1520 TAKAYA Y et al.

Circulation Journal
Official Journal of the Japanese Circulation Society
ORIGINAL ARTICLE
http://www. j-circ.or.jp Heart Failure

Risk Stratification of Acute Kidney Injury Using the Blood

Urea Nitrogen/Creatinine Ratio in Patients With
Acute Decompensated Heart Failure
Yoichi Takaya, MD; Fumiki Yoshihara, MD; Hiroyuki Yokoyama, MD;
Hideaki Kanzaki, MD; Masafumi Kitakaze, MD; Yoichi Goto, MD; Toshihisa Anzai, MD;
Satoshi Yasuda, MD; Hisao Ogawa, MD; Yuhei Kawano, MD

Background:  Risk stratification of acute kidney injury (AKI) is important for acute decompensated heart failure
(ADHF). The aim of this study was to determine whether clinical markers, such as the blood urea nitrogen/creatinine
ratio (BUN/Cr) or BUN or creatinine values alone, stratify the risk of AKI for mortality.

Methods and Results:  In all, 371 consecutive ADHF patients were enrolled in the study. AKI was defined as serum
creatinine ≥0.3 mg/dl or a 1.5-fold increase in serum creatinine levels within 48 h. During ADHF therapy, AKI occurred
in 99 patients; 55 patients died during the 12-month follow-up period. Grouping patients according to AKI and a
median BUN/Cr at admission of 22.1 (non-AKI+low BUN/Cr, non-AKI+high BUN/Cr, AKI+low BUN/Cr, and AKI+high
BUN/Cr groups) revealed higher mortality in the AKI+high BUN/Cr group (log-rank test, P<0.001). Cox’s proportional
hazard analysis revealed an association between AKI+high BUN/Cr and mortality, whereas the association with
AKI+low BUN/Cr did not reach statistical significance. When patients were grouped according to AKI and median
BUN or creatinine values at admission, AKI was associated with mortality, regardless of BUN or creatinine.

Conclusions:  The combination of AKI and elevated BUN/Cr, but not BUN or creatinine individually, is linked with
an increased risk of mortality in ADHF patients, suggesting that the BUN/Cr is useful for risk stratification of
AKI.  (Circ J 2015; 79: 1520 – 1525)

Key Words: Acute decompensated heart failure; Acute kidney injury; Blood urea nitrogen/creatinine ratio; Prognosis

T
here is increased focus on cardiorenal syndrome because
of its association with adverse outcomes.1,2 An increase
in serum creatinine levels during acute decompen-
sated heart failure (ADHF) therapy has emerged as one of the
most potent prognostic factors.3–9 However, because there are
multiple mechanisms underlying increases in serum creatinine
levels, conflicting results have been reported. For example,
relief of congestion following aggressive diuresis results in
increased serum creatinine levels, but is associated with better
outcomes.10 An increase in serum creatinine levels has prog-
nostic value only in patients with persistent congestion.11
Therefore, although attending physicians must not make blind
assumptions and need to evaluate the clinical significance of
increased serum creatinine levels, few clinical markers have
been identified to enable such assessment. Recently, we
reported that late (≥5 days from admission) but not early (≤4
days from admission) onset of acute kidney injury (AKI) was
linked with a high mortality rate, and that blood urea nitrogen
(BUN) levels at admission were related to the late onset of
AKI.12
Editorial p 1446
Serum creatinine levels primarily reflect glomerular filtra-
tion rate, because creatinine essentially passes through the
renal tubules without being reabsorbed. Activation of neuro-
hormonal factors, such as the sympathetic nervous system,
renin-angiotensin-aldosterone system, and arginine vasopres-
sin, results in the disproportionate reabsorption of urea,13–15
leading to an increase in the BUN/creatinine ratio (Cr). Ele-
vated BUN/Cr, which is a surrogate marker for severe heart
failure,16–19 may identify a form of AKI associated with mor-
tality. In the present study, we hypothesized that the BUN/Cr
is useful for attending physicians to assess the risk stratifica-
tion of AKI during ADHF therapy. The aim of the present
study was to determine whether clinical markers of renal

