Download Impact of Left Ventricular End-Diastolic Wall

Clinical Chemistry 55:7
1347–1353 (2009)
Proteomics and Protein Markers
Impact of Left Ventricular End-Diastolic Wall Stress on
Plasma B-Type Natriuretic Peptide in Heart Failure with
Chronic Kidney Disease and End-Stage Renal Disease
Shinichiro Niizuma,1,3 Yoshitaka Iwanaga,4* Takaharu Yahata,2 Yodo Tamaki,3 Yoichi Goto,2
Hajime Nakahama,1 and Shunichi Miyazaki4
BACKGROUND: Plasma B-type natriuretic peptide (BNP)
is a diagnostic and prognostic marker in heart failure
(HF). Although renal function is reported as an important clinical determinant, precise evaluations of the relationships of renal function with hemodynamic factors in determining BNP have not been performed.
Therefore, we evaluated the association of plasma BNP
concentrations with LV end-diastolic wall stress
(EDWS) in a broad range of HF patients including
those with chronic kidney disease (CKD) and endstage renal disease (ESRD).
METHODS:
In 156 consecutive HF patients including
those with CKD and ESRD, we measured plasma BNP
and performed echocardiography and cardiac catheterization. LV EDWS was calculated as a crucial hemodynamic determinant of BNP.
RESULTS:
Plasma BNP concentrations increased progressively with decreasing renal function across the
groups (P ⬍ 0.01) and were correlated with LV
EDWS (r ⫽ 0.47) in the HF patients overall. This
relationship was also present when patients were
subdivided into systolic and diastolic HF (P ⬍ 0.01).
In multivariable analysis, higher EDWS was associated with increased BNP concentration independently of renal dysfunction (P ⬍ 0.01). Anemia, systolic HF, and decreased BMI also contributed to
increased BNP concentrations.
CONCLUSIONS: These results suggest that LV EDWS is a
strong determinant of BNP even in patients with CKD
and ESRD. Anemia, obesity, and HF type (systolic or
diastolic) should also be considered in interpreting
plasma BNP concentrations in HF patients. These find-
1
Division of Hypertension and Nephrology; and 2 Division of Cardiology, National
Cardiovascular Center, Suita, Japan; 3 Department of Cardiovascular Medicine,
Kyoto University Graduate School of Medicine, Kyoto, Japan; 4 Division of
Cardiology, Department of Internal Medicine, Kinki University School of Medicine, Osakasayama, Japan.
* Address correspondence to this author at: Division of Cardiology, Department
of Internal Medicine, Kinki University School of Medicine, 377–2 Ohno-Higashi,
Osakasayama 589-8511, Japan. Fax ⫹81-72-368-2378; e-mail yiwanaga@
med.kindai.ac.jp.
Received November 28, 2008; accepted March 24, 2009.
ings may contribute to the clinical management of HF
patients, especially those complicated with CKD and
ESRD.
© 2009 American Association for Clinical Chemistry
Chronic kidney disease (CKD)5 is frequently associated
with a progressive decrease in glomerular filtration rate
(GFR), which leads to end-stage renal disease (ESRD)
(1 ). The number of patients with CKD as well as ESRD
is increasing markedly worldwide (2, 3 ). Several investigators have documented that patients with CKD are
at higher risk of cardiovascular disease than the general
population, and show a higher rate of cardiovascular
mortality (4–6 ). In particular, ESRD patients have a
500-fold greater rate of cardiovascular mortality than
age-matched controls with normal renal function (7 ).
Heart failure (HF) is also an increasingly prevalent
condition and the leading cause of death among cardiovascular diseases in patients with CKD and ESRD
(8 ). There may be some interaction between heart disease and kidney disease, and HF patients who have
CKD or ESRD show a worse prognosis (9, 10 ). Thus,
early diagnosis and aggressive management of HF are
needed in patients with CKD and ESRD. Conversely,
early recognition and management of CKD are also
necessary in patients with HF.
