Clin J Am Soc Nephrol. 2011 August; 6(8): 1887–1894.

doi: 10.2215/CJN.11451210

PMCID: PMC3359530

Original Articles

A Randomized Study of Allopurinol on Endothelial Function and Estimated Glomular Filtration Rate in

Asymptomatic Hyperuricemic Subjects with Normal Renal Function

Mehmet Kanbay, * Bulent Huddam,† Alper Azak,† Yalcin Solak,‡ Gulay Kocak Kadioglu,† Ismail Kirbas,§

Murat Duranay,† Adrian Covic,‖ and Richard J. Johnson¶

*Department of Medicine, Division of Nephrology, Kayseri Training and Research Hospital, Kayseri,

Turkey;

†Department of Medicine, Division of Nephrology, Ankara Training and Research Hospital, Ankara,

Turkey;

‡Department of Medicine, Division of Nephrology, Selcuk University, Meram School of Medicine, Konya,

Turkey;

§Department of Radiology, Fatih University School of Medicine, Ankara, Turkey;

‖Nephrology Clinic, Dialysis and Renal Transplant Center, C.I. Parhon University Hospital, Gr. T. Popa

University of Medicine and Pharmacy, Iasi, Romania; and

¶Division of Renal Diseases and Hypertension, University of Colorado-Denver, Denver, Colorado

Corresponding author.

Correspondence: Dr. Mehmet Kanbay, Alparslan Mahallesi, Umit sokak, No. 25/14, Melikgazi, Kayseri,

Turkey., Phone: 90505-266-88-66; Fax: +90 3323237121; E-mail: drkanbay@yahoo.com

Received December 27, 2010; Accepted April 1, 2011.

Copyright© 2011 by the American Society of Nephrology

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Abstract

Summary

Background and objectives

Endothelial dysfunction is an early manifestation of vascular injury and contributes to the development

of atherosclerotic cardiovascular disease. Recent studies have implicated hyperuricemia as a risk factor

for cardiovascular disease. We hypothesized that lowering uric acid in subjects with asymptomatic

hyperuricemia with allopurinol might improve endothelial dysfunction, BP, estimated GFR (eGFR), and

inflammatory markers.

Design, setting, participants, & measurements

Subjects with asymptomatic hyperuricemia and no history of gout and 30 normouricemic control

subjects were enrolled in this 4-month randomized prospective study. Thirty hyperuricemic patients

received 300 mg/d allopurinol and were compared with 37 hyperuricemic patients and 30

normouricemic subjects in matched control groups. Flow-mediated dilation (FMD), eGFR, ambulatory BP

monitoring, spot urine protein-creatine ratio, and highly sensitive C-reactive protein were measured at

baseline and at 4 months.

Results

Age, gender, lipid profile, eGFR, hemoglobin, glucose, and level of proteinuria were similar in

hyperuricemic subjects and controls at baseline. As expected, hyperuricemic patients had higher levels

of highly sensitive C-reactive protein and lower FMD compared with normouricemic patients.

Allopurinol treatment resulted in a decrease in serum uric acid, a decrease in systolic BP, an increase in

FMD, and an increase in eGFR compared with baseline. No significant difference was observed in the

control hyperuricemic and normouricemic groups. In a multiple regression analysis, FMD levels were

independently related to uric acid both before (beta = −0.55) and after (beta = −0.40) treatment.

Conclusions

Treatment of hyperuricemia with allopurinol improves endothelial dysfunction and eGFR in subjects

with asymptomatic hyperuricemia.

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Introduction

Asymptomatic hyperuricemia is commonly viewed as an entity that should not be treated (1,2).

However, there is increasing evidence that hyperuricemia may not be completely benign. Numerous

studies and meta-analyses have found that elevated uric acid levels predict the development of

hypertension, stroke, diabetes, and heart disease (3–6). The reverse seems also true: short-term trials

also suggest a benefit from lowering uric acid on BP (7–9), insulin resistance (10), estimated GFR (eGFR)

(9,11,12), C-reactive protein (CRP) levels (9,11), and endothelial dysfunction (13). However, most of

these studies were short term or were not randomized, and only a few prospective randomized trials

have been performed (8,11,14). Furthermore, many of these studies included subjects with

hypertension, diabetes mellitus, chronic kidney disease, or cardiovascular disease and did not evaluate

healthy individuals whose only abnormality was hyperuricemia. Thus, it is still unknown whether

treatment of asymptomatic hyperuricemia in low-risk patients would provide benefit to patients in

terms of renal function, endothelial dysfunction, and BP. We therefore decided to prospectively

determine the effect of allopurinol treatment on renal function, proteinuria, serum CRP, BP, and

endothelial dysfunction (assessed by flow-mediated dilation [FMD]) in asymptomatic hyperuricemic

patients with normal renal function and no evidence of cardiovascular disease.

