ORIGINAL ARTICLE

Effects of nicorandil on the reduction of BNP levels in patientswith chronic kidney disease

Tomonori Kimura • Harumi Kitamura • Kazunori Inoue • Noritaka Kawada •

Isao Matsui • Yasuyuki Nagasawa • Yoshitsugu Obi • Maki Shinzawa •

Yasuhiko Sakata • Takayuki Hamono • Hiromi Rakugi • Yoshitaka Isaka

Received: 6 April 2011 / Accepted: 2 August 2011 / Published online: 23 August 2011

� Japanese Society of Nephrology 2011

Abstract

Background Patients with chronic kidney disease (CKD)

still frequently experience cardiovascular events despite

recent progress in treatment. We examined whether nico-

randil, a hybrid nitrate and adenosine triphosphate-sensi-

tive potassium channel opener, could improve a biomarker

and physiological markers of cardiovascular events.

Methods Patients with advanced stage CKD (stage III–V

with or without peritoneal dialysis) were included in this

trial if they were considered at high risk for cardiovascular

events [past history of cardiovascular diseases, past history

of coronary angiography, presence of endothelial dys-

function measured by reactive hyperemia peripheral arte-

rial tonometry, and presence of high brain natriuretic

peptide (BNP) values]. Patients were randomly assigned to

be treated with or without oral nicorandil, 15 mg/day. BNP

values and endothelial function (augmentation index, pulse

wave velocity, and reactive hyperemia peripheral arterial

tonometry) before and 1 month after the initiation of the

trial were assessed.

Results Nineteen patients (15 men, 4 women) with a

mean age of 61 ± 10 (SD) years were included. The

median baseline BNP value was 75.3 (interquartile range,

32.1–138.8) pg/ml, and the BNP level was significantly

reduced in the nicorandil group (P \ 0.05). Regression

analysis demonstrated that only the use of nicorandil is

related to a decrease of BNP levels [standardized b coef-

ficient, -75.1 (95% CI, -19.7 to -130.6), P = 0.01].

There were no significant changes in the rest of the

parameters in the nicorandil group in comparison to the

control group. The change in BNP levels was correlated

with changes in the augmentation index (P \ 0.01) and

central pulse pressure (P = 0.03).

Conclusions Nicorandil treatment may reduce the level

of BNP by reducing the central blood pressure in CKD

patients.

Keywords Nicorandil � Chronic kidney disease (CKD) �Peritoneal dialysis (PD) � Brain natriuretic peptide (BNP) �Endothelial function

Introduction

The number of patients with chronic kidney disease (CKD)

is increasing these days, and CKD patients are at increased

risk for cardiovascular events [1–4]. It is extremely

important to prevent cardiovascular events because they

are not only lethal, but also decrease the quality of life after

recovery [5, 6]. In order to prevent cardiovascular events in

CKD and dialysis patients, evidence-based international

guidelines have been established [7, 8]. These guidelines

are now prevalent among nephrologists and play an

important role in preventing cardiovascular events. How-

ever, CKD patients, especially dialysis patients, still fre-

quently experience cardiovascular events despite the recent

progress in treatment [1, 3, 9, 10]. Thus, we still need

further clinical options to prevent cardiovascular diseases.

On the other hand, CKD patients are known to have high

T. Kimura � H. Kitamura � K. Inoue � N. Kawada �I. Matsui � Y. Nagasawa � Y. Obi � M. Shinzawa �T. Hamono � H. Rakugi � Y. Isaka (&)

Department of Geriatric Medicine and Nephrology,

Osaka University Graduate School of Medicine,

B6, 2-2 Yamada-oka, Suita, Osaka 585-0871, Japan

e-mail: isaka@kid.med.osaka-u.ac.jp

Y. Sakata

Department of Cardiology, Osaka University Graduate

School of Medicine, B6, 2-2 Yamada-oka,

Suita, Osaka 585-0871, Japan

123

Clin Exp Nephrol (2011) 15:854–860

DOI 10.1007/s10157-011-0522-1

levels of cardiovascular biomarkers represented by brain

natriuretic peptide (BNP) [11–13]. CKD patients are also

assumed to have worse endothelial function, although the

prevalence is unclear [14–16]. Both high BNP levels and

endothelial dysfunction are strongly associated with car-

diovascular diseases, and monitoring them allows the

possibility to optimize treatment in CKD patients at high

risk for cardiovascular events.