Received December 15, 2014; revised manuscript received February 19, 2015; accepted March 8, 2015; released online April 8, 2015   Time
for primary review: 28 days
Department of Cardiology (Y.T., H.Y., H.K., M.K., Y.G., T.A., S.Y., H.O.), Department of Hypertension and Nephrology (F.Y., Y.K.),
National Cerebral and Cardiovascular Center, Suita, Japan
Mailing address:  Fumiki Yoshihara, MD, Department of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, 5-7-1
Fujishiro-dai, Suita 565-8565, Japan.   E-mail: fyoshi@hsp.ncvc.go.jp
ISSN-1346-9843  doi: 10.1253/circj.CJ-14-1360
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.79, July 2015

Risk Stratification of AKI 1521

Table 1.  Clinical Characteristics

All patients Non-AKI+low Non-AKI+high AKI+low AKI+high
P value
(n=371) BUN/Cr (n=133) BUN/Cr (n=139) BUN/Cr (n=51) BUN/Cr (n=48)
Age (years) 73±13 71±13 75±12 73±11 76±12 0.029
No. males (%) 221 (60) 104 (78) 56 (40) 32 (63) 29 (60) <0.001　
BMI (kg/m2) 22.9±4.0 23.4±3.7 22.2±4.0 23.2±4.0 23.3±4.7 0.067
Etiology of heart failure
  Ischemia 127 (34) 52 (39) 35 (25) 24 (47) 16 (33) 0.016
  Non-ischemia 244 (66) 81 (61) 104 (75) 27 (53) 32 (67)
  History of heart failure 156 (42) 59 (44) 49 (35) 26 (51) 22 (46) 0.179
hospitalization
   Clinical scenario 1 197 (53) 65 (49) 82 (59) 33 (65) 17 (35) 0.008
   Clinical scenario 2 117 (32) 46 (35) 42 (30) 11 (22) 18 (38) 0.266
   Clinical scenario 3 57 (15) 22 (17) 15 (11) 7 (14) 13 (27) 0.072
SBP (mmHg) 140±37 141±37 144±35 149±38 122±36 0.002
DBP (mmHg) 79±22 79±21 80±22 86±23 70±21 0.011
Heart rate (beats/min) 94±26 93±25 93±28 98±29 94±24 0.782
LVEF (%) 36±16 35±15 39±17 33±12 35±17 0.368
Physical examinations
   Rales (>1/2 lung fields) 113 (30) 35 (26) 42 (30) 20 (39) 16 (33) 0.367
   Jugular venous distension 236 (64) 80 (60) 94 (68) 30 (59) 32 (67) 0.379
  Peripheral edema 222 (60) 74 (56) 90 (65) 25 (49) 33 (69) 0.051
Laboratory measurements
  Hemoglobin (g/dl) 11.7±2.2 12.2±2.2 11.6±2.3 11.1±2.2 11.0±2.0 0.001
  Hematocrit (%) 34.7±6.6 36.1±6.4 34.6±6.7 32.9±6.2 32.9±6.2 0.003
  Albumin (g/dl) 3.5±0.4 3.6±0.4 3.5±0.4 3.4±0.4 3.4±0.5 0.067
  Sodium (mEq/L) 138±4　　 138±4　　 138±4　　 137±5　　 137±4　　 0.197
  BUN (mg/dl) 27±15 19±8 27±10 33±16 42±21 <0.001　
  Creatinine (mg/dl) 1.23±0.67 1.13±0.43 0.94±0.34 2.04±0.94 1.50±0.78 <0.001　
  BUN/Cr 23.3±8.3 17.1±3.0 29.6±6.8 16.6±4.1 29.3±7.1 <0.001　
  eGFR (ml/min/1.73 m2) 50±24 53±20 57±22 31±18 43±31 <0.001　
   Log BNP (pg/ml) 2.82±0.42 2.76±0.39 2.78±0.44 3.08±0.30 2.85±0.45 <0.001　
Medications during hospitalization
   ACEI and/or ARBs 249 (67) 96 (72) 92 (66) 30 (59) 31 (65) 0.380
  β-blockers 241 (65) 91 (68) 85 (61) 34 (67) 31 (65) 0.657
  Aldosterone antagonists 168 (45) 61 (46) 62 (45) 19 (37) 26 (54) 0.509
   Intravenous diuretics dose (mg) 272±835 141±533 184±716 462±1,177 398±820 0.023
  Intravenous dopamine 30 (8) 6 (5) 7 (5) 8 (16) 9 (19) 0.004
  Intravenous dobutamine 69 (19) 21 (16) 13 (9) 16 (31) 19 (40) <0.001　
  Intravenous nitrates 164 (44) 59 (44) 60 (43) 29 (57) 16 (33) 0.187
  Intravenous vasodilators 232 (63) 83 (62) 90 (65) 27 (53) 32 (67) 0.458
Data are presented as the mean ± SD or as n (%). ACEI, angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; ARBs, angioten-
sin receptor blockers; BMI, body mass index; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; Cr, creatinine ratio; DBP, diastolic
blood pressure; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.

