RADIATION RESEARCH 179, 46–52 (2013)0033-7587/13 $15.00
Ó2013 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RR2863.1

The Association Between Chronic Kidney Disease and Cardiovascular
Disease Risk Factors in Atomic Bomb Survivors
Nobuko Sera,a,1 Ayumi Hida,a Misa Imaizumi,a Eiji Nakashimab and Masazumi Akahoshia
Departments of a Nagasaki Clinical Studies and b Statistics, Radiation Effects Research Foundation, Nagasaki, JapanINTRODUCTION
Sera, N., Hida, A., Imaizumi, M., Nakashima, E. andAkahoshi, M. The Association Between Chronic Kidney
Disease and Cardiovascular Disease Risk Factors in Atomic
Bomb Survivors. Radiat. Res. 179, 46–52 (2013).

High-dose radiation therapy to the chest or neck has beenshown to induce ischemic heart disease (IHD) (1, 2) andstroke (3, 4), but the effect of low-dose radiation on heartdisease is controversial (5, 6). Atomic bomb (A-bomb)radiation increases both cardiovascular disease (CVD)mortality (7) and the incidence of myocardial infarction(8). It is also associated with aortic calcification (9) andretinal arteriosclerosis (10), suggesting that general atherosclerosis is involved in the connection between A-bombradiation and CVD.
Atomic bomb radiation is associated with systolic anddiastolic blood pressure trends of the younger exposed
subjects (7) and cholesterol trends of all exposed subjects
shifted upward in the growth-curve analysis (11). Also, it
has been reported that A-bomb radiation was associatedwith increased risk of hypertension in a longitudinal followup study from 1958–1998 (12) and prevalence ofdyslipidemia in a cross-sectional study (13). In addition, it
is associated with an increase in many inflammatory
markers, including C-reactive protein (CRP), interleukin-6,
and interferon-c, as well as the erythrocyte sedimentation
rate (14, 15) and may be associated with diabetes mellitus(DM) (11). Thus, A-bomb survivors show an increase inmetabolic CVD risk factors and inflammatory markers inmuch the same way as people with metabolic syndrome(MetS), suggesting the possibility that MetS plays a role inthe development of CVD in A-bomb survivors. Indeed, fatty
liver, a surrogate marker for MetS, is associated with Abomb radiation dose (13) and CVD risk factors (16), and it
predicts IHD (17).
Chronic kidney disease (CKD) as a clinical entity has
started to draw attention only recently, with its categorization advocated by the U.S. National Kidney Foundation in2002 (18): it is a risk factor for CVD (19, 20). The MetS and
the increase of MetS components (obesity, high bloodpressure, dyslipidemia and impaired glucose tolerance)
predicted the development of CKD in a longitudinal followup study (21), and the cumulative incidence of CKD wassignificantly higher in subjects with MetS (22). The
aforementioned findings in A-bomb survivors suggest thatCKD may also have a role in the development of CVD.

Atomic bomb (A-bomb) radiation is associated withcardiovascular disease (CVD) and metabolic CVD risk
factors. Chronic kidney disease (CKD) is also known to bea risk factor for CVD and little is known whether CKD is
associated with A-bomb radiation. To examine whether CKD
is associated with CVD risk factors or with A-bomb radiationin A-bomb survivors, we classified renal dysfunction in 1,040
A-bomb survivors who were examined in 2004–2007 as
normal [n ¼ 121; estimated glomerular filtration rate (eGFR)
90 ml/min/1.73 m2]; mild (n ¼ 686; eGFR 60–89 ml/min/1.73m2); moderate (n ¼ 217; eGFR 30–59 ml/min/1.73 m2); or
severe (n ¼ 16; eGFR ,30 ml/min/1.73 m2). Also, we
diagnosed subjects in the moderate and severe renal
dysfunction groups as having CKD (n ¼ 233; eGFR ,59
ml/min/1.73 m2). After adjusting for age, gender, and smoking
and drinking habits, we looked for an association between
renal dysfunction and hypertension, diabetes mellitus (DM),hyperlipidemia, and metabolic syndrome (MetS), and between renal dysfunction and A-bomb radiation. Hypertension[odds ratio (OR), 1.57; 95% confidence interval (CI), 1.12–
2.20, P ¼ 0.009]; DM (OR, 1.79; 95% CI, 1.23–2.61, P ¼
0.002); hyperlipidemia (OR, 1.55; 95% CI, 1.12–2.14, P ¼
0.008); and MetS (OR, 1.86; 95% CI, 1.32–2.63, P , 0.001)
were associated with CKD (moderate/severe renal dysfunction), and hyperlipidemia and MetS were also associated withmild renal dysfunction. CKD (OR/Gy, 1.29; 95% CI, 1.01–
1.63, P ¼ 0.038) and severe renal dysfunction (OR/Gy, 3.19;
95% CI, 1.63–6.25, P , 0.001) were significantly associatedwith radiation dose. CKD associated with radiation may haveplayed a role in the development of CVD among A-bomb
survivors. Ó 2013 by Radiation Research Society