Nicorandil is not only a nitric oxide donor, but also an

adenosine triphosphate (ATP)-sensitive potassium-channel

opener [17, 18]. It is widely used as a coronary vasodilator,

and is associated with better long-term prognosis in

patients with stable angina and in hemodialysis patients

[19, 20]. Nicorandil presumably acts as a pharmacological

preconditioning agent and/or improves endothelial function

[21–23].

In this study, we investigated the potential role of

nicorandil on CKD and peritoneal dialysis (PD) patients by

assessing BNP levels and endothelial function.

Methods

Study design and patients

This study used the prospective randomized open blinded

endpoints (PROBE) design, which is similar to routine

clinical practice. This study was designed to assess the

improving effects of clinical surrogate markers, which are

associated with higher risk for cardiovascular diseases.

Men and women aged at 20–75 who were being treated for

advanced stages of CKD (estimated glomerular filtration

rate [24] below 60 ml/min with or without PD) at Osaka

University Hospital were included in this trial if they met at

least one of the following criteria: presence of angina, past

history of cardiovascular disease, past history of coronary

angiography, presence of endovascular dysfunction mea-

sured by Endo-PAT, and presence of a high BNP value.

Exclusion criteria included past history of organ trans-

plantation, presence of liver cirrhosis, treatment with anti-

cancer drugs, and treatment with nicorandil. We aimed to

assess the add-on effect of nicorandil; however, CKD

patients are known to be treated with a number of drugs

with frequent prescription changes. Therefore, we gave up

on long-term analysis and decided to assess the very short-

term effect of nicorandil (1 month) to avoid the effect of

changes of other drugs, and we enrolled stably controlled

patients who did not need drug changes during the obser-

vational period. The short duration of the observational

period also had the advantage that changes in body weight,

and thereby body fluid levels, were relatively small in each

individual. All data were recorded electronically by the

study monitors. Written informed consent was obtained

from each patient before participation. This study was

approved by the ethics committee of Osaka University

Hospital.

Trial procedure

Patients were recruited between February 2008 and

September 2010. Eligible patients were randomly assigned

to the nicorandil or control group. Nicorandil was orally

administered at a dose of 15 mg/day (5 mg t.i.d.). We used

permuted-block randomization with a block size of four

(sex and age). Compliance and tolerability were assessed

by primary physicians at the outpatient department.

Measurements

The BNP concentration in each plasma sample was mea-

sured by chemiluminescence enzyme immunoassay (MIO2

Shionogi BNP, Shionogi, Osaka, Japan). The inter- and

intra-assay variability of BNP measurement is less than 5%

according to the manufacturer. Physiological parameters

[augmentation index (AI), central blood pressure, pulse

wave velocity (PWV), and reactive hyperemia-peripheral

arterial tonometry (RH-PAT)] were measured by nonin-

vasive devices. Patients were instructed not to take morn-

ing pills and breakfast before the measurements because

drugs and meals are known to affect the results of these

measurements. PD patients were instructed not to undergo

dialysis during the measurements. Radial AI was measured

as previously described [25, 26]. Briefly, the radial pulse

wave was recorded using automated hands-free applanation

tonometry (HEM-9000AI, Omron Health Care). The aug-

mentation index (AI) was calculated as the ratio of the

amplitude of the late systolic peak (P2) to the amplitude of

the early systolic peak (P1). AI reflects the degree to which

central arterial pressure is enhanced by wave reflection, and

higher AI values suggest increased central arterial stiffness.

