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Circ J 2008; 72: 1152 1157

Decreased Renal Function as an Independent Predictor


of Re-Hospitalization for Congestive Heart Failure
Kimiaki Komukai, MD; Takayuki Ogawa, MD; Hidenori Yagi, MD; Taro Date, MD;
Hiroshi Sakamoto, MD; Yasuko Kanzaki, MD; Kenri Shibayama, MD;
Koichi Hashimoto, MD; Keiichi Inada, MD; Kosuke Minai, MD; Kazuo Ogawa, MD;
Tsuneharu Kosuga, MD; Makoto Kawai, MD; Kenichi Hongo, MD;
Ikuo Taniguchi, MD; Michihiro Yoshimura, MD
Background Patients with congestive heart failure (CHF) are often re-hospitalized, worsening both their quality of life and prognosis. Although renal dysfunction reportedly increases the risk of CHF, the association
between renal dysfunction and re-hospitalization for CHF remains unclear.
Methods and Results Patients with CHF and decreased renal function were reviewed. The estimated glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients with
decreased renal function (estimated GFR on admission <45 mlmin1 1.73 m2) were re-hospitalized more frequently than were patients with preserved renal function (estimated GFR on admission 45). Patients with
decreased renal function were older and had higher rates of anemia, worsening renal function during hospitalization, and previous hospitalization for CHF. Independent predictors of re-hospitalization for CHF identified with
multivariate analysis were age, previous hospitalization for CHF, decreased renal function, and non-use of an
angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker.
Conclusions Renal dysfunction is an independent predictor of re-hospitalization for CHF, so careful follow-up
is needed, even after discharge. (Circ J 2008; 72: 1152 1157)
Key Words: Chronic kidney disease; Estimated glomerular filtration rate; Previous hospitalization

atients with congestive heart failure (CHF) are frequently re-hospitalized, worsening their quality of
life, and re-hospitalization for CHF is also associated with increased mortality rates.1,2 Therefore, re-hospitalization for CHF should be avoided. Renal insufficiency
increases the risk of CHF,35 but most studies that have investigated the role of renal function in CHF have included
only subjects with no known CHF or mild-to-moderate
CHF and excluded patients with severe renal dysfunction.
Patients hospitalized for CHF have more severe disease
and impaired renal function, but little is known about the
relation between renal dysfunction and re-hospitalization
because of CHF. Thus, the aim of the present study was to
investigate whether renal dysfunction is associated with rehospitalization for CHF after successful discharge.

Methods
The study protocol was approved by the Ethics Committee of The Jikei University School of Medicine (19-092
[5023]).
Patients with CHF who had been admitted from January
(Received October 4, 2007; revised manuscript received February 3,
2008; accepted February 24, 2008)
Division of Cardiology, Department of Internal Medicine, The Jikei
University School of Medicine, Tokyo, Japan
Mailing address: Kimiaki Komukai, MD, Division of Cardiology,
Department of Internal Medicine, The Jikei University School of
Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
E-mail: komu@jikei.ac.jp
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

2003 through December 2004 and followed up after discharge at the outpatient clinic were reviewed. CHF was
diagnosed by 2 or more cardiologists on the basis of the
Framingham criteria. Patients were excluded if they had
CHF complicated by acute myocardial infarction, were
undergoing or starting dialysis during the follow-up period,
or had undergone cardiac surgery during the follow-up
period. With these selection criteria, 109 patients were
enrolled. The duration of follow-up was 61,466 days
(mean, 496 days; median, 348 days).
The estimated glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease
equation6 coefficient modified for Japanese patients: estimated GFR = 0.741175 Cr 1.154 age0.203 (ml min1
1.73 m2). For women, the estimated GFR was multiplied
by a correction factor of 0.742.
The 109 patients were divided into 2 groups: decreased
renal function (estimated GFR on admission <45 mlmin1
1.73 m2; 42 patients) and preserved renal function (estimated GFR on admission 45 mlmin1 1.73 m2; 67 patients). The 2 groups were compared on the basis of age,
sex, New York Heart Association (NYHA) class on admission, prescribed anti-CHF drugs at discharge, and the rates of
coronary artery disease, valvular heart disease, cardiomyopathy, atrial fibrillation, hypertension, diabetes mellitus
(DM), dyslipidemia, anemia, systolic dysfunction, previous
hospitalization for CHF, and worsening renal function during hospitalization. Cardiomyopathy was defined according
to heart catheterization or previous diagnosis. Hypertension
was defined as systolic blood pressure 140 mmHg, diastolic
blood pressure 90 mmHg, or previous history. DM was
defined as fasting plasma glucose concentration 126 mg/dl,
Circulation Journal Vol.72, July 2008