1 Address for correspondence: Radiation Effects Research Foundation, 1-8-6 Nakagawa, Nagasaki 850-0013, Japan; e-mail: sera@rerf.
or.jp.

46

CHRONIC KIDNEY DISEASE IN ATOMIC BOMB SURVIVORS47

Out of the 1,040 potential participants, we analyzed the relationshipbetween CKD and radiation dose for 746 participants whose A-bombradiation dose was estimated.
Clinical Examination and Laboratory Methods

FIG. 1. Flow of Adult Health Study (AHS) subjects into analysis.
Subjects who did not have their waist circumference or pulse wave
velocity (PWV) measured were excluded. Subjects who were nottaking medication for hyperlipidemia, but were post prandially
hypertriglyceridemic, were excluded because it was impossible todetermine whether they had hyperlipidemia (HLP).

Therefore, we examined here whether CKD is associatedwith MetS with its individual components, and withradiation dose in A-bomb survivors.
METHODS
Participants
The Adult Health Study (AHS) was established in 1958 by the
Atomic Bomb Casualty Commission, now the Radiation EffectResearch Foundation (RERF), to study the late effects of radiationin Hiroshima and Nagasaki A-bomb survivors. The AHS conductsbiennial health examinations whose clinical information complements
death and tumor registry data. A detailed description of the program
has been published elsewhere (23).
From 2004 through 2007, 1,366 people (521 men and 845 women)in the Nagasaki AHS cohort underwent clinical examinations, andhematological, biochemical, electrocardiogram and pulse wave
velocity (PWV) measurements. They were excluded from the study
if they had not undergone waist circumferences or PWV measurements or if they were not taking medication for hyperlipidemia but had
postprandial hypertriglyceridemia (because we could not determine
whether they had hyperlipidemia), leaving 1,040 participants (Fig. 1),
all providing written informed consent. There were two subjects withsevere renal dysfunction without undergoing extracorporeal dialysis
among 83 AHS subjects who did not undertake PWV measurement.
Fasting blood (more than 10 h after last meal) was drawn in 585
participants among 1,040 study participants.

