Shinshu Med J, 68⑶：131～138, 2020

Impact of Ambulation Status in Patients with End-stage Renal Disease
on Hemodialysis due to Diabetic Nephropathy : The PREDICT Study
Tamon Kato1）＊, Yusuke Miyashita2）, Hidenao Sone3）, Tetsutaro Mizukami3）8）, Yutaka Kanno4）
Tomomasa Oguchi5）, Daisuke Yokota6）, Noriyo Shiotsuki7）, Etsuko Mizukami8）, Masuo Terashima9）
Masakazu Aruga10）, Hisanori Yui1）, Shusaku Maruyama1）, Hideki Kobayashi1）, Daisuke Kashiwagi1）
Ayumu Nagae1）, Takahiro Sakai1）, Tatsuya Saigusa1）, Soichiro Ebisawa1）, Ayako Okada1）
Hirohiko Motoki1） and Koichiro Kuwahara1）
1） Department of Cardiovascular Medicine, Shinshu University School of Medicine
2） Department of Cardiology, Nagano Red Cross Hospital3） Shoen Clinic
4） Kanno Dialysis and Vascular Access Clinic5） Department of Dialysis Center, Aizawa Hospital6） Department of Cardiology, Matsumoto Kyoritsu Hospital
7） Azumi General Hospital8） Kashiwabara Clinic9） Hotaka Hospital10） Fujimori Hospital

Background : Hemodialysis (HD) patients often have severe morbidity and mortality, with critical limb ischemia(CLI) being a cause of major amputation and death. In the clinical setting, the predictive ability of patientambulatory status on outcome in patients on HD due to diabetic nephropathy (DN) is not well known.
Aim : To investigate the association of ambulatory status with clinical outcome in end-stage renal disease
patients on HD and its predictive ability for CLI-free survival.
Methods : In the multi-center, observational Prospective REgistry with the DIalysis patient due to diabetes toprevent CriTical limb ischemia (PREDICT) study, 173 patients on HD due to DN were enrolled between April
2012 and August 2013 from 9 institutions. We investigated ambulatory status, ankle-brachial index, lower limb
artery lesions by duplex ultrasound, and laboratory findings every 6 months for 2 years. The primary endpoint
was CLI-free survival at 2 years.
Results : Complete follow-up was possible for 164 patients (94.2 ％) at 2 years. Average age was 68 (range :58-74) years and average HD duration was 49.4 (range : 23.5-90.5) months. The CLI-free survival rate ofambulatory patients was significantly higher than that of non-ambulatory patients (84.9 ％ vs. 62.7 ％, p＝0.0006).
Survival rate was also significantly higher in the ambulatory group (89.2 ％ vs. 69.8 ％, p＝0.01). Cox regression
analysis revealed a significant association between ambulatory status and CLI or death (hazard ratio 6.06, 95 ％confidence interval 1.34-732.3 ; p＝0.02).
Conclusion : This study revealed that ambulatory status might predict mid-term CLI-free survival in HD
patients with DN. Shinshu Med J 68 : 131―138, 2020
(Received for publication January 20, 2020 ; accepted in revised form February 3, 2020)
Key words : hemodialysis, critical limb ischemia, ambulatory status, prognosis＊

Corresponding author : Tamon Kato
Department of Cardiovascular Medicine,
Shinshu University School of Medicine, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : katot20110408@gmail.com

No. 3, 2020

Ⅰ

Introduction

The number of end-stage renal disease (ESRD)
patients on hemodialysis (HD) due to diabetic ne­
131Kato・Miyashita・Sone et al.

phropathy (DN) is increasing worldwide, with over2012 and August 2013. We investigated symptoms,

350,000 patients currently receiving HD therapy inambulatory status, ankle-brachial index (ABI), lower

Japan and approximately 30,000 individuals starting

limb artery lesions by duplex ultrasound, and hema­1）

HD treatment every year . Mortality among ESRD

tological findings every 6 months for 2 years. Thispatients remains high, 30-50 ％ of which is caused

study was approved by the Shinshu University

by cardiovascular disease2）-5）. Critical limb ischemia

School of Medicine Institutional Review Board (no.