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Materials and Methods

Study Design and Participants

This is a prospective, randomized 7-month intervention trial conducted at Ankara Research and Training

Hospital between December 2009 and June 2010. The study was approved by the Local Ethics

Committee and was conducted in accordance with the ethical principles set forth by the Declaration of

Helsinki. All of the participants were included after signing informed consent forms. The primary

endpoint of the study was whether allopurinol treatment would affect endothelial dysfunction, BP, and

eGFR in asymptomatic hyperuricemic subjects without a history of any comorbid disease compared with

untreated controls. A total of 105 consecutive patients who attended the outpatient general internal

medicine clinic and had normal renal function and fulfilled inclusion criteria were recruited for the study.

Of these, 72 patients were hyperuricemic (defined as serum uric acid >7 mg/dl), whereas the remaining

33 patients were normouricemic. Seventy-two hyperuricemic patients were randomly assigned to

receive either allopurinol 300 mg/d for 4 months or no treatment to serve as controls by means of

computer-generated random numbers. A flow diagram of the study design is depicted in Figure 1. All of

the groups had levels of serum uric acid, highly sensitive CRP (hsCRP), morning spot urine protein-

creatine ratio, systolic and diastolic BP, eGFR, and FMD at baseline and at the end of the 4-month study

period.

Inclusion criteria consisted of subjects with adult (>18 years) asymptomatic hyperuricemia without

presence of diabetes, hypertension, heart failure, gout, or overt cardiovascular disease (n = 72). An

additional control group without hyperuricemia who also had no evidence for the same comorbid

conditions was also included (n = 33). To minimize any confounding effect of conditions that may

influence endothelial function, patients with a history of coronary artery disease, active smokers, and

patients receiving angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, or

supplemental vitamin pills were excluded. Subjects with a history of diabetes, those on oral

hypoglycemic agents or insulin, or those with a fasting glucose level greater than 126 mg/dl were also

excluded. The patients were monitored for potential adverse effects of allopurinol on a monthly basis

via system review and a comprehensive physical examination.

Laboratory Testing

Blood and biochemistry panels including fasting blood glucose, serum uric acid, morning spot urine

protein-creatine ratio, hsCRP, and LDL cholesterol were analyzed by a hospital autoanalyzer at onset of

the study and were repeated at the end of the 4-month study period for all patients. The eGFR was

calculated using the Cockcroft-Gault formula.

Flow-mediated Dilation

The determination of endothelial dysfunction was performed according to Celermajer et al. (15).

Measurements were made by a single observer who was blinded to the randomization status of the

patients using an ATL 5000 ultrasound system (Advanced Technology Laboratories Inc., Bothell, WA)

with a 12-MHz probe. All of the vasoactive medications were withheld for 24 hours before the

procedure. The subjects remained at rest in the supine position for at least 15 minutes before the

examination started. The subject's arm was comfortably immobilized in the extended position to allow

consistent recording of the brachial artery 2 to 4 cm above the antecubital fossa. Three adjacent

measurements of end-diastolic brachial artery diameter were made from single two-dimensional

frames. All of the ultrasound images were recorded on S-VHS videotape for subsequent blinded analysis.

A pneumatic tourniquet was inflated to 200 mmHg with obliteration of the radial pulse. After 5 minutes,

the cuff was deflated. Flow measurements were made 60 seconds after deflation. The maximum FMD

diameters were calculated as the averages of the three consecutive maximum-diameter measurements.

The FMD was then calculated as the percentage of change in diameter compared with baseline resting

diameters.

Ambulatory BP Monitoring

All of the subjects underwent 24 hours of ambulatory BP monitoring (ABPM) on a usual working day.