Participants visited RERF’s Nagasaki Laboratory for a clinicalexamination every 2 years. A trained nurse recorded information on
current and past disease and medications. We used both current
smoking/alcohol information on the health examination andquestionnaires from mail surveys taken before each visit anddivided participants into three categories: never, past and current
smokers/drinkers. Three category variables were used to complete
the analysis.
Standing height (m) and body weight (kg) were measured without
socks and outer clothing. Body mass index (BMI) was calculated asbody weight divided by the square of the standing height (kg/m2).
Sitting blood pressure (mmHg) was measured on the left arm after anadequate sedentary period using the first Korotkoff phase for systolicblood pressure and the fourth or fifth for diastolic blood pressure.
Waist circumference was measured at navel level with the participant
standing.
Blood samples were drawn for biochemical measurements, andserum blood urea nitrogen (mg/dl), creatinine (mg/dl), uric acid (mg/dl), total cholesterol (mg/dl), high-density lipoprotein cholesterol(HDL-cholesterol, mg/dl), low-density lipoprotein cholesterol (LDLcholesterol, mg/dl), triglycerides (mg/dl), and blood glucose (mg/dl)
were measured by an automated procedure (Hitachi 7170S, HitachiLtd, Tokyo) with quality control monitored in accordance with theCollege of American Pathologists (Northfield, IL). We measured
adiponectin by ELISA (Otsuka, Osaka, Japan), hemoglobin A1c(HbA1c value, Japan Diabetes Society) by HPLC (HA-8150, Arcray,Tokyo), insulin by a chemiluminescent ELISA (Lumipulse f, Fujirebio
Diagnostics, Tokyo), high sensitivity C-reactive protein (hs-CRP) by achemiluminescent ELISA (Nissui, Tokyo), and hemoglobin (Hb) byan automated procedure (Sysmex XE-2100, Sysmex, Kobe, Japan).
We expressed HbA1c as the U.S. National Glycohemoglobin
Standarization Program HbA1c value by adding 0.4% to the measured
Japan Diabetes Society value (24).
Insulin resistance was evaluated on the basis of a homeostasis
model assessment of insulin resistance (HOMA-IR), which is usedwidely in epidemiological research, with the following formula:
HOMA-IR ¼ fasting insulin (lU/ml) 3 fasting blood glucose (mg/dl)/
405. Analyses for blood glucose, triglyceride, insulin and HOMA-IR
were conducted in 585 participants, whose fasting blood (more than
10 h after last meal) were drawn, because the effect that blood glucose,
triglyceride and insulin have are strongly affected by eating, andobviously increase in individuals after a meal, in comparison with thetime when they are in a fasting state. Brachial-ankle pulse wave
velocity (ba-PWV) was measured to assess arterial stiffness using BP203RPEII (Omron, Kyoto, Japan).
Radiation DoseAs the renal dose for individual subjects is not available, for our
statistical analysis we used a shielded total kerma dose based on
Dosimetry System 2002 (DS02) (25) with adjustment of the c andneutron doses for 35% dose error, truncating them at 4 Gy, to reduceradiation effect estimation bias (26). We thought shielded total kerma
dose would be appropriate for analysis of CKD, which seems to be
more of a secondary condition caused by the systemic vascularpathology that is attributable to DM and hypertension, as evidenced by
the breakdown of patients who started undergoing dialysis for endstage renal disease in Japan. As this tendency is seemingly more
pronounced in CKD, we think radiation effects on the overall vascularsystem play a more important role in CKD, and thus used a shielded
total kerma dose.

48

SERA ET AL.

TABLE 1
Clinical and Biochemical Profile of the Study Subjects by Renal Dysfunction
Renal dysfunction level (eGFR)
FactorNormal (90)n ¼ 121

Mild (60–89)
n ¼ 686

Moderate (30–59)
n ¼ 217

Severe (,29)
n ¼ 16

P for
trend

Pa fortrend

eGFR (ml/min/1.73 m2)
Age (year)
Male n (%)
Past smokers (%)
Current smokers (%)
Past drinkers (%)
Current drinkers (%)
Weight (kg)
Waist (cm)BMI (kg/m2)
SBP (mm Hg)
BUN (mg/dL)
Cre (mg/dL)
Uric acid (mg/dL)
T-cho (mg/dL)
HDL-cho (mg/dL)
LDL-cho (mg/dL)
TG (mg/dL)
HbA1c (%)
Insulin (lU/mL)
Glucose (mg/dL)
HOMA-IR
Hemoglobin (g/dL)
Adiponectin (lg/mL)
HS-CRP (mg/dL)
ba-PWV (cm/sec)

99.4 6 9.4
67.5 6 6.0
35 (28.9)25 (20.7)
23 (19.0)
35 (28.9)
46 (38.0)
52.0 6 8.8
81.7 6 8.7
22.0 6 3.2
132.9 6 20.0
13.0 6 2.9
0.51 6 0.07
4.43 6 1.02
205.3 6 34.0
59.4 6 15.2
113.5 6 29.6
122.3 6 100.9
6.08 6 1.11
6.98 6 4.03
101.5 6 17.6
1.83 6 1.39
13.5 6 1.2
9.51 6 5.03
0.24 6 0.74
1781.3 6 419.0