(CLI) is a cause of major amputation and death in2366) and by the ethics committee of each participat­

6）

peripheral artery disease (PAD) . Major amputation

ing institution. The study was conducted in accor­of lower limbs reduces quality of life, decreases activ­

dance with the Declaration of Helsinki. Informed

ities of daily living, and may raise treatment costs.

consent was obtained from each participant.

HD patients constitute roughly a quarter of PAD

Ｂ

Patient population

patients in daily clinical practice. Although endovas­

The patient flowchart for this study is presented

cular treatment (EVT) is a less invasive therapy for

in Fig. 1. A total of 173 patients without CLI receiv­

PAD, patients receiving EVT may still experienceing HD due to DN between April 2012 and August

heavy calcification in target lesions and extended

2013 were initially enrolled. There were no non-arteriosclerosis. Earlier PAD detection and interven­ambulatory subjects due to PAD since CLI patientstion are therefore needed.

were excluded from the study. Nine patients were

Frailty has been defined as a progressive syn­excluded due to transfer to another hospital (4 pa­

drome or state of increased vulnerability to stressful

tients), withdrawal of consent (3 patients), or lack ofsituations resulting from aging-associated decline

clinical data (2 patients). Ultimately, 164 patientsthat is characterized by a reduction in biologicalwere followed for 2 years.

functional reserves. Frailty increases the risk of poorＣ

Definitions

outcomes, such as disease progression, disability,

Amputation-free survival was defined as freedom

hospitalization, and death7）-9）. Both frailty and sarco­

from major amputation, revascularization, or all-penia are important concepts in the quest to prevent

cause death. Ambulatory status was defined as thephysical dependence as the field of geriatrics shifts

ability to walk unassisted in daily life and, in the casetowards indications of the early stages of disability.

of medical examinations, enter the consultation room

Although their definitions are still developing, these

without the need of a wheelchair or stretcher. Am­

10）

notions clearly overlap in many physical aspects .

bulatory status was judged by HD medical atten­

Approximately one third of patients on HD are frail

dants using a frailty scale13）. Limb arterial stenosis

and thus at increased risk of mortality11）12）. The

was defined as peak systolic velocity ≥200 mm/sec,present study aimed to clarify the association ofpeak systolic velocity ratio ＞2.4, or duplex ultra­

ambulatory status with clinical outcome in HD pa­

sound findings. The indication for revascularization

tients with DN.

was based on symptomatic and duplex arterial ste­
Ⅱ Methods

Ａ

Study design

nosis criteria. CLI was defined as gangrene, nonhealing ischemic ulcer, or ischemic rest pain. CLIfree survival was defined as freedom from the

The Prospective REgistry with the DIalysis pa­

composite of all-cause death and the onset of CLI.

tient due to diabetes to prevent CriTical limb isch­

Revascularization was performed for clinical symp­

emia (PREDICT) study was a prospective, observa­

toms of ≥ 50 ％ restenosis on duplex ultrasound or

tional, multi-center investigation that included a totalangiography. Major adverse limb events (MALEs)of 13 institutions in and around the city of Matsumoto,included all-cause death, major amputation, andJapan. Recruited subjects were consecutive patientslower limb revascularization.

receiving HD treatment due to DN between April

Ｄ

132

Study endpoints
Shinshu Med J

l. 68

Ambulation status in hemodialysis

Fig. 1 Patient flow chart
A total of 173 patients were enrolled. After the exclusion of 9 patients, 164 patients were followed for 2 years.