They were instructed to act and work normally. ABPM was performed using a Reynolds Medical Tracker

NIBP2 oscillometric monitor. Each patient used an arm cuff of similar size to the one used for routine

office BP measurement in the nondominant arm. The device was programmed to measure BP every 15

minutes between 6:00 a.m. and 11:00 p.m., and every 30 minutes between 11:00 p.m. and 6:00 a.m. All

of the subjects were instructed to rest or sleep between 10:00 p.m. and 6:00 a.m.

Statistical Analyses

All of the data are presented as the means ± SDs unless stated otherwise. Continuous variables were

checked for the normal distribution assumption using the Kolmogorov-Smirnov statistics. ANOVA test

was used for multiple group comparisons of normally distributed variables. χ2 was used to test

differences in frequency distributions. All of the potential (physiologically meaningful) determinants of

the FMD were investigated in a univariate screening procedure, using the Pearson coefficient of

correlation test. The nonparametric Spearman rho coefficient of correlation was used to assess

correlations between variables without normal distribution. One-way ANOVA, t test, and paired-sample

t test were used to compare numeric data. Significant determinants identified from this analysis were

studied in a multiple regression model using the F statistic. All of the variables associated with these

parameters with a level of significance <0.1 were included in the tested model. The variables were

forced in the model using a stepwise procedure. P < 0.05 for the final model was considered as

statistically significant. The data were analyzed using the SPSS 15.0 for Windows software (SPSS Inc.,

Chicago, IL). The sample size was calculated by the Power and Sample Size V.3.0 program (Vanderbilt

University, Department of Biostatistics, Free Software). The criteria for sample size calculation were as

follows: 95% confidence intervals, 80% power, and a decrease in serum uric acid levels (2 mg/dl for

allopurinol treatment, according to our previous study (9). According to these criteria, 24 patients were

to be recruited in each group. Considering the possibility of laboratory and other process mishaps, we

decided to include at least 30 patients in each group.

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Results

Baseline Characteristics

Demographic, clinical, and laboratory data at baseline in the three groups are shown in Table 1. There

was no difference among the groups with respect to age, gender, blood glucose, and LDL cholesterol

levels at baseline. As expected, hyperuricemic patients had higher hsCRP levels and lower FMD and

eGFR values compared with normouricemic controls. FMD correlated inversely with uric acid levels

when the three groups were combined (rho = −0.58, P = 0.001; Figure 2). No significant difference in

baseline spot urine protein to creatinine ratio and 24-hour ABPM-derived BP levels were noted between

hyperuricemic and normouricemic subjects, consistent with the inclusion criteria to study only

normotensive subjects.

Effects of Allopurinol Treatment on Serum Uric Acid, hsCRP, Proteinuria, eGFR, and FMD Values

Treatment with allopurinol in the 37 hyperuricemic subjects for 4 months resulted in a significant

decrease in serum uric acid, a decrease in systolic BP and hsCRP, and an increase in eGFR and FMD

compared with baseline values (P < 0.05 for all [Table 2]). In contrast, control hyperuricemic and

normouricemic subjects showed no change in these parameters from baseline, although a trend for

improvement in uric acid levels, FMD, and systolic and diastolic BP was observed in the untreated

hyperuricemic controls (Table 2). In addition, there was a significant improvement in hsCRP in the

hyperuricemic control group when compared with baseline values (P < 0.05). Flow-mediated dilation at

baseline and at 16 weeks in the allopurinol, hyperuricemic, and normouricemic control groups are

presented in Figure 3. All of the patients in the allopurinol group tolerated the drug, and there were no

adverse effects detected by physical examination or reported by patients.

Univariate and Multivariate Analyses for the FMD

A multiple regression model incorporating variables expected to influence FMD (gender, age, eGFR,

hsCRP, and systolic BP), as well as serum uric acid was performed both before (at baseline) and after

treatment. FMD levels were independently related to uric acid levels both before (P = 0.03) and after (P

= 0.024) treatment (Table 3).

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Discussion

The salient findings of this study were that lowering serum uric acid with allopurinol led to

improvements in estimated GFR, systolic BP, and endothelial dysfunction assessed by FMD. However,

we could not document any significant improvement in hsCRP, proteinuria, or diastolic BP after

treatment with allopurinol, compared with untreated hyperuricemic or with normouricemic controls.