function, such as the BUN/Cr or BUN or creatinine values
alone, stratify the risk of AKI for mortality in patients with
ADHF.
Methods
Study Population
We retrospectively investigated 433 consecutive patients with
ADHF admitted to the Cardiac Care Unit of the National
Cerebral and Cardiovascular Center (Osaka, Japan) between
May 2006 and April 2009, as described previously.12 Briefly,
ADHF was diagnosed on the basis of the guidelines of the
European Society of Cardiology.20 All patients had New York
Heart Association functional Class III or IV and were treated
with intravenous diuretics. To assess AKI caused exclusively
on the basis of the pathophysiology and treatment of ADHF,
we excluded patients who underwent cardiac surgery (n=8),
invasive procedures requiring contrast administration (n=23),
or continuous renal replacement therapy on admission (n=4),
as well as those on intermittent renal replacement therapy
since prior to admission (n=11). Patients discharged within
48 h of admission due to non-cardiac complications were also
excluded (n=6). The present study was performed according
to the principles of the Declaration of Helsinki and was
approved by the Ethics Committee of the National Cerebral
and Cardiovascular Center (approval ID: M22-25). All
patients provided written informed consent.

Circulation Journal  Vol.79, July 2015

1522
Table 2.  Factors Related to AKI
Univariate analysis
OR (95% CI)
Age >75 years 1.38 (0.87–2.20)
Male 1.12 (0.70–1.81)
SBP <100 mmHg 1.61 (0.87–2.91)
LVEF <35% 1.04 (0.66–1.65)
BUN >24 mg/dl 3.99 (2.43–6.69)
Creatinine>1.0 mg/dl 3.67 (2.22–6.27)
BUN/Cr >22.1 0.90 (0.57–1.43)
BNP >500 pg/ml 2.56 (1.52–4.48)
Intravenous dobutamine 3.66 (2.14–6.32)
Intravenous vasodilators 0.84 (0.53–1.36)
CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.
Clinical Assessments
All patients were systematically characterized with regard to
demographics, medical history, physical examinations, and
medications during hospitalization. Decisions regarding the
intravenous administration of agents were made on the basis
of clinical indications. Laboratory measurements were per-
formed on admission for all patients. After admission, the
timing of laboratory measurements was left to the discretion
of the attending physicians.
AKI was defined as absolute serum creatinine ≥0.3 mg/dl or
a 1.5-fold increase in serum creatinine levels within 48 h accord-
ing to the AKI Network creatinine criteria.21 Serum creatinine
levels were monitored during ADHF therapy, and changes
within 48 h were calculated. AKI was identified when serum
creatinine levels increased to ≥0.3 mg/dl or there was a 1.5-
fold increase compared with values measured within the past
48 h, as described previously.12 The BUN/Cr and BUN and
creatinine values were evaluated at the time of admission.
Patients were divided into 4 groups according to the presence
of AKI and median values of the BUN/Cr, BUN, or creatinine.
Endpoint
The study endpoint was defined as all-cause mortality. A
12-month follow-up was performed during a clinical visit or
via telephone interviews with the patient, his or her relatives,
or physicians. Independent investigators who had no role in
patient follow-up and treatment obtained information regard-
ing outcomes.
Statistical Analysis
Data are presented as mean ± SD for continuous variables and
as a number and percentage for categorical variables. The
significance of differences in clinical characteristics among
