiffness [17,28].
Allopurinol, a xanthine oxidase inhibitor, is commonly
prescribed for patients with gout as a uric acid lowering agent.
During the catalytic reaction that produces uric acid, xanthine
oxidase generates reactive oxidative species, which may contribute
to the development of endothelial dysfunction, hypertension and
vascular damage . Accumulating evidence from interventional
studies indicates that allopurinol improves endothelial dysfunction
[14,30], lowers left ventricular mass , and may slow
progression of CKD and lower CV risk . The results of this
current study suggest that some of the beneficial effect of
allopurinol may occur through reducing arterial stiffness.
Even among allopurinol users there was a high prevalence of
hyperuricaemia. Although several large observational studies have
reported a strong association between hyperuricaemia and CV
morbidity or mortality, the evidence for hyperuricaemia as a risk
factor or risk marker of CVD is conflicting . Despite a
significant association between allopurinol use and PWV, we
found no significant direct association between serum uric acid
levels and PWV. In a small group of patients with chronic heart
failure, George et al demonstrated that the mechanism of
improvement in endothelial function with allopurinol was
Figure 2. Differences in pulse wave velocity according to use of allopurinol and age quartiles.
attributable to reduced oxidative stress and not to uric acid
reduction . CKD is known to be associated with increased
oxidative stress and acute-phase inflammation, which may both
contribute to increased CV risk . We found no significant
difference in the levels of hsCRP between allopurinol users and
non-allopurinol users, suggesting that inflammation was not a
prominent mechanism in this association. Advanced glycation end
product (AGE) has a bi-directional relationship with oxidative
stress, including studies showing that increased oxidative stress is
associated with formation and accumulation of AGE .
Level of tissue AGE as measured by SAF, which positively
correlated with arterial stiffness, was found to be significantly lower
in the allopurinol users when compared to non-allopurinol users,
indicating that this biological pathway may be relevant to the link
between allopurinol use and PWV described here.
Smoking pack years
Presence of diabetes mellitus
Peripheral PP (/5 mmHg)
Use of allopurinol
Mean change of PWV
Adjusted R2 for model = 0.348, p,0.001.
Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CI = confidence interval; PP = pulse pressure, PWV = pulse wave velocity;
SAF = skin autofluorescence.
As arterial stiffness and BP are closely related, it is possible that
the effect of allopurinol on arterial stiffness may be mediated
through improved BP. A recent meta-analysis showed that
allopurinol is associated with a small but significant reduction in
BP . Several hypotheses have been postulated to explain this
apparent association. The antioxidant effect of allopurinol was
considered to play a major role in improving endothelial function
and blood pressure regulation . Nonetheless, there was no
clear consensus to-date with regards to the effects of oral
antioxidant on arterial blood pressure. While some demonstrated
blood pressure lowering effect of antioxidant vitamins [47,48],
others did not  and one study showed paradoxical blunting
of exercise training-induced improvement in endothelial function
with antioxidant administration . In addition to its antioxidant
property, there is emerging evidence that allopurinol can block the
deleterious cardiovascular effect of angiotensin II . In this
current study we found a significant difference in both peripheral
and central BP between allopurinol users and non-allopurinol
users, despite a comparable prevalence of ACEI/ARB use and
total numbers of anti-hypertensive agents between groups.
However, after adjustment in a multivariate analysis, the use of
allopurinol remained significantly associated with arterial stiffness.
This suggests a distinct direct effect of allopurinol on vascular
stiffness that is independent of BP and the use of ACEI/ARB. This
observation is supported by an RCT of 66 patients with mild to
moderate hypertension which reported a favourable effect of
allopurinol on aortic compliance, independent of ACEI or
thiazide-based antihypertensive therapy .
There were a number of limitations in this study. Due to the
observational, cross-sectional nature of the study and
nonrandomised use of allopurinol, the association between allopurinol
use and lower arterial stiffness reported here does not prove
Although there were unequal distributions of gender, race,
BMI, current smoking status and differences in serum uric acid
between the groups, these are unlikely to have resulted in bias.
Male gender was associated with higher PWV, however despite a
higher proportion of males amongst allopurinol users, use of
allopurinol remained associated with a lower PWV. In addition,
people of Afro-Caribbean ethnicity had a lower PWV; most of the
Afro-Caribbean participants were non-allopurinol users. The
unequal distribution of gender and race between the groups was
therefore unlikely to have resulted in bias against non-allopurinol
use. As the number of non-white participants was small, we were
unable to confidently examine the influence of allopurinol in
different ethnic groups; this should be an area for future study.
Although there were differences in BMI and serum uric acid level
between the groups, these parameters did not have a significant
bivariate association with PWV; hence, they were unlikely to
confound the findings. Smoking history is known to have
significant influence on arterial stiffness and there was a higher
proportion of current smokers in the allopurinol non-user group.
In addition, the comparatively lower peripheral and central
pressures in the allopurinol user group might have contributed to
lower PWV as BP is a strong determinant of arterial stiffness.
However, after adjusted for haemodynamic parameters and
smoking history in the regression model, use of allopurinol
remained associated with lower PWV.
Although all available confounding variables were included in
this study, there may be other potential unknown confounders as
the biology of vascular disease in CKD is complex. The
measurement of hsCRP was performed only at single time-point
rather than the two time-points two weeks apart recommended by
the American Heart Association . We did not have
measurements of endothelial dysfunction, which is closely linked
to arterial stiffness and CKD . Finally, encouraging results
have been reported on an effect of allopurinol in improving renal
function in patients with asymptomatic hyperuricaemia  or
delaying disease progression in patients with CKD [15,60].
However, due to the cross-sectional nature of the data we were
unable to examine this relationship.
In summary, the data shown here suggests that allopurinol is
independently associated with lower arterial stiffness in patients
with progressive CKD. This adds to accumulating evidence of the
favourable effect of allopurinol on cardiovascular outcomes in a
well-defined CKD cohort and indicates one mechanism by which
this may occur. This study provides further justification for a large
definitive RCT examining the therapeutic potential of allopurinol
to reduce cardiovascular risk in people with CKD.
The authors would like to acknowledge the support of the staff in the renal
outpatients department at University Hospital Birmingham, the research
and development department at University Hospital Birmingham and the
remainder of the recruiting RIISC study team.
Conceived and designed the experiments: SJS MD CJF PC. Performed the
experiments: KPN SJS MDJ PY RA MD. Analyzed the data: KPN CJF
PC. Wrote the paper: KPN CJF PC.
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