Endothelial dysfunction is considered a harbinger for hypertension and cardiovascular disease (16). FMD

as a physiologic measure of endothelial function has been validated and used in many settings to

investigate endothelial function (17). Several studies have reported an inverse relationship between uric

acid and endothelial function/FMD (13,18–21), although this has not uniformly been noted (22). A

number of studies have also reported that lowering uric acid with allopurinol may improve endothelial

function in individuals with a variety of conditions, including subjects with heart failure (23–25), those

with diabetes (26), heavy smokers (27), or those with obstructive sleep apnea (28). However, to our

knowledge, only one study examined the effect of allopurinol on endothelial function in subjects with

asymptomatic hyperuricemia (13). In this study allopurinol was administered for 4 months to 32

hyperuricemic patients who were at high risk for cardiovascular disease. Compared with baseline values

and with normouricemic untreated controls, allopurinol treatment significantly increased FMD values, in

parallel with a reduction in serum uric acid levels. Clearly, these subjects were not truly healthy subjects,

because many of them were diabetic, hypertensive, and/or were on medications that may potentially

effect endothelial dysfunction per se. In our study, we purposefully excluded potential confounding

factors, which could affect endothelial function, by specifically selecting subjects who did not have

diabetes, hypertension, or who were not receiving statins, angiotensin-converting enzyme inhibitors, or

angiotensin-receptor blockers. Thus, the importance of our study is that it suggests that endothelial

function can be improved with allopurinol therapy, even in subjects with asymptomatic hyperuricemia

and no history of gout who lack all evidence of cardiovascular disease. Our results showed that with

allopurinol treatment, mean FMD values were increased by 0.4%. FMD has been shown to be an

independent predictor of future cardiovascular events in population-based studies (29,30). The higher

the baseline FMD, the more likely the patient will experience a future cardiovascular event. Thus,

reduction of FMD with administration of allopurinol might have important long-term implications.

Prospective randomized trials are yet to be conducted to demonstrate whether this is the reality.

We also documented that the lowering of uric acid with allopurinol can improve eGFR. An elevated uric

acid has been consistently shown to predict a fall in GFR in the adult without kidney disease (31–34).

Recent small interventional trials have also shown that lowering uric acid can improve renal function in

subjects with CKD (11,12). In a previous study, we showed a favorable effect of 3-month allopurinol

treatment on estimated GFR, in a population of asymptomatic hyperuricemic patients (9). Mean

creatinine clearance determined via collection of 24-hour urine increased from 79 ± 32 to 93 ± 37

ml/min, after allopurinol treatment. In this study, eGFR values (calculated using the Cockcroft-Gault

equation) increased slightly but significantly from a baseline of 86 ± 19 to 89 ± 18 ml/min per 1.73 m2 at

the end of the allopurinol treatment phase.

We documented a decrease in 24-hour systolic ambulatory BP with allopurinol treatment. The

allopurinol-treated subjects had a decrease of 10 mmHg in systolic BP, whereas the hyperuricemic

controls and normouricemic controls had decreases in systolic BP of 6 and 3 mmHg, respectively. Studies

in experimental animal models of hyperuricemia have suggested that uric acid can raise BP, likely via the

induction of oxidative stress, endothelial dysfunction, and activation of the renin-angiotensin system

(35–38). These studies have suggested that an elevated level of uric acid may be more important for

new-onset hypertension rather than long-standing hypertension, in which renal microvascular disease

may be the key factor driving the hypertensive response (39). A recent small clinical trial reported that

allopurinol can lower BP in newly diagnosed hypertension in adolescents (7,8). We also previously

reported that allopurinol improved both systolic and diastolic BP in 48 adults with normal renal function,

of whom most had hypertension (34 out of the 48) or high-normal BP (9). Thus, this study is the first

demonstrating a BP-lowering effect of lowering serum uric acid via allopurinol, even in normotensive

adults, thus extending our previous findings. Notably, allopurinol selectively reduced systolic BP but not

diastolic BP. It is possible that this may relate to the normal baseline values of BP readings of the

hyperuricemic patients. Our previous study (9) included patients who were hypertensive at baseline. It is

recognized that the higher the baseline BP, the greater the effect of a given drug that reduces BP.