B-type natriuretic peptide (BNP) is synthesized in
the ventricular myocardium in response to ventricular
stretching and wall stress (11 ). BNP and N-terminal
pro-BNP (NT-proBNP), which are associated with the
severity of HF and left ventricular (LV) function, are
useful markers for diagnosis, management, and prog-
Previously published online at DOI: 10.1373/clinchem.2008.121236
5
Nonstandard abbreviations: CKD, chronic kidney disease; GFR, glomerular
filtration rate; ESRD, end-stage renal disease; HF, heart failure; BNP, B-type
natriuretic peptide; NT-proBNP, N-terminal pro-BNP; LV, left ventricular; EDWS,
end-diastolic wall stress; NYHA, New York Heart Association; Cr, creatinine; Hb,
hemoglobin; eGFR, estimated GFR; EF, ejection fraction; RWT, relative wall
thickness; LVMI, LV mass index; EDP, end-diastolic pressure; BMI, body mass
index; AF, atrial fibrillation; HF, heart failure; LVEDVI, LV end-diastolic volume
index; SHF, systolic HF; DHF, diastolic HF.
1347
nosis in patients with normal renal function (11–14 ).
Recently, the prognostic potential of plasma BNP concentrations has been investigated in several studies on
patients with CKD and patients on hemodialysis and
peritoneal dialysis (15, 16 ). However, the diagnostic
accuracy of plasma BNP and NT-proBNP concentrations for HF has been reported to be reduced in this
setting (17 ). It is not yet clear whether, in HF patients
with CKD and ESRD, increased plasma BNP concentrations might be due to more hemodynamic stimuli or
might result from other factors such as anemia, obesity
and cachexia, or impaired renal clearance of natriuretic
peptide, despite similar hemodynamic stimuli.
Accordingly, we conducted the present study to
clarify the relationship between plasma BNP concentrations and possible determinants, including severity
of renal dysfunction, anemia, obesity/cachexia, and hemodynamic factors in HF patients across all CKD
groups, including ESRD. In particular, we performed
an analysis of left ventricular end-diastolic wall stress
(EDWS), which we previously found to be a crucial
hemodynamic determinant of plasma BNP concentrations (11 ), to clarify the precise contribution of hemodynamic factors to the regulation of plasma BNP in this
setting.
Materials and Methods
STUDY PATIENTS
One hundred fifty-six patients who had been referred
for HF [New York Heart Association (NYHA) ⱖ class
II] between October 2003 and May 2005 were enrolled
in the present study. The diagnosis of HF was based
on the European Society of Cardiology criteria. For
all participants, cardiac catheterization and echocardiograms were performed at a compensated congestive heart failure stage (before discharge). Patients
who did not undergo LV catheterization were excluded. Plasma BNP, serum creatinine (Cr), and hemoglobin (Hb) were measured on the day before
cardiac catheterization.
RENAL FUNCTION
Serum creatinine values obtained for all patients were
used to estimate GFR using the abbreviated Modification of Diet in Renal Disease study formula (18 ): estimated GFR (eGFR, mL/min/1.73 m2) ⫽ 186 ⫻
Cr⫺1.154 ⫻ age⫺0.203 (⫻ 0.742 if female). The severity
of renal dysfunction was classified as normal, CKD, or
ESRD by using eGFR. CKD and ESRD were defined as
15 ⱕ eGFR ⬍60 and eGFR ⬍15, respectively. Among
the patients with ESRD, 38 underwent regular 4-h sessions of hemodialysis 3 times weekly. Plasma BNP concentrations were measured in blood samples drawn
from the arteriovenous fistula immediately before a he1348 Clinical Chemistry 55:7 (2009)
modialysis session on the day before coronary cardiac
catheterization. The underlying disease etiologies in
patients with ESRD were chronic glomerulonephritis
in 13, nephrosclerosis in 13, diabetic nephropathy in
13, and other causes in 2.
CARDIAC CATHETERIZATION
Left ventricular pressure was recorded with a 5-F pigtail catheter connected to a fluid-filled transducer. Left
ventricular volume and ejection fraction (EF) were determined by left ventriculography with contrast medium using the Kennedy’s formula (19 ).