Renal Dysfunction and CHF Re-Hospitalization

1153

60

Table 1 Baseline Characteristics of the Patients

N
Age (years)
Gender (male, %)
Hypertension (%)
DM (%)
Dyslipidemia (%)
Underlying heart disease (%)
Ischemic heart disease
Valvular heart disease
Cardiomyopathy
Atrial fibrillation
Estimated GFR (mlmin1 1.73 m2)
Serum creatinine (mg/dl)
Worsening renal function (%)
Anemia (%)
NYHA (%)
I
II
III
IV
Systolic dysfunction (%)
Previous hospitalization with CHF (%)
Prescription at discharge (%)
ACEI/ARB
-blocker
Loop diuretics
Aldosterone blocker

Prevalence (%)

Overall
109
71.91.3
67.0
55.0
36.7
38.5
30.3
16.5
18.3
49.5
53.52.4
1.170.06
22.9
22.0

50
40
30
20
10
0

3
4
CKD stage

Fig 1. Renal function of the patients. Chronic kidney disease (CKD)


stage 1, estimated glomerular filtration rate (GFR) 90 (mlmin1
1.73 m2); stage 2, estimated GFR 60 and <90; stage 3, estimated
GFR 30 and <60; stage 4, estimated GFR 15 and <30; stage 5, estimated GFR <15.

9.2
25.7
15.6
49.5
58.9
32.1

Re-hospitalization free

1.0

56.0
59.6
80.7
37.6

DM, diabetes mellitus; GFR, glomerular filtration rate; NYHA, New York
Heart Association; CHF, congestive heart failure; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker.

a casual concentration 200 mg/dl, or a history of previous


treatment. Dyslipidemia was defined as serum total cholesterol concentration 220 mg/dl, serum high-density lipoprotein-cholesterol concentration 40 mg/dl, serum triglyceride
concentration 150 mg/dl, or previous treatment.7 Anemia
was defined as a serum hemoglobin concentration on admission <11 g/dl.8,9 Systolic dysfunction was defined as an
ejection fraction on admission, estimated with echocardiography, of less than 50%. Worsening renal function during
hospitalization was defined as serum creatinine concentra-

0.8
0.6
0.4
0.2
0.0
0

500

1000

1500

Days
Fig 2. Kaplan-Meier curve of re-hospitalization for congestive heart
failure.

1.0
75
0.8

Sensitivity

Re-hospitalization free

1.0
0.8

p<0.001

90

60

0.6

45

0.4
30

0.2
0.0
0.0

15
0.2

0.4

0.6

0.8

1.0

1-specificity

0.6

estimated GFR 45

0.4
estimated GFR <45

0.2
0.0
0

500

1000
Days

Circulation Journal Vol.72, July 2008

1500

Fig 3. Kaplan-Meier curves of re-hospitalization


for congestive heart failure (CHF) in patients with
preserved renal function and patients with decreased
renal function. Inset: receiver-operating characteristic curve for the ability of estimated glomerular
filtration rate (GFR) to detect re-hospitalization for
CHF at 1 year. Number beside the filled point indicates estimated GFR. Area under the curve, 0.639;
sensitivity, 0.52; specificity, 0.77.

KOMUKAI K et al.

1154

Table 2 Baseline Characteristics of Patients With Preserved Renal Function and Patients With Decreased Renal Function

N
Estimated GFR (mlmin1 1.73 m2)
Serum creatinine (mg/dl)
Worsening renal function (%)
Age (years)
Gender (male, %)
Hypertension (%)
DM (%)
Dyslipidemia (%)
Underlying heart disease (%)
Ischemic heart disease
Valvular heart disease
Cardiomyopathy
Atrial fibrillation
NYHA III (%)
Systolic dysfunction (%)
Previous hospitalization with CHF (%)
Anemia (%)
Prescription at discharge (%)
ACEI/ARB
-blocker
Loop diuretics
Aldosterone blocker

Decreased renal function

Preserved renal function

p value

42
29.51.5
1.750.10
35.7
76.51.9
66.7
66.7
47.6
35.7

67
68.71.5
0.810.03
14.9
68.91.7
67.2
47.8
29.9
40.3

(<0.001)
(<0.001)
0.018
0.004
1.000
0.075
0.069
0.689

31.0
21.4
14.3
50.0
64.3
57.1
47.6
42.9

29.9
13.4
20.9
49.3
65.7
60.0
22.4
9.0

1.000
0.299
0.453
1.000
1.000
0.842
0.011
<0.001

47.6
61.9
81.0
33.3

61.2
58.2
80.6
40.3

0.173
0.841
1.000
0.544

See Table 1 for abbreviations.