Interestingly, our study did not confirm a beneficial effect of lowering uric acid on either CRP levels or on

urinary protein excretion. Other studies, however, do suggest that lowering uric acid can improve

inflammatory markers in subjects with CKD (11), heart failure (10), and stroke survivors (40). We also

found that allopurinol improved CRP levels in mostly hypertensive adults with asymptomatic

hyperuricemia (9).

It should be mentioned that the beneficial effects of allopurinol treatment observed in this cohort may

be the consequence of both lowering serum uric acid levels (thereby amelioration of uric acid mediated

pathophysiologic processes) and of inhibiting the xanthine oxidase enzyme system (thereby decreasing

oxidative stress generated during the production of uric acid). Some clinical and experimental studies

suggest that the benefit of blocking the xanthine-oxidase system on endothelial dysfunction may relate

to the inhibition of xanthine oxidase-associated oxidants as opposed to lowering uric acid. However, in a

recent study (10), the uricosuric drug benzbromarone (which is not a xanthine-oxidase inhibitor) was

shown to improve inflammatory markers and insulin resistance in patients with congestive heart failure,

suggesting a direct effect of lowering uric acid on inflammation.

In summary, our study is the first to examine the effect of lowering uric acid in subjects with

asymptomatic hyperuricemia who lack a history of gout, hypertension, or cardiovascular disease. An

improvement in endothelial function, systolic BP, and eGFR was observed. The effects were mild but

significant so that a larger number of patients and longer follow-up will be necessary before one can

determine whether such a strategy may provide long-term survival benefits. Our study was also limited

by being an open-label trial and lacked a placebo control. Allopurinol can also cause severe allergic

reactions, although there are early promising studies suggesting that side effects may be reduced by

screening subjects for HLA-B58 (41,42). Our study was also performed in adults, and some studies

suggest that the potential benefits of allopurinol could potentially be much more significant in

adolescents and younger subjects. Indeed, a multicenter trial has been proposed to the National

Institutes of Health to determine whether lowering uric acid in prehypertensive adolescents and young

adults may have benefit in preventing BP rise and the development of metabolic syndrome. Clearly,

more studies are necessary to assess the risk/benefit of lowering uric acid in subjects with asymptomatic

hyperuricemia.

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Disclosures

Dr. Johnson has patent applications related to lowering uric acid as a means to treat hypertension,

reduce the frequency of diabetes, and treat fatty liver. The other authors have no relationships or

financial interests with companies related to the findings of this work.

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Footnotes

Published online ahead of print. Publication date available at www.cjasn.org.

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Figures and Tables

Figure 1.

Flow diagram of study design.

Table 1.

Baseline characteristics of the study population

Normouricemic Control

Group (n = 30)

Hyperuricemic Control

Group (n = 37)

Allopurinol Group

(n = 30) P

Age (years, mean) 48.4 ± 9.2 50.4 ± 11.2 54.4 ± 8.0 0.13

Normouricemic Control

Group (n = 30)

Hyperuricemic Control

Group (n = 37)

Allopurinol Group

(n = 30) P

Male, n (%) 14 (46) 18 (48) 16 (53) 0.23

Hemoglobin (g/dl) 14.0 ± 1.4 13.9 ± 1.6 14.8 ± 1.2 0.07

Uric acid (mg/dl) 4.4 ± 0.9 7.9 ± 0.7 8.3 ± 1.1 <0.01

BMI (kg/m2) 28.4 ± 3.3 29.7 ± 3.4 28.4 ± 2.9 0.26

24 h systolic BP

(mmHg) 119.4 ± 11.2 123.2 ± 13.5 127.6 ± 10.4 0.08

24 h diastolic BP

(mmHg) 77.3 ± 6.1 75.6 ± 8.7 75.1 ± 7.8 0.06

eGFR (ml/min per

1.73 m2) 92.8 ± 13.7 84.3 ± 16.7 86.3 ± 19.4 0.04

Urine protein-

creatinine ratio 0.11 ± 0.04 0.12 ± 0.13 0.12 ± 0.09 0.52

hsCRP (mg/l) 3.3 ± 2.5 6.9 ± 3.4 7.4 ± 5.8 0.02

LDL-cholesterol

(mg/dl) 125.7 ± 38.3 113.5 ± 34.4 123.0 ± 30.7 0.44

Glucose (mg/dl) 89.8 ± 7.9 90.3 ± 6.4 94.3 ± 6.9 0.06

Flow-mediated

dilation (%) 9.16 ± 0.65 7.76 ± 0.86 7.74 ± 0.93 <0.01

View it in a separate window

Mean values are reported as ± SD. The bold values indicate P < 0.05, statistically significant. BMI, body

mass index; eGFR, estimated GFR; hsCRP, highly sensitive C-reactive protein.

