Shinshu Med J, 68⑶：139～147, 2020

Prognostic Impact of Cardio-renal-anemia Syndrome in Patients
at Risk for Heart Failure from the IMPACT-ABI study
Wataru Shoin＊, Soichiro Ebisawa, Tatsuya Saigusa
Takahiro Sakai, Yasutaka Oguchi, Ayako Okada
Hirohiko Motoki and Koichiro Kuwahara
Department of Cardiovascular Medicine, Shinshu University School of Medicine

Background : Cardio-renal-anemia syndrome (CRAS) is known as a vicious circle, since chronic heart failure(CHF), chronic kidney disease (CKD), and anemia are exacerbated by each other. However, it remains unclear
whether CKD and anemia would be associated with cardiovascular events in asymptomatic patients at risk for
HF.
Methods : We retrospectively enrolled patients without prior HF history who were hospitalized for cardiovascu­
lar diseases between 2005 and 2012. Patients were divided into two groups with or without RAS defined as
suffering from CKD (estimated Glomerular filtration rate (eGFR) ＜60 mL/min/1.73 m2) and anemia (hemoglobin＜13 g/dL in men and ＜12 g/dL in women). The primary endpoint was major adverse cardiovascular events(MACE), the composite of cardio-vascular death and HF hospitalization.
Results : A total of 1801 patients were enrolled. The mean age was 69.6±10.6 years, and 76 ％ were men. The
mean LV ejection fraction was 66.9±12.3 ％, and stage A HF was present in 73 ％ of the patients. Over a 4.6year median follow-up, primary endpoint was observed in 129 patients. In Kaplan-Meier analysis, patients withRAS (n＝217) showed worse prognoses than those without RAS (n＝1584). In multivariable Cox proportional haz­ards analysis, after the adjustment for age, sex, and conventional risk factors, RAS showed significant associa­
tion with the incidence of MACE (HR 1.86 ; 95 ％ CI 1.20-2.89, P＝0.005).
Conclusions : In patients at risk for HF, RAS was significantly associated with future cardiovascular events.
Investigation of the impact of early intervention for preventing CKD and anemia on those patientsʼ prognosis is
warranted. Shinshu Med J 68 : 139―147, 2020
(Received for publication January 7, 2020 ; accepted in revised form February 5, 2020)
Key words : cardio-renal-anemia syndrome, heart failure, chronic kidney disease, anemia

CKD, known to be exacerbating factors of CHF,

Ⅰ Introduction

are often associated with that (35-57 ％ of patients

Currently, the rapid aging of society has caused awith CHF have anemia4）5）, and 47-57 ％ of them have

rapid increase in the prevalence of CHF1）2）. Thoughstage 3 or greater CKD6）7）), and chronic heart failure

CHF in the elderly has a poor prognosis because of(CHF), chronic kidney disease (CKD), and anemia are

3）frequent readmission due to acute exacerbation , theable to be caused and exacerbated by each other.

appropriate stage or method of intervention to pre­This vicious cycle named as Cardio-renal-anemia

vent worsening of CHF is unclear. Anemia and/or(CRA) syndrome8） has begun to gather attention.
The interaction among CRA is complex, because＊

Corresponding author : Wataru Shoin
Department of Cardiovascular Medicine,
Shinshu University School of Medicine, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : wshoin@shinshu-u.ac.jp

No. 3, 2020

each of these three conditions could be results andcauses for each other, but the mechanism has been
gradually elucidated. CKD and anemia activate
the sympathetic system, the renin-angiotensin-aldo­139

Shoin・Ebisawa・Saigusa et al.

sterone system (RAAS), and the antidiuretic hormone.

dialysis were also excluded. Then 1,801 patients diag­

Those neurohormonal actions and the consequent

nosed as stage A or B HF were subsequently en­

fluid retention cause myocardial hypertrophy, necro­rolled and divided into four groups based on eGFR

sis, fibrosis and cardiomyopathy resulting in worsen­

and Hb : with/without CKD and/or anemia (Fig. 1).

ing of CHF9）. Then, CRA syndrome was reported

Furthermore, Groups 1-3 were combined without

as an independent predictor of all-cause mortality

the renal-anemia syndrome (RAS) group. The prima­

10）
-12）

in symptomatic HF. However, it remains unclear

ry endpoint was the composite of major adverse car­whether CKD and anemia are associated with thisdiovascular events (MACE), including cardiovascularvicious circle in patients at risk for asymptomatic HF.