73.6 6 8.8
72.5 6 6.7
263 (38.3)
179 (26.1)
72 (10.5)226 (32.9)
237 (34.5)
54.8 6 10.5*
84.8 6 9.8*
23.0 6 3.3*
130.6 6 17.1
14.9 6 3.4*
0.68 6 0.11*
5.02 6 1.21*
204.6 6 31.7
57.1 6 14.4
115.4 6 27.5
111.9 6 58.9
5.89 6 0.73*
7.40 6 4.65
100.2 6 14.1
1.86 6 1.34
13.4 6 1.4
10.52 6 5.64
0.16 6 0.612
1831.6 6 404.9*

49.7 6 7.1
76.1 6 6.6102 (47.0)
79 (36.4)
23 (10.0)
92 (42.4)
65 (30.0)
56.0 6 10.2*
85.5 6 9.5*
23.0 6 3.3*
129.2 6 18.7*
19.1 6 5.1*
0.99 6 0.19*
5.91 6 1.31*
202.3 6 32.2
52.8 6 12.5*
116.8 6 26.5*
116.9 6 53.0
6.016 0.80
7.91 64.893*
98.1 6 12.5
1.96 6 1.29
13.1 6 1.6
10.31 6 5.37
0.19 6 0.43
1919.3 6 434.5*

23.8 6 4.7
77.1 6 6.2
5 (31.3)
4 (25.0)
2 (12.5)
3 (18.8)
3 (18.8)
55.6 6 9.9*
89.3 6 10.0*
24.7 6 3.3*
137.3 6 16.8*
32.9 6 9.2*
1.92 6 0.66*
6.65 6 3.29*
224.4 6 57.9*
56.6 6 19.0
113.6 6 43.3
162.3 6 159.0
6.57 6 1.17*
18.33 6 28.13*
116.7 6 44.0*
7.78 6 14.9*
11.4 6 1.5*
13.77 6 5.56*
0.16 6 0.17
2017.0 6 45.8*

0.010,0.001
0.002-

0.6073-0.4648-0.002,0.0010.004
0.159,0.001,0.001,0.001
0.765,0.001
0.351
0.247
0.134
0.006
0.301
0.003
,0.001
0.157
0.029
0.006

,0.001,0.001,0.0010.088,0.001,0.001,0.001
0.071
0.002
0.048
0.205
0.124
,0.0010.147,0.001,0.001
0.797
0.331,0.001

Notes. Values are mean 6 SD unless otherwise indicated. P for trend test was performed without adjustment. Pa for trend test adjusted for age,gender, and smoking and drinking habits. TG, Insulin, Glucose and HOMA-IR are values of 585 subjects whose fasting blood are collected.
eGFR, estimated glomerular filtration rate; BMI, body mass index; SBP, systolic blood pressure; BUN, blood urea nitrogen; Cre, creatinine; Tcho, total cholesterol; HDL-cho, high-density lipoprotein cholesterol; LDL-cho, low-density lipoprotein cholesterol; TG, triglyceride; HbA1c,
hemoglobin A1c; HOMA-IR, homeostasis model assessment of insulin resistance; HS-CRP, highly sensitive C-reactive protein; ba-PWV,
brachial-ankle pulse wave velocity.
*P , 0.05 vs. normal group adjusted for age, gender, and smoking and drinking habits.
Diagnostic Criteria
1. CKD and renal dysfunction level. We calculated estimatedglomerular filtration rate (eGFR) using an equation adjusted for theJapanese: eGFR (ml/min/1.73 m2) ¼ 194 3 age–0.287 3 creatinine–1.094(for women, the eGFR was multiplied by 0.739) (27). Subjects weregrouped by renal function according to their eGFR as follows: 90
ml/min/1.73 m2 as normal, 60–89 ml/min/1.73 m2 as mildly
dysfunctional, 30–59 ml/min/1.73 m2 as moderately dysfunctional,
and ,30 ml/min/1.73 m2 as severely dysfunctional.
Also, we diagnosed subjects in the moderate and severe renal
dysfunction groups as having CKD according to the CKD guideline of
the U.S. National Kidney Foundation (18). The group with severe
renal dysfunction had a more serious form of CKD.
2. Hypertension. Subjects were diagnosed as hypertensive if they
had a systolic blood pressure 140 mmHg, a diastolic blood pressure
90 mmHg, or were taking anti-hypertensive medication.
3. Diabetes mellitus. Subjects were diagnosed as having DM ifthey had a fasting blood glucose 126 mg/dl, a postprandial glucose
200 mg/dl, HbA1c 6.5%, a blood glucose 200 mg/dl at 2 h in a
75-g oral glucose tolerance test, if they were under treatment for DM,or had a history of DM.
4. Hyperlipidemia. We diagnosed subjects as having hyperlipidemia if they had a total cholesterol level 220 mg/dl, an LDLcholesterol level 140 mg/dl, a fasting triglyceride level 150 mg/dl,
or if they were taking a lipid-lowering medication. A total of 106