ECHOCARDIOGRAPHY
We performed echocardiographic examinations in all
patients using a Sonos 5500 machine equipped with a
2.5-MHz probe. M-mode images were obtained to
measure left atrial and ventricular dimensions (20 ).
Relative wall thickness (RWT) was defined as 2 ⫻ (posterior wall thickness)/(LV end-diastolic dimension).
The left ventricular mass index (LVMI) was estimated
using the formula of Devereux et al. (21 ). In patients
with sinus rhythm, the pulsed Doppler transmitral flow
velocity was recorded to measure the ratio of peak mitral E-wave velocity to peak mitral A-wave velocity
(E/A ratio) and the deceleration time of the mitral
E-wave velocity. Based on hemodynamic and echocardiographic data, end-diastolic and systolic meridional
wall stresses were calculated as follows: WS ⫽ 0.334 ⫻
P(LVID)/WT(1 ⫹ WT/LVID), where WS is wall stress,
P is LV pressure [i.e., peak systolic pressure or enddiastolic pressure (EDP), which was obtained during
cardiac catheterization], LVID is left ventricular internal dimension, and WT is wall thickness (11 ).
STATISTICAL ANALYSIS
We compared groups using ␹2 tests for proportions
and Mann–Whitney U tests or ANOVA for continuous
variables, as appropriate. We assessed the linearity of a
relationship between 2 variables by linear regression
analysis and calculated the Pearson correlation coefficient. Further multivariable analysis was performed to
evaluate the independent relationship between the severity of renal dysfunction and plasma BNP concentrations in concert with demographic variables, hemodynamic indexes, and laboratory data using JMP version
8.0. Variables included in the analysis were sex, age,
body mass index (BMI), NHYA class, hypertension,
diabetes, hyperlipidemia, atrial fibrillation (AF), heart
failure (HF) etiology, medications, hemodynamic and
echocardiographic indexes, and laboratory data; P ⬍
0.05 was considered significant. Results are expressed
as mean ⫾ SE.
BNP and Chronic Kidney Disease in Heart Failure
Table 1. Patient characteristics.a
n
Age, years
Female
BMI, kg/m2
Normal
CKD
ESRD
58
57
41
Table 2. Echocardiographic and
hemodynamic parameters.a
P
60.4 (2.0) 69.2 (1.8) 65.0 (1.3) ⬍0.01
19 (32)
16 (28)
11 (27)
0.81
22.1 (0.6) 22.0 (0.4) 21.1 (0.4)
0.28
b
LVEDD, mm
PWT, mm
Normal
CKD
ESRD
P
58.8 (1.0)
63.4 (1.2)
54.8 (1.4)
⬍0.01
9.7 (0.3)
9.2 (0.2)
10.4 (0.4)
⬍0.01
RWT
0.33 (0.01) 0.29 (0.01) 0.40 (0.02) ⬍0.01
LAD, mm
44.3 (1.1)
eGFR, mL/min/
1.73m2
78 (2)
44 (1)
5 (0)
⬍0.001
E/A
1.64 (0.22) 1.68 (0.16) 1.21 (0.14)
0.18
Hypertension
24 (41)
31 (55)
33 (83)
0.08
DCT, msec
194 (12)
195 (13)
0.64
Diabetes
14 (24)
29 (51)
21 (53)
0.06
LVMI, g/m2
165 (6)
176 (7)
179 (9)
0.41
Hyperlipidemia
21 (36)
30 (53)
16 (40)
0.18
EF, %
37.8 (1.9)
36.6 (2.0)
39.4 (2.4)
0.68
DHF
16 (28)
14 (25)
11 (27)
0.94
LVEDVI, mL/m
120 (6)
123 (6)
116 (9)
0.42
AF
18 (31)
16 (29)
11 (27)
0.92
LVSP, mmHg
121 (5)
122 (4)
149 (6)
⬍0.01
0.18
LVEDP, mmHg
14.3 (0.7)
17.2 (1.0)
17.1 (1.0)
0.04
EDWS, kdynes/cm2 40.6 (2.3)
56.0 (3.6)
47.1 (6.0)
0.01
Diagnosis
b
OMI or ICM
18 (31)
25 (44)
21 (51)
Valvular heart
disease
19 (32)
18 (32)
13 (32)
HHD
9 (14)
2 (4)
2 (5)
DCM
14 (24)
12 (21)
5 (12)
ACE inhibitor or
ARB
37 (63)
39 (68)
11 (26)
Beta blocker
22 (37)
30 (54)
22 (55)
0.13
Diuretics
36 (62)
49 (81)
7 (17)
⬍0.001
Aldosterone
receptor
blocker
20 (34)
21 (36)
1 (2)
⬍0.001
a
b
Medication
⬍0.001
Laboratory
a
b
2
512 (48) 1947 (391) ⬍0.001
BNP, ng/L
287 (31)
Cr, mg/L
7.3 (1.7) 12.1 (1.7) 79.5 (2.1) ⬍0.001
Hb, g/L
135 (3)
130 (3)
100 (6)
⬍0.001
Values are mean (SE) or n (%).