Table 3 Predictors of Re-Hospitalization for CHF: Univariate Analysis

Age (per 1 year increase)


Gender male
Hypertension
DM
Dyslipidemia
Underlying heart disease
Ischemic heart disease
Valvular heart disease
Cardiomyopathy
Atrial fibrillation
Previous hospitalization with CHF
NYHA III
Systolic dysfunction
Decreased renal function
Worsening renal function
Anemia
Prescription at discharge
ACEI/ARB
-blocker
Loop diuretics
Aldosterone blocker

Hazard ratio

95%CI

p value

1.028
1.088
0.546
1.010
0.640

1.0071.050
0.6151.925
0.3220.927
0.5801.757
0.3651.119

0.009
0.772
0.025
0.973
0.117

1.057
1.970
0.907
1.275
4.105
0.798
0.982
2.418
1.030
1.361

0.5981.870
1.0583.671
0.4571.798
0.7512.164
2.3827.074
0.4611.379
0.5721.685
1.4254.103
0.5611.889
0.7512.468

0.848
0.033
0.779
0.369
<0.001
0.419
0.947
0.001
0.925
0.310

0.572
0.820
1.186
1.456

0.3380.969
0.4791.404
0.5972.354
0.8572.475

0.038
0.820
0.626
0.165

CI, confidence interval. See Table 1 for other abbreviations.

tion at discharge elevated 0.2 mg/dl or more10 compared


with the value on admission.
Continuous variables are expressed as means SE and
were compared by unpaired t-tests. Categorical variables are
expressed as percentages and were compared by chi-square
tests. Curves of cumulative rates of re-hospitalization-free
survival were constructed with the Kaplan-Meier method
and compared by the log-rank test. Univariate analysis or
multivariate analysis for predictors of re-hospitalization was
performed with the Cox proportional hazard test. Statistical
significance was indicated by a p-value less than 0.05.

Results
The baseline characteristics of the patients are shown in

Table 1 and Fig 1 shows the prevalence of renal dysfunction


according to the chronic kidney disease stage.11 Presence or
absence of proteinuria was not considered. The estimated
GFR was less than 60 mlmin1 1.73 m2 in 63% of patients.
Fig 2 shows the re-hospitalization-free Kaplan-Meier curve
for all patients. Patients with decreased renal function were
more likely to be re-hospitalized (p<0.001, Fig 3). The cutoff value of 45 ml min1 1.73 m2 was determined by a
receiver-operating characteristic curve for the ability of
estimated GFR to detect CHF re-hospitalization at 1 year
(Fig 3 inset). The re-hospitalization-free rate at 1 year was
67.6% in patients with preserved renal function and 42.5%
in patients with decreased renal function. Patients with decreased renal function were older and more likely to have
anemia or to have previously been hospitalized because of
Circulation Journal Vol.72, July 2008

Renal Dysfunction and CHF Re-Hospitalization

1155

Table 4 Predictors of Re-Hospitalization for CHF: Multivariate Analysis

Previous hospitalization with CHF


Age (per 1-year increase)
ACEI/ARB prescription at discharge
Decreased renal function
Anemia
Hypertension
Worsening renal function
Valvular heart disease

Hazard ratio

95%CI

3.513
1.036
0.532
1.856
0.514
0.689
0.712
0.975

1.8646.620
1.0101.063
0.2990.947
1.0273.354
0.2501.056
0.3751.265
0.3761.351
0.4742.006

p value
<0.001
0.006
0.032
0.041
0.070
0.229
0.299
0.945

See Tables 1,3 for abbreviations.

CHF. Worsening renal function during hospitalization was


more frequent in patients with decreased renal function
(Table 2). Worsening renal function was not related to
intravenous use of loop diuretics, ANP, nitrates, or catecholamines (data not shown). Predictors of re-hospitalization because of CHF identified with univariate analysis
were age, previous CHF hospitalization, absence of hypertension, presence of valvular heart disease, decreased renal
function, and non-use of an angiotensin-converting enzyme
inhibitor (ACEI) or an angiotensin-receptor blocker (ARB)
(Table 3). Background characteristics that differed significantly between the patients with decreased renal function
and those with preserved renal function, and factors that
were identified as predictors of re-hospitalization on univariate analysis were subjected to multivariate analysis,
which revealed that independent predictors of re-hospitalization were previous hospitalization for CHF, age, non-use
of ACEI/ARB, and decreased renal function (Table 4).