Figure 2.

Scatter plot shows the significant negative association between the change in uric acid and flow-

mediated dilation (FMD).

Table 2.

The mean serum uric acid, flow-mediated dilation (FMD), and mean systolic (SBP) and diastolic (DBP)

blood pressure at baseline and 16 weeks later

Allopurinol Group (n = 30)

Hyperuricemic Control

Group (n = 37)

Normouricemic Control

Group (n = 30)

Baseline 16

weeks P Baseline 16 weeks P Baseline 16 weeks P

Uric acid

(mg/dl) 8.3 ± 1.1 5.8 ± 1.5 <0.001 7.9 ± 0.7

7.2 ±

0.83 0.70 4.4 ± 0.9 4.5 ± 0.86 0.26

FMD (%) 7.74 ± 8.12 ± 0.003 7.76 ± 0.86 7.77 ± 0.52 9.16 ± 0.65 9.24 ± 0.18

Allopurinol Group (n = 30)

Hyperuricemic Control

Group (n = 37)

Normouricemic Control

Group (n = 30)

Baseline 16

weeks P Baseline 16 weeks P Baseline 16 weeks P

0.93 1.56 0.85 0.66

eGFR (ml/min

per 1.73 m2)

86.3 ±

19.4

89.6 ±

12.6 0.001 84.3 ± 16.7

84.4 ±

16.3 0.77 92.8 ± 13.7 93.3 ± 9.2 0.63

hsCRP (mg/dl) 7.4 ± 5.8 4.6 ± 3.7 0.003 6.9 ± 3.4 5.9 ± 3.8 0.04 3.3 ± 2.5 3.4 ± 2.2 0.79

Mean SBP

(mmHg)

127.6 ±

14.4

116.9 ±

11.7 0.005

123.2 ±

13.5

116.8 ±

9.9 0.26

119.4 ±

11.2

116.4 ±

13.4 0.46

Mean DBP

(mmHg) 75.1 ± 7.8

74.9 ±

12.4 0.19 75.6 ± 8.7

73.9 ±

13.9 0.22 77.3 ± 6.1

76.2 ±

11.8 0.39

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The bold values indicate P < 0.05, statistically significant. eGFR, estimated GFR; hsCRP, highly-sensitive C-

reactive protein.

Figure 3.

Flow-mediated dilation (FMD) at baseline and 16 weeks after in allopurinol, hyperuricemic, and

normouricemic control group.

Table 3.

Analysis of association between flow-mediated dilation (FMD) and some different parameters by

multivariate linear regression both before and after allopurinol treatment

Multivariate β (P) 95% CI for β

Before treatment

uric acid (mg/dl) −0.42 (0.03) −1.42 to −3.17

age (year) 0.57 (0.16) −0.17 to 0.34

male gender 0.39 (0.06) −0.83 to 1.46

hsCRP (mg/L) −0.13 (0.12) −1.08 to 0.46

eGFR (ml/min per 1.73 m2) −0.42 (0.14) −0.75 to 0.04

systolic BP (mmHg) 0.44 (0.17) −0.01 to 0.03

After treatment

Multivariate β (P) 95% CI for β

uric acid (mg/dl) −0.37 (0.024) −0.52 to −0.23

age (year) 0.04 (0.87) −0.20 to 0.34

male gender 0.32 (0.05) −0.46 to 0.93

hsCRP (mg/L) −0.18 (0.09) −0.70 to 0.86

eGFR (ml/min per 1.73 m2) −0.46 (0.96) −0.10 to 0.26

systolic BP (mmHg) 0.08 (0.65) −0.03 to 0.33

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The bold values indicate P < 0.05, statistically significant; β, beta value; CI, confidence interval; hsCRP,

highly sensitive C-reactive protein; eGFR, estimated GFR.

Abstract

Introduction

Materials and Methods

Results

Discussion

Disclosures

Footnotes

References

Figures and Tables

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