The primary endpoint in this study was CLI-free

CLI-free survival group than in the CLI or deathsurvival at 2 years. The secondary endpoints weregroup (11.2 ％ vs. 20.5 ％, p＝0.03). Ambulatory pa­

survival and MALE at 2 years. Multivariate analysis

tients were significantly more frequently observed inwas employed to determine the predictors of death

the CLI-free survival group than in the CLI or deathand CLI in the HD population.

group (84 ％ vs. 48.7 ％, p＝0.003). ABI was signifi­Ｅcantly more frequent in the CLI-free survival group

Statistical analysis
Normal variables are expressed as numbers andthan in the CLI or death group (1.1 [range : 0.49-1.47]

percentages. Continuous variables are expressed as

vs. 0.9 [range : 0.26-1.36] p＝0.005), as was PSV (71the mean ± standard deviation for non-skewed data

[range : 31-251] vs. 60 [range : 13-103] mm/sec p＝and median (interquartile range) for skewed data.

0.01). The CLI-free survival group had significant­Categorical variables were reported as frequencies

ly higher albumin level (3.8 [range : 3.6-3.9] vs. 3.4

and compared with the chi-square test. Comparisons[range : 3.0-3.7] g/dL, p＝0.0003), hemoglobin levelof the means between groups were performed using(10.7 [range : 10.1-11.4] vs. 10.2 [range : 9.6-10.8] g/dL,

analysis of variance (ANOVA) and either the Bonfer­

p＝0.008), and HDL level (41.3 [range : 3-52] vs. 36.7

roni test or the non-parametric test. Survival curves[range : 29-40] mg/dL, p＝0.03) and lower CRP level

were constructed for time-event variables with

(0.1 [range : 0.05-0.2] vs. 0.15 [range : 0.06-0.46] mg/L,

Kaplan-Meier estimates and compared using the

p＝0.03) and BNP level (177.1 [range : 71.4-389.1] vs.

log-rank test. Cox regression analysis was used to280.6 [range : 133.6-695.4] pg/mL, p＝0.04).

identify independent predictors of CLI-free survival

CLI-free survival was assessed at 12 and 24 months

and all-cause death. A p-value of ＜0.05 was consid­

using Kaplan-Meier testing. The CLI-free survival

ered statistically significant. Data were analyzed

rate of the ambulatory group was significantlywith JMP 13 software (SAS Institute, Cary, Northhigher than that of the non-ambulatory group (94.3

Carolina, U.S.A.).

％ vs. 84.5 ％ at 12 months and 84.9 ％ vs. 62.7 ％Ⅲ

Results

at 24 months [p＝0.006], respectively) (Fig. 2). The
survival rate of the ambulatory group was also sig­

The baseline patient characteristics are shown innificantly higher than that of the non-ambulatory

Table 1. CLI-free survival patients were significant­group (95.1 ％ vs. 87.1 ％ at 12 months and 89.2 ％ vs.

ly younger than CLI or death patients (65 [range :69.8 ％ at 24 months [p＝0.01], respectively) (Fig. 3).

34 - 91 ] v s . 71 [ r a n g e : 38 - 88 ] y e a r s , p＝0 . 003 ) . A

MALE avoidance rates in the ambulatory and non-history of PAD was significantly less frequent in theambulatory groups were 92.7 ％ and 81.7 ％ at 12

No. 3, 2020

133

Kato・Miyashita・Sone et al.
Table 1

Patient characteristics

CLI free survival
n＝125

CLI or death
n＝39

p valueAge (year)
Male (％)
BMI
HD duration (months)
Hypertension (％)
Dyslipidemia (％)
Insulin user (％)
Smoking (％)
CAD (％)CVD (％)PAD (％)
History of heart failure (％)
Ambulatory (％)
ABIPSV (mm/sec)
LVEF (％)

65 (34-91)
94 (75.2)
22.8 (15.2-30.2)
46.7 (1-291)
112 (89.6)
34 (27.2)
61 (48.8)
73 (58.4)
17 (13.6)
13 (10.4)
14 (11.2)
49 (39.2)
105 (84)
1.1 (0.49-1.47)
71 (31-251)
64.1 (38-77)

71 (38-88)
27 (69.2)
22.9 (14.7-29.6)
73.6 (5-190)
30 (76.9)
11 (28.2)
29 (74.4)
13 (33.3)
11 (28.2)
5 (12.8)8 (20.5)
19 (48.7)
19 (48.7)
0.9 (0.26-1.36)
60 (13-103)
66.2 (22-78)