the 4 groups was analyzed using 1-way analysis of variance
for continuous variables and the Chi-squared test for categor-
ical variables. Factors related to AKI were assessed using
multivariate analysis. Variables (ie, age, sex, systolic blood
pressure, left ventricular ejection fraction, BUN levels, creati-
nine levels, BUN/Cr, plasma B-type natriuretic peptide [BNP]
levels, intravenous administration of dobutamine, and intrave-
nous administration of vasodilators) were entered using a P
value of <0.10 as the selection criterion. Odds ratios (ORs) are
presented with 95% confidence intervals (CIs). Survival rates
were estimated using Kaplan-Meier analysis, and the signifi-
cance of differences was analyzed using the log-rank test.
Predictors of 12-month mortality were assessed using Cox
Circulation Journal  Vol.79, July 2015
TAKAYA Y et al.
Multivariate analysis
P value OR (95% CI) P value
0.175
0.627
0.128
0.857
<0.001　 2.36 (1.30–4.36) 0.005
<0.001　 1.93 (1.04–3.60) 0.036
0.656
<0.001　 1.57 (0.88–2.87) 0.126
<0.001　 2.79 (1.58–4.95) <0.001　
0.482
proportional hazard analysis. In multivariate analysis, we entered
variables, including age, sex, systolic blood pressure, hemo-
globin levels, plasma BNP levels, and intravenous administra-
tion of dobutamine, as well as the combination of AKI with
either BUN/Cr, BUN, or creatinine, using a P value of <0.10
as the selection criterion. Hazard ratios (HRs) are presented
with 95% CIs. Statistical analysis was performed with JMP
version 8.0 (SAS Institute Inc, Cary, NC, USA) and signifi-
cance was defined as P<0.05.
Results
Study Population
After excluding patients (see Methods) and the loss of a fur-
ther 10 patients at the 12-month follow-up, 371 patients
remained in the study. The clinical characteristics of the study
population are given in Table 1. The mean patient age was
73±13 years, and 60% of patients were male; 55 patients died
during the 12-month follow-up period.
AKI
AKI occurred in 99 patients during ADHF therapy. Multi-
variate analysis revealed that AKI was independently related
to BUN levels, creatinine levels, and intravenous administra-
tion of dobutamine (Table 2).
Combination of AKI and BUN/Cr
Patients were group according to the presence of AKI and a
median value of the BUN/Cr at admission of 22.1 into the
following groups: non-AKI+low BUN/Cr (n=133), non-
AKI+high BUN/Cr (n=139), AKI+low BUN/Cr (n=51), and
AKI+high BUN/Cr (n=48). The AKI+high BUN/Cr group had
lower systolic blood pressure, hemoglobin and hematocrit
levels, higher BUN levels, and was more frequently treated
with intravenous dopamine and dobutamine than the other
groups (Table 1).
Kaplan-Meier survival curves showed that the AKI+high
BUN/Cr group had a significantly higher 12-month mortality
rate than the other groups (log-rank test, P<0.001; Figure A).
The mortality rate was significantly higher in the AKI+high
BUN/Cr group than in the AKI+low BUN/Cr group (long-
rank test, P=0.025). Univariate Cox proportional hazard anal-
ysis revealed that the risk of mortality was significantly higher
in the AKI+high BUN/Cr and AKI+low BUN/Cr groups com-
pared with the non-AKI+low BUN/Cr group. Multivariate
analysis revealed that the relative risk remained significantly
Risk Stratification of AKI 1523

Figure.   Kaplan-Meier survival curves according to the presence of acute kidney injury (AKI) and median values of the blood urea
nitrogen (BUN)/creatinine ratio (Cr) (A), BUN (B), or creatinine (C).