OMI, old myocardial infarction; ICM, ischemic cardiomyopathy; HHD,
hypertensive heart disease; DCM, dilated cardiomyopathy; ARB, angiotensin receptor blocker.
Results
49.3 (1.4)
181 (12)
44.3 (1.1)
0.06
Values are mean (SE).
LVEDD, left ventricular end-diastolic dimension; PWT, posterior wall thickness; LAD, left atrial dimension; E/A, ratio of peak mitral E-wave velocity
to peak mitral A-wave velocity; DCT, deceleration time of early diastolic
filling; LVSP, left ventricular peak systolic pressure; LVEDP, left ventricular
end-diastolic pressure.
sterone receptor blockers, or diuretics. Hb levels were
significantly lower in ESRD patients than in normal
and CKD patients (P ⬍ 0.01). Geometric and functional parameters obtained by echocardiography or
cardiac catheterization are shown in Table 2. In all
of the patients, mean (SD) EF was 47.8% (1.2%)
and mean LVMI, LV end-diastolic volume index
(LVEDVI), and LV EDWS were 172.7 (5.3) g/m2, 119.9
(4.0) mL/m2, and 47.9 (2.3) kdynes/cm2, respectively.
Among the 3 groups, although there was no significant
difference in EF, LVEDVI, or LVMI, patients with CKD
showed higher EDWS than those in the normal and
ESRD groups. Patients with ESRD showed higher RWT
(more concentric remodeling) and left ventricular systolic pressure than those in the normal and CKD
groups.
PATIENT CHARACTERISTICS
The baseline clinical characteristics in HF patients according to the degree of renal dysfunction [normal
(n ⫽ 58), CKD (n ⫽ 57), ESRD (n ⫽ 41)] are shown in
Table 1. The proportion of patients with eGFR between
15 and 29 (i.e., stage 4 CKD) was only 12% in the CKD
group. In all of the patients, the mean age was 64.7 (1.1)
years, and 29% of the patients were female. Patients
with CKD and ESRD showed a high prevalence of old
myocardial infarction or ischemic cardiomyopathy.
Patients in the ESRD group were less likely to be taking
ACE inhibitors or angiotensin receptor blockers, aldo-
ASSOCIATION BETWEEN PLASMA BNP CONCENTRATIONS AND
THE SEVERITY OF RENAL FUNCTION
As shown in Fig. 1A, plasma BNP concentrations increased progressively with the degree of renal dysfunction [normal, 287 (31) ng/L; CKD, 512 (48) ng/L;
ESRD, 1947 (391) ng/L; P ⬍ 0.01]. Overall, 102 patients had an LV EF of ⱕ45%. These comprised the
systolic heart failure (SHF) group. The diastolic heart
failure (DHF) group comprised 54 patients with preserved systolic function (LV EF ⬎45%) (22 ). Mean EFs
were 28.9% (0.9%) and 54.6% (0.8%), respectively.