0.003
0.98
0.4
0.09
0.68
0.91
0.79
0.08
0.08
0.84
0.03
0.19
0.003
0.005
0.01
0.38

Laboratory
Alb (g/dI)
Hb (g/dI)
HbAlc (％)
LDL (mg/d1)
HDL (mg/d1)
CRP (mg/L)
BNP (pg/ml)

3.8 (3.6-3.9)
10.7 (10.1-11.4)
6.6±1.1
82.5 (68.3-104)
41.3 (33-52)
0.1 (0.05-0.2)
177.1 (71.4-389.1)

3.4 (3-3.7)
10.2 (9.6-10.8)
6.7±1.2
96 (70-106)
36.7 (29-40)
0.15 (0.06-0.46)
280.6 (133.6-695.4)

0.0003
0.008
0.53
0.42
0.03
0.03
0.04

CAD : coronary artery disease, CVD : cerebral vascular disease, PAD : peripheral artery disease,
ABI : ankle brachial index, PSV : peak systolic velocity, LVEF : left ventricle ejection fraction,
Alb : albumin, Hb : hemoglobin, LDL : low-density lipoprotein cholesterol, HDL : high-density
lipoprotein cholesterol, CRP : C-reactive protein, BNP : brain natriuretic peptide

months and 81.6 ％ and 58.6 ％ at 24 months, respec­

pendent predictor of CLI or death in multivariate

tively, and were significantly higher in the ambulato­

analysis (HR 0.32, 95 ％ CI 0.11-0.87 ; p＝0.03) (Tablery group at 24 months (p＝0.006) (Fig. 4).

4).

Death occurred in 27 patients during the study
period due to heart failure (2 patients), arrhythmia (4ⅣDiscussion

patients), stroke (5 patients), pneumonia (5 patients),

The present study clarified the 2-year clinical out­

sepsis from CLI (4 patients), malignant tumor (4 pa­

come of patients receiving HD due to DN. CLI-freetients), or other (3 patients) (Table 2). Cardiac deathsurvival was significantly associated with younger

accounted for 22 ％ of deaths. Univariate analysis

age and ambulation status. The ambulatory grouprevealed age (hazard ratio [HR] 13.7, 95 ％ confidence

also had longer amputation-free survival, survival,

interval [CI] 1.94-117.6 ; p＝0.002), past history ofand freedom from MALE. Moreover, ambulatory

coronary artery disease (HR 2.89, 95 ％ CI 1.09-7.35 ;status was a strong independent predictor of CLI-

p＝0.03), ambulatory status (HR 0.29, 95 ％ CI 0.13-

free survival in the HD population.

0.65 ; p＝0.003), and albumin (HR 0.07, 95 ％ CI 0.08-

The crude death rate of dialysis patients in 20110.74 ; p＝0.017) to be significantly associated with CLI

was 10.2 ％ in Japan1）. The main causes of death inor death (Table 3). Ambulatory status was an inde­

this study were cardiac death (22.2 ％), stroke (18.5

134Shinshu Med J

l. 68

Ambulation status in hemodialysis

Fig. 2 CLI-free survival at 2 years in HD patients
The CLI-free survival rate of the ambulatory group was significantly higher than that of the non-ambulatory group.

Fig. 3 Survival at 2 years in HD patients
The survival rate of the ambulatory group was significantly higher than that of the non-ambulatory group.

％), malignant tumor (14.8 ％), and infection (33.3 ％),score based on fatigue, resistance as measured by1）

which were similar to previous reports from Japan .

stair climbing, ambulation, and illness-related weight

Nakai et al. observed cardiac death (25 ％), cerebro­

loss were significantly associated with mortality14）.

vascular disorder (5.4 ％), malignant tumor (11.6 ％),We observed contradictions in the results of ABI andinfection (24.5 ％ ), and cardiac infarction (3.6 ％ ) as

PSV in this study, possibly due to calcification

factors related to death1）. Chao reported that frailty

change of the vessels.