Table 3.  Risk Stratification of AKI for 12-Month Mortality Using the BUN/Cr
Univariate analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value
Non-AKI+low BUN/Cr 1 (reference) 1 (reference)
Non-AKI+high BUN/Cr 0.79 (0.34–1.84) 0.591 0.79 (0.33–1.84) 0.583
AKI+low BUN/Cr 3.06 (1.39–6.81) 0.006 2.11 (0.93–4.80) 0.072
AKI+high BUN/Cr 6.34 (3.14–13.4) <0.001　 4.71 (2.25–10.2) <0.001　
Adjusted for age, sex, SBP, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine.
HR, hazard ratio. Other abbreviations as in Tables 1,2.

higher in the AKI+high BUN/Cr group, whereas that for the
AKI+low BUN/Cr group did not reach statistical significance
(Table 3).
Combination of AKI and BUN or Creatinine
When patients were grouped according to the presence of AKI
and a median BUN value at admission of 23.0 into non-
AKI+low BUN (n=164), non-AKI+high BUN (n=108), AKI+
low BUN (n=24), and AKI+high BUN (n=75) groups, Kaplan-
Meier survival curves showed that the AKI+high BUN group
had a higher 12-month mortality rate than the other groups
(log-rank test, P<0.001; Figure B). However, there were no
significant differences in mortality rate between the AKI+high
BUN and AKI+low BUN groups (log-rank test, P=0.350).
Multivariate Cox proportional hazard analysis revealed that
both the AKI+high BUN and AKI+low BUN groups were
associated with 12-month mortality (Table 4).
When patients were divided according to the presence of

Circulation Journal  Vol.79, July 2015

1524 TAKAYA Y et al.

Table 4.  Risk Stratification of AKI for 12-Month Mortality Using BUN

Univariate analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value
Non-AKI+low BUN 1 (reference) 1 (reference)
Non-AKI+high BUN 1.88 (0.81–4.45) 0.141 1.33 (0.56–3.23) 0.518
AKI+low BUN 4.77 (1.62–12.9) 0.006 3.83 (1.27–10.6) 0.019
AKI+high BUN 7.34 (3.67–15.9) <0.001　 4.26 (1.99–9.76) <0.001　
Adjusted for age, sex, SBP, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine.
Abbreviations as in Tables 1–3.

Table 5.  Risk Stratification of AKI for 12-Month Mortality Using Creatinine

Univariate analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value
Non-AKI+low creatinine 1 (reference) 1 (reference)
Non-AKI+high creatinine 1.80 (0.78–4.36) 0.171 1.39 (0.59–3.39) 0.454
AKI+low creatinine 6.32 (2.37–16.5) <0.001　 4.88 (1.71–13.3) 0.004
AKI+high creatinine 6.90 (3.34–15.6) <0.001　 4.15 (1.90–9.81) <0.001　
Adjusted for age, sex, SBP, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine.
Abbreviations as in Tables 1–3.