death (CVD) and heart failure requiring hospitaliza­

In this study, we sought to investigate the associa­

tion. The secondary endpoints were cardiovasculartion of a combination of renal dysfunction and anemia

death and heart failure requiring hospitalization.

with the incidence of adverse cardiovascular (CV)Ｂ

events, in asymptomatic patients at risk for HF.
Ⅱ Methods
Ａ

Study design

Definitions
The ACC/AHA stages A and B of HF are defined

as follows : Stage A, at risk for HF (i.e. hypertension,
diabetes mellitus, obesity, atherosclerotic disease,metabolic syndrome, familial history of cardiomyopa­

The current study was performed using integrat­thy) but without structural heart disease or symp­

ed data from the impressive predictive value of ABI

toms of HF ; Stage B, structural heart disease but

for clinical long-term outcomes in patients with car­without signs or symptoms of HF15）. In the present

diovascular disease examined by the ABI (IMPACT-

study, structural heart disease was defined by clini­

13）ABI) study . The IMPACT-ABI study was a retro­cal and echocardiographic findings as follows : priorspective cohort study that enrolled 3,131 consecutive

myocardial infarction, cardiomyopathy, valvularpatients who were admitted to Shinshu University

heart disease, reduced left ventricular ejection frac­for cardiovascular disease and examined by ABI be­tion (LVEF, 40 ％)13）, enlarged LV end-diastolic diam­

tween January 2005 and December 2012. Clinical, de­eter ＞55 mm)16）, or LV mass index ＞115 g/m2 in men

mographic, laboratory, and follow-up data were col­or ＞95 g/m2 in women17）. Valvular heart disease waslated from hospital records or by contacting patients

specifically defined as severe aortic or mitral valvu­

and their family. The present study was registeredlar disease using echocardiography. Cardiovascularwith the University Hospital Medical Information

death was defined as mortality due to acute myocar­

Network Clinical Trials Registry (UMIN-CTR), as

dial infarction, significant cardiac arrhythmia, conges­

accepted by the International Committee of Medical

tive heart failure, stroke, or other cardiovascular

Journal Editors (UMIN-ID ; 000020276). The study

causes. CKD was defined as eGFR calculated by the

protocol was performed in accordance with the ethi­

Cockcroft-Gault Equation of less than 60 ml/min/

cal guidelines of the Declaration of Helsinki and was

1.73 m2 (classified as GFR categories G3a-G5 in Kidney

approved by the Ethics Committee of Shinshu Uni­

Disease : Improving Global Outcomes guideline), andversity School of Medicine. Because of the retrospec­

anemia was defined as Hb levels less than 13 g/dL intive nature of the current study, informed written

males and 12 g/dL in females according to World

consent for participation was not obtained from

Health Organization criteria. Hypertension (HT) was

patients and data were analyzed anonymously.

defined as current systolic blood pressure ＞140

Twenty-five patients with inadequate eGFR and/mmHg and/or diastolic blood pressure ＞90 mmHg

or Hb data were excluded. 633 patients with prioror use of antihypertensive agents. Dyslipidemia was

symptomatic HF (stage C or D HF), 524 patientsdefined as total cholesterol ＞220 mg/dl, low-density

without risk of HF defined in the 2013 ACCF/AHA

lipoprotein cholesterol ＞140 mg/dl, high-density li­

HF guideline14）, and 147 patients with CKD on hemo­

poprotein cholesterol ＜40 mg/dl, triglycerides ＞150

140

Shinshu Med J

ol. 68Prognostic impact of cardio-renal-anemia syndrome in patients at risk for heart failure

Fig. 1 Study design
IMPACT-ABI, impressive predictive value of ankle brachial index (ABI) for clinical longterm outcome in patients with cardiovascular disease examined using ABI ; eGFR, estimatedglomerular filtration rate ; Hb, hemoglobin ; HF, heart failure ; CKD, chronic kidney disease ; RA
syndrome, renal-anemia syndrome.

mg/dl, or use of cholesterol-lowering agents. Diabe­tes mellitus was defined as fasting blood glucose ＞
126 mg/dl and/or casual plasma glucose ＞200 mg/

Ⅲ Results
The baseline patient characteristics, classified bydl, HbA1c ＞6.5 ％ or use of hypoglycemic agents.