No. 3, 2020

135

Kato・Miyashita・Sone et al.

Fig. 4 Freedom from MALE at 2 years in HD patients
The freedom from MALE rate of the ambulatory group was significantly higher than that of the non-ambulatory group.

Table 2

Several studies have analyzed the risk factors for

Causes of deathmortality in HD patients. Age, low body mass index

Death
n＝27
Heart failure
VF/Sudden death
StrokePneumoniae
Sepsis from CLI
Malignant Tumor
Others(BMI), low albumin, low hemoglobin, and high CRP
were susceptibility factors for all-cause mortality in

2
4
5
5
4
4
3

an HD population15）, while Ishi et al. associated age,diabetes, low BMI, cardiac artery disease history, lowhemoglobin, and low albumin with all-cause deathand cardiac death16）. Frailty was also identified as arisk factor in HD patients17）. However, the compo­
nents of frailty varied in each study and included

VF : ventricular fibrillationsuch parameters as weight loss, exhaustion, low
Table 3

Risk factor
Age
Male
Dyslipidemia
Hypertension
HD duration
Smoking
Insulin
CAD
CVD
Past history of heart failure
Ambulatory
Albumin

Univariate analysis for factors associated CLI or death
Hazard ratio

95 ％ confidence interval

p value

13.7
1.10
1.47
0.62
2.55
0.80
1.42
2.89
1.41
1.91
0.29
0.07

1.94-117.6
0.85-2.7
0.59-3.1
0.10-9.47
0.17-62.1
0.30-1.98
0.23-0.62
1.09-7.35
0.04-8.93
0.43-7.52
0.13-0.65
0.08-0.74

0.002
0.81
0.41
0.38
0.34
0.64
0.35
0.03
0.51
0.09
0.003
0.017

CAD : coronary artery disease, CVD : cerebral vascular disease136

Shinshu Med J

l. 68

Ambulation status in hemodialysis
Table 4Multivariate analysis for factors associated with CLI or death

Risk factor

Hazard ratio

95 ％ confidence interval

p valueAge

7.2

0.73-85.3

0.09

CAD
Ambulatory
Albumin

2.85
0.32
0.41

0.68-8.61
0.11-0.87
0.03-5.48

0.06
0.03
0.50

CAD : coronary artery disease

physical activity, slow gait speed, and weak grip
17）

18）

medical staff. Whether a patient can walk or not may

in addition to physician subjectivity . In

have real-world implications on PAD treatment deci­

this study, the patients were divided into two groups

sions, with intervention for non-ambulatory patientsby ambulatory status, which we believed to be ahaving a diminished prognosis requiring more care­very clear cutoff line. Our results indicated that am­

ful attention.

strengthbulation was strongly related to clinical outcomes.

Ⅴ

Thus, the maintenance of ambulation may represent

Limitations

This study had several limitations that may havea concrete goal in patient care and rehabilitation.
The convalescence of HD patients may be im­affected clinical outcomes. First, the sample size andproved by appropriate nourishment and exercise,study period were limited and need validation in19）such as walking . As is the case for sarcopenia, it

larger and longer trials. Second, there may havewill be necessary to examine the precise merits ofbeen selection bias by attending physicians in that

diet, aerobic exercise, and rehabilitation in the future.

patients with co-morbities or unfavorable conditions

The present study indicated that maintaining an

may have been avoided during recruitment. Lastly,

ambulatory status was important for a more favor­

specific details were unavailable for HD and CLI

able outcome in patients.

treatment.

Nutrition, muscular strength, quantity of muscle,Ⅵ

anemia, and other factors are known to influence theConclusion

prognosis of HD patients14）19）20）. By including ambu­

This study revealed an association between ambu­

lation, more precise convalescence predictions will belatory status and mid-term CLI-free survival in HD

possible by examining prediction factors compositely.

patients with DN. As ambulatory status is a strong

Meanwhile, the goal of ambulation for treatment andpredictor of CLI-free survival in DN patients, careful

rehabilitation remains a simple and easily understoodattention is required and early fragility intervention

endpoint that can be coordinated smoothly among

is advised for non-ambulatory patients.