AKI and a median creatinine value at admission of 1.04 into
non-AKI+low creatinine (n=149), non-AKI+high creatinine
(n=123), AKI+low creatinine (n=25), and AKI+high creati-
nine (n=74) groups, Kaplan-Meier survival curves showed
that the AKI+high creatinine and AKI+low creatinine groups
had a higher 12-month mortality rate (log-rank test, P<0.001;
Figure C). The mortality rate in the AKI+high creatinine
group was similar to that in the AKI+low creatinine group
(log-rank test, P=0.828). Multivariate Cox proportional hazard
analysis revealed that both the AKI+high creatinine and
AKI+low creatinine groups were associated with 12-month
mortality (Table 5).
Discussion
The major findings of the present study are that the combina-
tion of AKI with an elevated BUN/Cr at admission was linked
with an increased risk of mortality in patients with ADHF, and
that BUN or creatinine values alone at admission did not influ-
ence the risk of AKI for mortality. Our findings suggest that
the BUN/Cr is useful for risk stratification of AKI.
AKI is not always related to mortality in patients with ADHF.
Several studies have shown that increases in serum creatinine
levels caused by relief of congestion are not associated with
permanent renal damage and adverse outcomes.10,11,22–25 There-
fore, the mechanisms underlying the development of AKI are
important to determine clinical outcomes in patients with
ADHF. The present study provides important evidence that an
elevated BUN/Cr at admission, which reflects neurohormonal
activation, identifies a form of AKI associated with mortality
in patients with ADHF. Furthermore, because risk stratifica-
tion for AKI can be prepared at the time of admission, it could
provide useful information for attending physicians to make
decisions regarding continuing decongestion therapy for ADHF
in patients with a lower BUN/Cr despite increased creatinine
levels, in contrast with consideration of additional strategies
for ADHF in AKI patients with a higher BUN/Cr.
Although it has been established that creatinine and esti-
mated glomerular filtration rate portend adverse outcomes in
patients with HF,16 the BUN/Cr is reported to be strongly
associated with adverse outcomes, especially in the setting of
acute decompensation of HF.19 In the setting of ADHF, activa-
tion of neurohormonal factors, such as the sympathetic ner-
vous system and renin-angiotensin-aldosterone system, causes
renal vasoconstriction and decreases glomerular filtration rate,
which reduces urea excretion. Neurohormonal activation also
increases flow- and concentration-dependent urea absorption.
Arterial underfilling secondary to low cardiac output stimu-
lates the release of arginine vasopressin, which promotes urea
reabsorption.13–15,27 Under the condition of neurohormonal
activation, creatinine is freely filtered through the glomerulus
and is not reabsorbed, whereas urea is disproportionately reab-
sorbed, leading to an elevated BUN/Cr. Therefore, an elevated
BUN/Cr more closely reflects neurohormonal activation than
elevated creatinine or decreased estimated glomerular filtra-
tion rate, and is linked with adverse outcomes in patients with
ADHF.16,19,28 Furthermore, the BUN/Cr has been used for the
differentiation of HF-induced renal dysfunction from intrinsic
renal disease.13,14,16 In the setting of fluid and sodium excess,
such as in HF, urea excretion is disproportionately reduced in
relation to decreased glomerular filtration rate and urea absorp-
tion is promoted, leading to an elevated BUN/Cr. Conversely,
the cause of intrinsic renal disease is irreversible nephron loss
and urea clearance is thus reduced in parallel to the glomerular
filtration rate, resulting in a normal BUN/Cr. Therefore, an
elevated BUN/Cr may be useful for detecting severe HF-
induced AKI, which is associated with an increased risk of
mortality. In addition, the present study showed that the inci-
dence of AKI was related to both BUN and creatinine levels,
but not the BUN/Cr, at baseline. These results suggest that a
high BUN/Cr may stratify AKI patients according to the risk
of mortality, but not stratify ADHF patients at risk of AKI.
Study Limitations
First, the present study was a retrospective observational study
in a single center. Our findings need to be confirmed in larger
trials. Second, the BUN/Cr is influenced by non-neurohor-
monal factors, such as protein diet, cachexia, and muscle

Circulation Journal  Vol.79, July 2015

Risk Stratification of AKI
wasting, but these factors were not assessed in this study.
Third, because the timing of laboratory measurements was left
to the discretion of the treating physicians, the time interval
for measurements of serum creatinine was not just 48 h, result-
ing in potential underestimation of the incidence of AKI.
Fourth, AKI defined by the AKI Network criteria includes
serum creatinine and urine output data,21 but we used only
serum creatinine. Data regarding volume depletion were not
obtained. Fifth, urinalysis was performed in only 121 (33%)
patients. This rate was too low to clarify the clinical signifi-
cance of the urinalysis data. Finally, direct hemodynamic
parameters were not obtained.
Conclusions
The combination of AKI with an elevated BUN/Cr at admis-
sion, but not with values of BUN or creatinine individually, is
linked with an increased risk of mortality in patients with
ADHF. Our findings suggest that the prognostic value of AKI
is dependent on the BUN/Cr at admission, and that the BUN/
Cr is useful for risk stratification of AKI. Further studies are
needed to validate these findings and investigate therapeutic
strategies to improve clinical outcomes in patients with ADHF.
Acknowledgments
This work was supported by the Program for Promotion of Fundamental
Studies in Health Sciences of the Pharmaceuticals and Medical Devices
Agency in Japan.
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