Clinical Chemistry 55:7 (2009) 1349
A
*
B
*
10
Log [BNP (ng/L)]
Log [BNP (ng/L)]
10
*
9
8
7
6
5
*
*
7
6
5
4
3
2
2
ESRD
*
8
3
CKD
*
9
4
Normal
*
Normal CKD ESRD
Normal CKD ESRD
SHF
DHF
Fig. 1. (A), Analysis of BNP concentration according to the severity of renal dysfunction; normal (n ⴝ 58), CKD (n ⴝ
57), ESRD (n ⴝ 41); (B), subgroup analysis in SHF (n ⴝ 102) vs DHF (n ⴝ 54); *P < 0.05.
Plasma BNP concentrations were significantly higher
in SHF than in DHF groups [SHF, 997 (144) ng/L;
DHF, 445 (71) ng/L; P ⬍ 0.01]. As shown in Fig. 1B,
plasma BNP concentrations increased progressively
with the degree of renal dysfunction even when patients were divided into 2 groups: SHF and DHF (P ⬍
0.01). In patients with DHF, however, no significant
difference was observed between the normal and CKD
groups.
CORRELATION OF PLASMA BNP CONCENTRATIONS WITH
HEMODYNAMIC PARAMETERS AND OTHER FACTORS
Log LV EDWS, EF, and EDP were moderately correlated with log plasma BNP concentrations (r ⫽ 0.47,
0.45, 0.40, respectively; P ⬍ 0.01) and LVMI was significantly, but poorly, correlated (r ⫽ 0.17, P ⫽ 0.03)
(Fig. 2). When anemia was defined as Hb ⬍12 g/dL for
women and Hb ⬍13 for men, it was present in 51%
(n ⫽ 79) of the total patients and in 26%, 44%, and
95% of those in the normal, CKD, and ESRD groups.
There were no differences in BMI among the 3 groups.
Both hemoglobin concentrations and BMI were moderately correlated with log plasma BNP concentrations
(r ⫽ ⫺0.44 and ⫺0.35, P ⬍ 0.01).
LV EDWS were significantly higher in SHF than in
DHF groups [SHF, 55.7 (3.1) kdynes/cm2; DHF, 33.1
(1.7) kdynes/cm2; P ⬍ 0.01]. Although log LV EDWS
was positively correlated with the log BNP concentrations in the SHF group (r ⫽ 0.54, P ⬍ 0.01), no association was observed in the DHF group (P ⫽ 0.76).
The individual correlation coefficients for each renal category (normal, CKD, ESRD) between log BNP
and echocardiographic/hemodynamic parameters are
shown in Supplemental Table 1, which accompanies
the online version of this article at www.clinchem.org/
1350 Clinical Chemistry 55:7 (2009)
content/vol55/issue7. The correlation between log
BNP and log EDWS appears weak in patients with
ESRD compared with the other 2 groups (r ⫽ 0.400,
0.704, 0.782, respectively).
RELATIONSHIP OF RENAL FUNCTION, EDWS, AND OTHER
CONFOUNDERS WITH PLASMA BNP CONCENTRATIONS
The plasma BNP concentrations in all HF patients according to the groups of renal dysfunction and tertiles
of the EDWS level are shown in Fig. 3. Plasma BNP
concentrations increased progressively with the grade
of EDWS in both the normal and CKD groups. In the
ESRD group, there were no significant differences between the low and middle EDWS groups. However,
patients with ESRD and high EDWS showed the highest plasma BNP concentrations. Multivariable linear
regression analysis revealed that the group defined in
terms of renal dysfunction and the levels of log EDWS
were both independent determinants of log BNP concentrations (P ⬍ 0.01). In addition, HF type (systolic vs
diastolic), hemoglobin concentrations, and BMI were
independently associated with the log BNP level. In
contrast, LVMI was unrelated to plasma BNP once the
effects of renal dysfunction, log EDWS, HF type, Hb,
and BMI were considered (Table 3). The fit (R2) of the
model including these variables was 0.63.