the presence of the CKD and/or anemia, are present­Ｃ

ed in Table 1. A total of 1801 patients participated,

Statistics
Data are reported as the mean ± standard devia­

with a median follow-up of 4.6 years. The mean age

tion for continuous variables and as frequencies andwas 69.6±10.6 years, and 76 ％ were men. The mean

percentages for categorical variables. Continuous

LV ejection fraction was 66.9±12.3 ％, and stage A

variables were compared using variance analysis and

HF was present in 73 ％ of the patients. Anemia wascategorical variables were compared using Chi-present in 21 ％ and CKD in 39 ％. The patients withsquare test. The time to the first event of any one ofRAS (n＝218) were significantly older. The ratio of

the components of MACE was described with thestage A HF showed no significant difference be­use of Kaplan-Meier survival curves and we applied

tween each group. The morbidity of dyslipidemia

the log-rank test to compare the incidence of thewas lower, and that of hypertension and ACE-I/

endpoint between groups. We conducted a time-to-

ARB use and diabetes mellitus were greater in theevent analysis using Cox proportional hazards re­patients with RAS. The patient characteristics, clas­

gression to determine the predictors of primary end­sified by the incidence of MACE, are shown in Table

point. All statistical analyses were performed using

2. The patients in MACE (＋) group were significant­

SPSS version 25 software (SPSS Ink., Chicago, IL,ly older, had more ACE-I/ARB use, histories of priorUSA).

cerebral infarction and atrial fibrillation. History of

No. 3, 2020141

Shoin・Ebisawa・Saigusa et al.
Table 1Comparison of baseline characteristics according to RA syndrome

Age (y.o.)MenStage A HF
Stage B HF
Hypertension
Dyslipidemia
Diabetes mellitus
Ischemic heart disease
Prior myocardial infarction
Prior cerebral infarction
Abdominal aortic aneurysm
Atrial fibrillation
Serum creatinine (mg/dL)
eGFR (ml/min/1.73 m2)
Hemoglobin (g/dL)
LV ejection fraction (％)
Medication n＝914
ACE-Inhibitor or ARB
β-blocker
StatinAntiplatelet agents

Table 2

Hemoglobin (g/dL)
LV ejection fraction (％)
Medication n＝914
ACE-Inhibitor or ARB
β-blocker

142

RAS (＋)
n＝218

p value68.8±10.6
1215 (77)1136 (72)447 (28)
1212 (77)835 (53)532 (34)535 (34)321 (20)118 (7)212 (13)145 (9)0.86±0.25

75.8±8.1
162 (74)
168 (78)
50 (22)185 (85)
96 (44)92 (42)73 (34)36 (17)27 (12)47 (22)19 (9)
1.45±0.70＜0.001
0.426
0.074
0.074
0.006
0.016
0.012
0.079
0.190
0.012
0.001
0.842
＜0.00168.5±17.9
14.3±1.566.9±12.2

40.2±12.8
11.4±1.1
66.9±12.4＜0.001＜0.001
0.978

839 (53)404 (26)782 (49)979 (62)132 (65)
62 (30)93 (46)138 (63)

0.036
0.318
0.129
0.677

Comparison of baseline characteristics according to MACE

Age (y.o.)MenStage A HF
Hypertension
Dyslipidemia
Diabetes mellitus
Ischemic heart disease
Prior myocardial infarction
Prior cerebral infarction
Abdominal aortic aneurysm
Atrial fibrillation
Serum creatinine (mg/dL)
eGFR (ml/min/1.73 m2)

StatinAntiplatelet agentsRAS (－)
n＝1583MACE (－)
n＝1672MACE (＋)
n＝129

p value69.4±10.6
1272 (76)1219 (73)1303 (78)881 (53)583 (35)560 (34)323 (19)
124 (7)233 (14)143 (9)0.91±0.36

73.1±9.0
105 (81)
86 (67)
94 (73)50 (39)41 (32)48 (37)34 (26)21 (16)26 (20)21 (16)1.13±0.69＜0.001
0.170
0.126
0.184
0.002
0.478
0.390
0.054
＜0.001
0.053
0.003
0.001

65.8±19.5
14.0±1.767.1±12.1

56.4±19.7
13.3±1.864.3±13.9＜0.001＜0.0010.013

885 (53)435 (27)819 (51)
1041 (62)86 (67)30 (24)56 (44)76 (59)

0.003
0.404
0.137
0.451
Shinshu Med J

ol. 68Prognostic impact of cardio-renal-anemia syndrome in patients at risk for heart failure

Fig. 2A Kaplan-Meier curves for MACE (including cardiovascular death and hospitalization for heart failure)according to RA syndromeMACE, major adverse cardiac events ; CVD, cardiovascular death ; HF, heart failure ; RA, renal-anemia

dyslipidemia, serum hemoglobin, and eGFR werein Group 2, 19 ％ in Group 3, 32 ％ in Group 4, respec­

lower than the MACE (－) group.

tively) (Fig. 2B). Although CVD incidence did not

MACEs were observed in 129 patients (7 ％). CVD

significantly differ in each group (P＝0.364), hospital­

events occurred in 78 patients and hospitalization for

ization for HF was significantly greater in the RAS (＋)

worsening HF in 62. Incidence of MACEs was sig­group (7 ％ in Group 1, 2 ％ in Group 2, 10 ％ in Groupnificantly greater in the patients with RAS (29 patients,

3, 26 ％ in Group 4, respectively, P＜0.0001).