The radial pulse wave was transformed to an estimation of

the corresponding central aortic pulse wave from which

central systolic blood pressure (cSBP) and central pulse

pressure (cPP) were identified. The brachial-ankle PWV

was measured by sequentially recording ECG-gated carotid

and femoral artery waveforms to assess arterial stiffness

using a volume-plethysmographic apparatus (Form/ABI,

Omron Health Care) [14]. RH-PAT was measured with

End-PAT2000 (Itamar, Israel) as previously described

[27–29]. Briefly, pneumatic PAT probes were placed on

one finger of each hand for continuous recording of the

PAT signal. The patients were in the supine position and

had both hands on the same level in a comfortable envi-

ronment. After 5 min of baseline measurement, arterial

flow to one upper arm was occluded by inflation of the

blood pressure cuff with suprasystolic pressure (usually

Clin Exp Nephrol (2011) 15:854–860 855

123

40 mmHg above systolic pressure). After the 5-min

occlusion, the cuff was deflated to allow for reactive or

flow-mediated hyperemia, and another PAT signal was

recorded for another 5 min. The PAT index was calculated

as the ratio of the average amplitude of the PAT signal over

a 1-min time interval starting 1 min after cuff deflation

divided by the average amplitude of the PAT signal of a

3.5-min time period before cuff inflation (baseline); PAT

index values from the study arm were then standardized to

the control arm to compensate for potential systemic

changes. This method provides an objective measurement

of endothelial function. Patients with artery-to-vein fistulae

in their arms were excluded from the study because these

fistulae affect the PAT index by modulating the blood flow

to the fingers. The definitions of variables were diabetes

[The International Classification of Diseases, Tenth Revi-

sion (ICD-10) codes E10–E14], hypertension (ICD-10

codes I10–I15), and past cardiovascular disease [ischemic

heart disease (ICD-10 codes I20–I25), heart failure (ICD-

10 code I50), and stroke (ICD-10 codes I60–I67)].

Statistical analysis

All analyses were based on the intention-to-treat principle.

Continuous variables were expressed as mean ± SD.

Baseline clinical parameters of two groups were compared

using the Mann-Whitney U test and Fisher’s exact test.

Changes of clinical parameters between groups were

assessed by Wilcoxon signed rank sum test. The relation-

ships between the changes and covariates were analyzed by

linear regression. Statistical significance was defined as

two-sided P \ 0.05. Data were analyzed with STATA

(version 10).

Results

Of 47 patients, 19 underwent randomization. These

patients were asymptomatic (no congestion and no angina)

and had no limits in daily life. Ten patients were assigned

to no additional treatment (control), and 9 were assigned to

nicorandil therapy (Fig. 1). The intention-to-treat popula-

tion consisted of 19 patients (10 in the control and 9 in the

nicorandil group), and none of the patients dropped out

during the trial.

Table 1 shows baseline characteristics of the treatment

groups. The mean age of all patients was 61 ± 10 (SD)

years, and 15 patients (79%) were men. The number of

antihypertensive agents was similar between groups. All

patients were treated with angiotensin-converting enzyme

inhibitors (ACEi) and/or angiotensin II receptor blockers

(ARB), and almost of the patients received erythropoietin

(94.7%). Blood pressure control was similar in the patients

assigned to the nicorandil and control groups, with mean

values of 142/79 and 143/83 mmHg, respectively, at the

end of follow-up.

The baseline and follow-up values of clinical parameters

are shown in Table 2. The mean baseline BNP value was

99.9 ± 92.8 pg/ml (Fig. 2), and BNP values at baseline

were higher in the nicorandil group than in the control

group (133.9 ± 86.0 vs. 69.3 ± 92.0, P \ 0.05). There

was no significant difference in the baseline values of the

other parameters. Changes in BNP values are shown in

Table 2 and Fig. 3. BNP values were stable in the control

group, whereas they were significantly reduced in the

nicorandil group (P \ 0.05). Although not significant, the

change in BNP values in peritoneal dialysis patients tended

to be higher (P = 0.08, data not shown). There were no

Assessed for eligibility (n = 58)Excluded (n = 39)Not meeting inclusion criteria (n = 28)Declined to participate (n = 11)

Randomized (n = 19)

Analyzed (n = 10) Analyzed (n = 9)

Allocated to control (n = 10)Received allocated control (n = 10)Did no receive allocated control (n = 0)

Lost to follow-up (n = 0)Discontinued intervention (n = 0)

Allocated to intervention (n = 9)Received allocated intervention (n = 9)Did no receive allocated intervention (n = 0)

Lost to follow-up (n = 0)Discontinued intervention (n = 0)

Fig. 1 Trial profile

856 Clin Exp Nephrol (2011) 15:854–860

123

significant changes in the rest of the parameters, including

body weight (Table 2). Univariate regression analysis

using baseline characteristics demonstrated that only the

use of nicorandil was related to a decrease in BNP

levels [standardized b coefficient, -75.1 (95% CI, -19.7

to -130.6), P = 0.01].

The linear regression models showed that the change in

BNP levels was correlated with those of the augmentation

Table 1 Baseline

characteristics of the patients

Values are described as

mean ± SD or %

ACEi angiotensin-converting

enzyme inhibitors, ARBangiotensin II receptor blockers,

PD peritoneal dialysis, APDautomated PD

*P \ 0.05

Characteristic Controls (n = 10) Nicorandil treatment (n = 9) P

Age (years) 64.0 ± 11.6 58.2 ± 9.3 0.23

Male gender (%) 8 (80) 7 (78) 1.00

Body mass index (kg/m2) 22.5 ± 2.6 23.7 ± 3.7 0.63

Origin of kidney disease (%)

Diabetic nephropathy 4 (40) 6 (67)