The results of a multivariable linear regression
analysis in the ESRD group vs the CKD combined normal group are shown in online Supplemental Table 2.
Only log EDWS remained a significant predictor for
log BNP concentrations in HF patients with ESRD. No
other confounder variables were found to be significant in this population.
BNP and Chronic Kidney Disease in Heart Failure
A
B
10
r = 0.47, P < 0.01
9
Log [BNP (ng/L)]
Log [BNP (ng/L)]
10
8
7
6
5
4
3
8
7
6
5
4
3
2
2
2.5
3
3.5
4
Log [EDWS
C
4.5
5
(kdynes/cm2)
2
5.5
]
0
50
100
150
200
250
300
350
LVMI (kg/m2)
D
10
10
r = –0.44, P < 0.01
9
8
7
6
5
4
3
Log [BNP (ng/L)]
Log [BNP (ng/L)]
r = 0.17, P = 0.03
9
r = –0.35, P < 0.01
9
8
7
6
5
4
3
2
2
60
80
100
120
140
160
180
200
13
18
23
28
33
38
BMI (kg/m2)
Hb (g/L)
Fig. 2. Correlations between log BNP concentration and log LV EDWS (A), LVMI (B), Hb concentration (C), and BMI
(D) in all patients.
‚, patients with normal GFR; 䡬, CKD; }, ESRD.
Discussion
HF is one of the leading causes of death in patients with
CKD and ESRD (7 ). There may be some interaction
between heart disease and kidney disease, and HF patients who have CKD and ESRD show a worse prognosis (9, 10 ). In our study population with HF, only 37%
of the patients had eGFR ⱖ60 mL/min/1.73 m2, and
the remainder had eGFR ⬍60 or were receiving
chronic dialysis. In terms of the diagnosis and management of HF, it is essential to consider the existence of
renal dysfunction. BNP and NT-proBNP are currently
the most widely used markers in the clinical setting of
HF. However, in most previous studies on the diagnostic and prognostic roles of BNP or NT-proBNP in HF,
8
Table 3. Predictors for log BNP concentrations in
multivariable regression analysis.a
7.5
7
6.5
6
Log [BNP (ng/L)]
Log BNP
5.5
5
␤ Coefficient
Parameter
4.5
4
3.5
2nd tertile
3
ESRD
1st tertile
CKD
EDWS
Normal
Renal function
Fig. 3. Relationship of renal function (normal, CKD,
ESRD) and LV EDWS with log BNP concentration.
Patients were divided into tertiles according to the EDWS
level (first tertile: ⬍33 kdynes/cm2, second tertile: 33–55,
third tertile: ⬎55).
P
NSb
LVMI
3rd tertile
BMI
⫺0.068
Hb
⫺0.065
0.023
HF type (SHF vs DHF)
0.260
⬍0.001
Log EDWS
0.678
⬍0.001
⫺0.017
⬍0.001
eGFR
⬍0.001
a
Significant univariable predictors were included in the multivariable regression model as continuous variables, and HF type was included as a
binary variable.
b
NS, not significant.
Clinical Chemistry 55:7 (2009) 1351
patients with CKD and ESRD have been excluded because of potentially increased BNP concentrations.
Thus, the utility of BNP measurement in HF has been
obviously limited in patients with renal dysfunction. It
is well known that the hemodynamic load is the most
important stimulus for BNP secretion in the myocardium based on the results of both basic and clinical
studies. We have recently shown that plasma BNP concentrations strongly reflect LV EDWS in HF patients
with normal creatinine concentrations, and this relationship was more robust than any other parameter
previously reported (11 ). Although several studies
have already demonstrated the association between
BNP and renal function in patients with HF or without
HF, hemodynamic factors were not adequately considered in the analysis (23–25 ). Accordingly, we performed
this study in a wide spectrum of HF patients with a concomitant analysis of EDWS and showed that both EDWS
and renal dysfunction may contribute to the increased
BNP concentrations independently in this setting.