13 ％ and 100 patients, 6 ％ , P＜0.001). Considering

In univariable Cox proportional hazards analysis,

the components of MACE, hospitalization for worsening

the presence of anemia or CKD was significantly as­

HF occurred more frequently in the patients withsociated with the incidence of MACE (HR 1.96 ; 95 ％RAS (19 patients, 9 ％ and 43 patients, 3 ％, P＜0.001),

CI 1.34-2.87, P＝0.001, and HR 1.94 ; 95 ％ CI 1.38-

but CVD events were equivalent between the 2 groups

2.75, P＜0.001), and the presence of RAS was a stron­(12 patients, 6 ％ and 69 patients, 4 ％, P＝0.364).

ger predictor than presence of only anemia or CKD

In Kaplan-Meier analysis for the incidence of pri­(HR 2.59 ; 95 ％ CI 1.72-3.92, P＜0.001). In multivari­mary endpoints, the patients with RAS showed sig­

able Cox proportional hazards analysis, RAS was annificantly worse prognoses than the patients without

independent predictor of MACE (HR 1.86 ; 95 ％ CI

RAS (the rate of MACE was 14 ％ in RAS (－) group1.20-2.89, P＝0.005) after adjustment for age, sex, andand 32 ％ in RAS (＋), respectively) (Fig. 2A). In addi­

conventional risk factors (Table 3).

tion, MACE incidence in the patients with RAS was
greater than in the patients with only anemia or
CKD (the rate of MACE was 12 ％ in Group 1, 14 ％No. 3, 2020

Ⅳ

Discussion

The major findings in the present study were as
143

Shoin・Ebisawa・Saigusa et al.

Fig. 2B Kaplan-Meier curves for MACE (including cardiovascular death and hospitalization for heart failure) for patients
divided into 4 groups with or without anemia and/or CKDMACE, major adverse cardiac events ; CVD, cardiovascular death ; HF, heart failure ; CKD, chronic kidney disease.

Table 3

Female Sex
Age per decadeHypertension
Dyslipidemia
Diabetes mellitus
Prior myocardial infarction
Prior cerebral infarction
Abdominal aortic aneurysm
Atrial fibrillation
LV ejection fraction
CRAS
AnemiaCKD

Cox proportional hazard analysis for MACE
Univariate HR(95 ％ CI)p value

0.72 (0.46-1.12)
1.66 (1.35-2.02)
0.78 (0.53-1.15)
0.56 (0.39-0.80)
0.88 (0.60-1.27)
1.43 (0.97-2.12)
2.24 (1.40-3.57)
1.73 (1.12-2.66)
1.83 (1.15-2.92)
0.98 (0.96-0.99)
2.59 (1.72-3.92)
1.96 (1.34-2.87)
1.94 (1.38-2.75)

0.147＜0.001
0.208
0.001
0.485
0.720
0.001
0.013
0.011
0.004
＜0.0010.001＜0.001

Multivariate HR(95 ％ CI)p value

0.79 (0.50-1.24)
1.55 (1.25-1.92)
0.77 (0.52-1.16)
0.62 (0.43-0.90)
0.90 (0.61-1.33)
1.30 (0.85-1.98)
2.03 (1.27-3.27)
1.26 (0.80-2.00)
1.60 (1.00-2.58)
0.98 (0.97-1.00)
1.86 (1.20-2.89)

0.3＜0.001
0.216
0.011
0.596
0.224
0.003
0.324
0.052
0.009
0.005

follows. 1) The prevalence of RAS in asymptomatic

tomatic HF in the present study (21 ％). 2) RAS was

patients at HF (12 ％) was lower than that in symp­

an independent predictor of MACE in those patients.