Benign nephrosclerosis 4 (40) 0 (0) 0.18

Chronic glomerular nephropathy 1 (10) 1 (10)

Others 1 (10) 2 (22)

Diabetes mellitus (%) 5 (50) 6 (67) 0.65

Hypertension (%) 10 (100) 8 (89) 0.47

Hyperlipidemia (%) 4 (40) 4 (44) 1.00

History of cardiovascular disease (%) 2 (20) 3 (33) 0.63

Use of ACEi and/or ARB (%) 10 (100) 9 (100) 1.00

Use of beta-blocker (%) 1 (10) 2 (22) 0.58

Use of calcium blocker 6 (60) 7 (78) 0.63

Use of diuretics (%) 7 (70) 5 (56) 0.58

Use of erythropoietin (%) 9 (90) 9 (100) 1.00

Use of statin (%) 3 (30) 1 (11) 0.58

Systolic blood pressure (mmHg) 151 ± 19 147 ± 22 0.65

Diastolic blood pressure (mmHg) 85 ± 12 87 ± 16 0.84

Heart rate (/min) 76 ± 17 78 ± 9 0.57

Creatinine (mg/dl) 8.7 ± 4.4 8.3 ± 4.2 0.94

Urea nitrogen (mg/dl) 61.5 ± 14.1 56.0 ± 12.0 0.57

Hemoglobin (g/dl) 11.0 ± 1.3 11.2 ± 1.2 1.00

Calcium phosphate (mg2/dl2)* 44.4 ± 9.1 39.7 ± 7.0 0.22

Intact parathyroid hormone (pg/ml) 172 ± 51 322 ± 201 0.07

Peritoneal dialysis (%) 7 (70) 7 (78) 1.00

Duration of PD (years) 1.8 ± 0.6 2.1 ± 1.9 0.95

Use of icodextrin (%) 2 (29) 4 (57) 0.59

Use of APD (%) 6 (86) 4 (57) 0.56

Urinary volume (ml) 800 ± 540 620 ± 460 0.70

Table 2 BNP and

physiological markers at

baseline and follow-up

Values are described as

mean ± SD

BNP brain natriuretic peptide,

AI augmentation index, cSBPcentral systolic blood pressure,

cPP central pulse pressure, SBPsystolic blood pressure, DBPdiastolic blood pressure, PPpulse pressure, PWV pulse wave

velocity, PAT peripheral arterial

tonometry

Parameter Control (n = 10) Nicorandil (n = 9) P

BNP (pg/ml) 69.3 ± 92.1 75.7 ± 96.4 133.9 ± 86.0 65.2 ± 45.3 0.04

AI (%) 73.6 ± 13.9 71.3 ± 11.6 78.0 ± 8.7 70.9 ± 10.4 0.54

cSBP (mmHg) 149.9 ± 21.6 141.3 ± 24.5 149.8 ± 22.1 139.8 ± 17.7 0.87

cPP (mmHg) 65.4 ± 19.0 58.4 ± 16.0 63.2 ± 16.2 60.9 ± 18.3 0.81

SBP (mmHg) 150.8 ± 19.0 143.4 ± 24.0 147.3 ± 21.6 141.9 ± 17.3 0.93

DBP (mmHg) 84.5 ± 11.5 82.9 ± 13.2 86.6 ± 15.6 78.9 ± 11.3 0.22

PP (mmHg) 66.3 ± 18.6 60.5 ± 16.6 60.8 ± 15.4 63.0 ± 18.4 0.62

Body weight (kg) 63.7 ± 11.3 63.0 ± 12.9 63.7 ± 11.6 63.4 ± 12.2 0.43

PWV (cm/s) 1848 ± 250 1815 ± 253 1979 ± 329 1873 ± 340 0.46

PAT index 1.93 ± 0.53 1.95 ± 0.64 2.25 ± 0.74 1.99 ± 0.65 0.27

Clin Exp Nephrol (2011) 15:854–860 857

123

index (P \ 0.01) and central pulse pressure (P = 0.03,

Fig. 4), but not with that of body weight (P = 0.27),

among the hemodynamic variables.

Discussion

The BNP values of most CKD patients are low and rela-

tively independent of kidney function even in advanced

stage CKD patients [13, 30, 31]. Moreover, BNP levels in

CKD patients also reflect poor prognosis. It has been

demonstrated that the BNP level is a predictor of not only

left ventricular hypertrophy, but also poor prognosis [11].