In the clinical setting, heterogeneity in BNP concentrations among individuals with HF has been recognized, and this has caused some confusion in interpreting results (11 ). A number of nonhemodynamic
factors such as age, sex, atrial fibrillation, obesity
(BMI), and anemia are presumed to have some contribution to the interindividual variability of plasma BNP
concentrations in the diagnosis and management of
HF patients (26–29 ). In the present study, anemia,
lower BMI, and SHF, in addition to EDWS and renal
dysfunction, contributed to increased BNP levels to
some extent. Anemia is a common phenomenon in HF
and is related to its severity. HF is strongly related to
CKD, and renal dysfunction is a well-known cause of
anemia. This vicious cycle has been described as the
cardiorenal anemia syndrome (30 ). Because all 3 conditions could closely influence each other and increase
BNP concentrations independently or mutually, it has
not been clear what increased BNP concentrations reflect in this complicated setting. In the present study,
hemoglobin added significant value to the multivariable linear regression model of BNP determinants in
addition to EDWS and renal dysfunction. This is consistent with the results reported by Hogenhuis et al.
(28 ), although their study did not adequately consider
hemodynamic factors. The high prognostic value of
BNP might be derived from the fact that BNP is an
integrated marker of cardiohemodynamic function,
renal function, and anemia, as demonstrated in the
present study.
Currently, the clinical utility of measurements of
BNP in HF patients with ESRD is very limited because
of lack of data. In the present study, the findings in
ESRD patients were clearly different from the other 2
groups, not only in terms of patient characteristics,
1352 Clinical Chemistry 55:7 (2009)
echo and hemodynamic data, but also in the relationship of BNP with other variables. In a subanalysis
shown in online Supplemental Table 2, only EDWS
remained a significant determinant of BNP concentrations in HF patients with ESRD. However, there might
be unknown factors or hidden confounders unique to
this population.
Epidemiological data indicate that up to 50% of
patients with HF symptoms suffer from DHF. Moreover, the prognosis of patients suffering from DHF is as
ominous as that of patients suffering from SHF (31 ).
However, little is known about the relationship between CKD and DHF. The contribution of LV diastolic
function to plasma BNP concentrations and the usefulness of BNP in the diagnosis of DHF have been demonstrated (32 ), and we also have shown that EDWS
could account for the increase in plasma BNP concentrations even in patients with DHF and normal renal
function (11 ). It has been suggested, however, that the
diagnostic accuracy of BNP may be lower in patients
with DHF than in those with SHF (33 ). In subanalyses
in the present study, there was no significant difference
in BNP concentrations between DHF patients with
normal renal function and those with CKD, and no
correlation of BNP concentrations with LV EDWS in
DHF patients. However, these findings might be a reflection of the lower diagnostic accuracy of BNP in patients with DHF, and clinicians are therefore advised to
interpret BNP concentrations in the diagnosis and
management of patients with DHF with caution.
Several limitations should be considered in interpreting our results. First, the study population was relatively small. Second, only plasma BNP concentrations
were considered in our study. Recently, the measurement of NT-proBNP increasingly has been used clinically because of its longer half-life and larger size. NTproBNP might be more dependent on renal clearance
than BNP (34 ). To date, most studies have demonstrated that both are equally useful, even in CKD and
HD patients (35 ). Finally, the study population was
comprised of patients who were in stable condition and
could tolerate LV cardiac catheterization; thus patients
who could not bear cardiac catheterization (e.g., patients with NYHA class IV HF) or would be at high risk
for contrast nephropathy were excluded. In particular,
our study design led to exclusion of some patients with
more severe CKD not on renal replacement therapy.
Therefore, the applicability of our results to the patients with more severe CKD not requiring dialysis
might be uncertain.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design,
BNP and Chronic Kidney Disease in Heart Failure
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon
manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Honoraria: None declared.
Research Funding: This study was supported by a research grant
from the Takeda Science Foundation and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science
(18590774).
Expert Testimony: None declared.
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
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