144

Shinshu Med J

ol. 68Prognostic impact of cardio-renal-anemia syndrome in patients at risk for heart failure3) Hypertension and diabetes mellitus known to bewater retention due to these hormonal responses

components of stage A HF were not associated withalso exacerbate inflammation by production of proin­adverse events. 4) History of atherosclerotic diseases

flammatory cytokines and cardiac hypertrophy lead­such as prior cerebral infarction, prior myocardial

ing to necrosis and/or fibrosis of myocardial cells9）.

infarction and abdominal aortic aneurysm were inde­

In addition, angiotensin II, aldosterone and macro­pendent predictors of adverse events.

phage-derived galectin-3 stimulated by them direct­

Previous studies reported that the prevalence ofly promote cardiac remodeling via induction of fibro­

CRAS ranged from 19 to 62 ％ and mortality ratess i s22）-24）. CK D a l s o c a u s e s hy pe r p ho s p ha t em i a ,were up to 51 ％ in patients with HF10）11）18）19）. The

decreasing circulating levels of vitamin D metabo­interactive links between the CRAS triad are com­lites, and increasing parathyroid hormone and fibro­

plex and multi-factorial with high potential for in­blast growth factor 2325）. These mineral and bonecreased morbidity, mortality, complexity and cost ofdisorder are associated with cardiovascular toxicity,care. Thus, early detection and optimal treatment ofleft ventricular hypertrophy26）27） and catabolism28）.

CKD, CVD, and anemia are important to prevent theAnemia leading to tissue hypoxia also activates theprevalence and progression of CRAS. Nowadays, ane­

sympathetic system and RAAS, and causes myocar­

mia is a main therapeutic target in CRAS ; however,dial damage by a similar mechanism9）.

overall its intensity, duration, and optimal hemoglobin

Ａ

Clinical implications

concentration are not well established. Moreover,

Recently, an “HF pandemic” has been striking ouralthough both renal dysfunction and anemia haveaging society. The prevalence of HF with multimor­

been extensively studied in HF cohorts, only a few

bidity also increases with age29）. Thus, effective inter­studies have thoroughly examined the impact ofventions for HF management are necessary for el­

renal dysfunction and anemia (renal-anemia syndrome)

derly patients, including treatment of concurrent

on the prognosis of patients at risk for HF.

decompensated chronic conditions, reduction of poly­In the present study, a combination of renal dys­

pharmacy, monitoring of patient exercise capacities,function and anemia showed a significant associationand prescription of physical exercise and nutritionalwith cardiovascular events in the earlier stage of HF.

supplementation30）31）. Prevention would be one of theThis result indicates that CRAS might be an ad­leading parts of the management of risk factors forvanced disease which consists of hypertension, diabe­

HF. Our findings corroborate the potential benefit oftes mellitus, dyslipidemia, and chronic inflammatoryoffering early intervention to asymptomatic patients

disorders, i.e. risk factors for HF. Indeed, the patho­with risk factors. This study also showed a positive

physiological mechanism in patients with HF with

impact of risk stratification of HF classification (i.e.

preserved ejection fraction is assumed to involvestage A/B) for future cardiovascular events. Thus,

those risk factors inducing micro-inflammation andrecognition of those risk factors and early interven­

oxidative stress that cause multi-organ failure in thetion for them would be effective strategies to stop

20）

novice model . Thus, renal protection and optimal

the rot of “HF pandemic” in Japan.

hemoglobin concentration would be the fundamentalＢapproach toward asymptomatic patients with RAS
and HF risk factors.

Limitations
Several limitations need to be noted in this study.

First, the follow-up period of this retrospective in­

The mechanism by which renal failure and anemia

vestigation was short. Second, the etiology of renalcause heart failure is as follows. Chronic low-grade

dysfunction or anemia was unknown. Third, the ret­inflammation due to various factors in CKD (i.e.

rospective nature of this study, reasons for admis­

visceral edema, oxidative stress, uremic toxins and sosion, and therapeutic strategy after discharge were21）on ) cause renin-angiotensin-aldosterone system

unknown. Finally, the impact of early intervention(RAAS) and sympathetic nerve activity. Sodium andfor preventing CKD and anemia on those patientsʼ

No. 3, 2020

145

Shoin・Ebisawa・Saigusa et al.

prognosis needs to be investigated in other trials

Ⅴ Conclusions

hopefully in a prospective manner. Despite these lim­
itations, RAS proved to be a significant risk factor of

In patients at risk for HF, CKD and anemia were

future cardiovascular events among asymptomatic

significantly associated with future cardiovascularpatients at risk for HF.

events. Investigation of the impact of early interven­tion for preventing CKD and anemia on those pa­
tients’ prognosis is warranted.
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