Discussion
Relation Between Renal Dysfunction and CHF
Re-Hospitalization
Our study found that renal dysfunction is an independent
predictor of re-hospitalization for CHF. Several factors may
be involved in the relationship between renal dysfunction
and CHF. One is the renin angiotensin system (RAS),
which is activated in renal dysfunction,12,13 particularly by
renal artery stenosis and renal ischemia. In renal dysfunction of any origin, the RAS is upregulated to maintain GFR
through the compensatory mechanisms of increased glomerular capillary pressure and hyperfiltration.13 Activation
of the RAS exacerbates CHF,13,14 and inhibition of the RAS
with an ACEI or ARB has been shown in many clinical trials
to improve prognosis. Inhibition of the RAS also preserves
renal function. However, ACEIs and ARBs are underused
in patients who have CHF and renal dysfunction,15,16 probably because they can lead to hyperkalemia and elevated
serum levels of creatinine.17 In the present study, the rate of
ACEI/ARB prescription did not different significantly between patients with preserved renal function and those with
decreased renal function. In addition, non-use of ACEI/ARB
and renal dysfunction were independently related to CHF
re-hospitalization. However, we did not examine doses or
serum concentrations of ACEIs and ARBs; underdosing of
ACEIs and ARBs in patients with renal dysfunction might
obscure the relationship between renal dysfunction and
re-hospitalization for CHF.
Renal dysfunction activates the sympathetic nervous system (SNS),18,19 mainly because of renal ischemia. Decreased
clearance of catecholamines is also involved. Angiotensin
II can also stimulate the SNS. Inhibition of the SNS byCirculation Journal Vol.72, July 2008

blockers is a first-line therapy for patients with CHF and


also has a beneficial effect on renal function.1820 In the present study, titration of -blockers to recommended dosage
was not confirmed. Underuse of-blockers might explain
why their non-use was not associated with re-hospitalization for CHF.
In an experimental model of CHF, sodium extrusion and
natriuresis in response to volume expansion was intact and
renal function was preserved,21 suggesting that retention of
both sodium and fluid is increased by renal dysfunction. Renal dysfunction induces anemia mainly because of impaired
erythropoietin production. Anemia decreases oxygen delivery. Compensatory mechanisms, such as increased preload,
reduced peripheral resistance, and increased cardiac output,
exacerbate CHF.22 Severe anemia also induces cardiac
ischemia, even without severe coronary artery stenosis.23
Although in the present study anemia was more frequent in
patients with decreased renal function, it did not correlate
with re-hospitalization for CHF. Recent studies found that
anemia was not an important prognostic indicator after hospitalization for CHF in extremely elderly patients,24 or in
patients with preserved systolic function.25 The effect of
anemia might depend on the patient population. In patients
with CHF sufficient diuresis sometimes worsens renal
function, probably by decreasing renal perfusion. In such
patients, diuretics are likely underused and patients are followed up under wet conditions. Patients in this condition
cannot tolerate volume overload. CHF is exacerbated by
ischemia; however, in patients with renal dysfunction,
coronary angiography would be performed less often because of the risk of contrast nephropathy. Even when
ischemia is detected with radioisotope scintigraphy, revascularization procedures are avoided for the same reason.
Other mechanisms that might be involved in the relationship between decreased renal function and re-hospitalization for CHF include endothelin production, endothelial
dysfunction, inflammation, oxidative stress, hypercoagulation5,12,26 and other, as yet unidentified, mechanisms.
Other Factors Related to Re-Hospitalization for CHF
In the present study, previous hospitalization was the
strongest predictor for re-hospitalization for CHF. Earlier
studies have shown that previous hospitalization increases
the rates of mortality and re-hospitalization for CHF.27,28
Hospitalization is required because of progression of CHF,
but hospitalization might directly worsen prognosis because
of the use of intravenous diuretics and catecholamines.1 Deconditioning during hospitalization decreases exercise tolerance, which worsens prognosis and increases the likelihood
of re-hospitalization.29,30 Hospitalization also worsens renal
function.31,32 Some studies have reported that worsening
renal function during hospitalization is related to CHF re-

KOMUKAI K et al.

1156

hospitalization,10,33 but the present study could not show


statistical significance, possibly because of the small number of the samples and relatively small decrease in renal
function. Preventing deterioration in renal function should
be considered during hospitalization and after discharge.
The present study also found that age was an independent
predictor of re-hospitalization for CHF, probably because
of comorbidity or associated deconditioning. Renal function
decreases as age increases,34 but in the present study age was
a predictor independent of renal function. Elderly patients
are at greater risk for infectious diseases, and infection exacerbates CHF. In addition, compliance with treatment is
worse in elderly patients.
In contrast to previous studies,35,36 NYHA class was not
associated with CHF re-hospitalization in the present study.
Small sample size, and higher rate of elderly subjects in the
present study might explain the difference. Estimation of
NYHA class can be difficult in the elderly, partly because
of a decrease in physical activity. In addition, NYHA class
was estimated on the time of admission in the present
study, so the NYHA class at discharge or during follow-up
might be a better index.

Conclusion
Decreased renal function is an independent predictor of
re-hospitalization for CHF. Even after successful discharge,
careful follow-up care is needed, especially for patients with
impaired renal function.
Acknowledgements
We thank Dr Okazaki for assistance with the manuscript and Dr
Matsushima for his helpful comment, especially on the statistics.

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