Actually, BNP levels in advanced stages of CKD are also

associated with left ventricular hypertrophy, which is

associated with cardiovascular disease [31]. On the other

-0-50

50-1

00

100-

150

150-

200

200-

250

250-

010

2030

40

Fre

quen

cy (

%)

BNP (pg / mL)

010

2030

40

Fre

quen

cy (

%)

PWV (cm/sec)

1000

-125

012

50-1

500

1500

-175

017

50-2

000

2000

-225

0

2250

-250

0

40-5

0

50-6

0

60-7

0

70-8

0

80-9

0

90-1

00

010

2030

40

Fre

quen

cy (

%)

AI (%)

-1.

0 -1.4

1.4-

1.8

1.8-

2.2

2.2-

2.6

2.6-

3.0

3.0-

010

2030

Fre

quen

cy (

%)

PAT index

020

4060

Fre

quen

cy (

%)

cPP (mmHg)

Fig. 2 Baseline distribution of

BNP and physiological markers.

AI augmentation index, PWVpulse wave velocity, cPPcentral pulse pressure, PATperipheral arterial tonometry

0

100

200

300

BN

P (

pg/m

L)

Control Nicorandil

Baseline Follow-up

*

Fig. 3 Box plot of BNP values at baseline and at follow-up.

*P \ 0.05

858 Clin Exp Nephrol (2011) 15:854–860

123

hand, the value of NT-proBNP is known to surge as the CKD

stage advances. NT-proBNP values have a stronger correla-

tion with eGFR than BNP values, and therefore the cutoff of

NT-proBNP for detecting cardiovascular events in CKD

may be less accurate [32, 33]. Therefore, we applied BNP, not

NT-proBNP, as a prognostic surrogate marker in this study.

It is reported that left ventricular end-systolic wall stress

is the key mechanical stimulus for cardiac BNP release

[34]. Our data demonstrated that the change in BNP levels

is correlated to the changes in AI and cPP. Both AI and cPP

directly reflect the stiffness of central arteries, which

impose on the left ventricular end-systolic wall stress [35].

Therefore, the relative change in BNP levels may represent

the reduction of left ventricular stress, which may result in

the decrease of left ventricular hypertrophy. It has also

been reported that nicorandil may reduce oxidative stress

and inflammation, which are also important in the patho-

genesis of endothelial dysfunction and left ventricular

stiffness [22]. In vivo studies have demonstrated that the

usage of nicorandil increases endothelium-derived nitric

oxide production by endothelial nitric oxide synthase

activation, inhibition of endothelial cell death, and anti-

inflammatory and anti-oxidative effects [36–39]. The

improvement of these pathogens also may have contributed

to the reduction of BNP in this study [21, 22].

Evidence-based guidelines for the management of CKD

patients are highly prevalent these days. For example,

drugs such as ACEi, ARB, and erythropoietin, which play

important roles in preventing cardiovascular events, are

now widely used. These drugs were also applied to almost

all patients in this study. However, even now, some CKD

patients still have high plasma BNP levels, as seen in this

and other studies [13, 30]. This study demonstrated that,

even in such well-controlled CKD patients, nicorandil may

improve BNP levels.

We also found that some patients in this study had

significant endothelial dysfunction. The AI and PWV val-

ues in this population had a wide range and were relatively

worse than in the general population. Recent studies have

shown that both radial AI and brachial PWV are easy to

use, highly reproducible, and related to cardiovascular

events, and therefore, they are easily applicable in daily

clinical settings [14, 25, 26]. Additionally, a lower PAT

index is known to be associated with coronary disease [28,

29], and the number of patients with a PAT index lower

than 1.35 and 1.82 were two (11.8%) and seven (36.8%),

respectively.

This study has several limitations. First, the number of

patients included was rather small, and the patients before

and after initiating peritoneal dialysis were examined

together. Second, the observational period was limited, as

described above. Third, although we carefully conducted an

ordinal randomization by baseline characteristics, this

method does not guarantee the randomization of surrogate

markers. There was a difference in BNP values between

groups, and this limits the understanding of the results.

Because measuring BNP takes more than a day, it is usually

difficult to use these values for randomization in outpatient

settings, and therefore, most studies use baseline charac-

teristics for randomization. It is also necessary to validate

the usage of BNP levels as a prognostic marker in CKD

patients. Despite these limitations, our results indicate a

possible benefit of nicorandil treatment for CKD patients.

In summary, our study demonstrated that nicorandil

treatment reduced the BNP levels of well-controlled CKD

patients. Nicorandil may have a beneficial role in pre-

venting cardiovascular events in CKD patients.

Conflict of interest None.

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