References
1） Nakai S, Watanabe Y, Masakane I : Overview of regular dialysis treatment in Japan. Ther Apher Dial 17 : 567-611,
20132） Foley RN, Parfery PS, Sarnak M : Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J
Kidney Dis 32 (5 Suppl. 3) : s112-119, 1998
3） Tonelli M, Wiebe N, Culleton B, et al : Chronic kidney disease and mortality risk : a systematic review. J Am Soc
Neprol 17 : 2034-2047, 2006
4） Parfrey PS, Foley RN : The clinical epidemiology of cardiac disease in chronic uremia. J Am Soc Nephol 10 : 16061615, 1999
5） Schiffirin EL, Lipman ML, Mann JF : Chronic kidney disease : effects on the cardiovascular system. Circulation
116 : 34-39, 2007
No. 3, 2020137

Kato・Miyashita・Sone et al.
6） Mustapha JA, Katzen BT, Neville RF, et al : Determinants of long-term outcomes and costs in the management ofcritical limb ischemia : a population-based cohort study. J Am Heart Assoc 7 : e009724, 20187） Clegg A, Young J, Iliffe S, et al : Frailty in elderly people. Lancet 381 : 752-762, 20138） Hogan DB, MacKnight C, Bergman H : Models, definitions and criteria of frailty. Aging Clin Exp Res 15 : 1-29, 2003
9） Vermeiren S, Vella-Azzopardi R, Beckwee D : Frailty and the prediction of negative health outcome : a meta-analy­
sis. J Am Med Dir Assoc 17 : 1163e17, 2016
10） Cruz-Jentoft AJ, Kiesswetter E, Drey M, Sieber CC : Nutrition, frailty and sarcopenia : Aging Clin Exp Res 29 : 4348, 201711） Johansen KL, Dalrymple LS, Delgado C, et al : Association between body composition and frailty among prevalent
hemodialysis patients : a US Renal Data System special study. J Am Soc Nephrol 25 : 381-389, 201412） Anand S, Johansen KL, Kurella Tamura M : Aging and chronic kidney disease : the impact on physical function andcondition. J Gerontol Med Sci 69 : 315-322, 201413） Rockwood K, Song X, MacKnight C, et al : A global clinical measure of fitness and frailty in elderly people. CMAJ
173 : 489-495, 2005
14） Chao CT, Wang J, Huang JW, et al : Frailty predicts an increased risk of end-stage renal disease with risk competi­tion by mortality among 165461 diabetic kidney disease patients. Aging and Disease 10 : 1270-1281, 201915） Ma L, Zhao S : Risk factors for mortality in patients undergoing hemodialysis : A systemic review and meta-analysis.
Int J Cardiol 238 : 151-158, 201716） Ishii J, Takahashi H, Kitagawa F et al : Multimarker-approach to risk stratification for long-term mortality inpatients on chronic hemodialysis. Circ J 79 : 656-663, 201517） Johansen KL, Delgado C, Kaysen GA et al : Frailty among patients receiving hemodialysis : Evolution of components
and associations with mortality. J Gerontol A Biol Sci Med Sci 74 : 380-386, 201918） Takeji Y, Yamaji K, Tomi Y, et al : Impact of Frailty on Clinical Outcomes in Patients with Critical Limb Ischemia.
Circ Cardiavasc Interv 11 : e006778, 201819） Johansen KL, Delgado C, Kaysen GA, et al : Frailty among patients receiving hemodialysis : evolution of components
and associations with mortality. J Gerontol A Biol Sci Med Sci 74 : 380-386, 201920） Rao M, Sharma M, Juneja R, Jacob S, Jacob CK : Calculated nitrogen balance in hemodialysis patients : influence ofprotein intake. Kidney Int 58 : 336-345, 2000

（2020. 1. 20 received ; 2020. 2. 3 accepted）

138

Shinshu Med J

l. 68