subjects were not taking medication for hyperlipidemia, but had
postprandial hypertriglyceridemia. These subjects were excluded inthis study because we could not determine whether or not they had
hyperlipidemia (Fig. 1).
5. MetS. We used the modified criteria on the MetS guidelines inJapan (28) and diagnosed MetS when waist circumference was 85
cm in men or 90 cm in women and subjects showed 2 of thefollowing 3 features: (1) serum triglyceride 150 mg/dl; HDLcholesterol 140 mg/dl, or the subject was being treated for
hyperlipidemia; (2) systolic blood pressure 130 mmHg,d iastolicblood pressure 85 mmHg, or subject was being treated for
hypertension; (3) fasting blood glucose 100 mg/dl or subject was
being treated for DM.
The definition of hypertension, DM and hyperlipidemia wererestricted to current medication use but not to past medication use.
Statistical Analysis
All statistical analyses were performed with the Statistical Analysis
System package for personal computers (SAS, Cary, NC). Baseline
covariate values were compared between the normal subjects and thesubjects with renal dysfunction using general linear model (GLM)
analysis adjusted for age, gender, and smoking and drinking habits.
Several factors (SBP, HDL cholesterol, triglyceride, HbA1c, HSCRP), which tend to be right-skewed, log transformation for statistical
testing was used (Table 1). Ordinal logistic regression analysis was

49

CHRONIC KIDNEY DISEASE IN ATOMIC BOMB SURVIVORSTABLE 2
Prevalence and Odds Ratio (95% Confidence Interval) of Cardiovascular Disease (CVD) Risk Factors by Renal
Dysfunction
Renal dysfunction
Number (%)
Odds ratio (95% confidence interval )CVD risk factor
Hypertension
Diabetes mellitus
Hyperlipidemia
Metabolic syndrome

P for
trend

Normal (n ¼ 121)

Mild (n ¼ 686)

Moderate (n ¼ 217)

Severe (n ¼ 16)

73 (60.3)
1
26 (21.5)
157 (47.1)
1
16 (13.2)
1419 (61.1)
0.96 (0.63–1.46)
101 (14.7)
0.64 (0.39–1.06)
379 (55.2)
1.75 (1.16–2.66)*
140 (20.4)
1.85 (1.04–3.29)*

153 (70.5)
1.39 (0.83–2.32)
48 (22.1)
1.08 (0.60–1.94)
128 (59.0)
2.34 (1.42–3.88)*
60 (27.6)
2.76 (1.44–5.26)*

15 (93.8)
8.20 (1.03–66.67)*
7 (43.8)
3.10 (1.02–9.43)*
13 (81.2)
6.37 (1.65–24.39)*
11 (68.8)
17.24 (5.13–58.82)*

0.041
0.100
,0.001,0.001

Note. P for trend was analyzed with ordinal logistic regression model adjusted for age, gender, and smoking and drinking habits.
*P , 0.05 vs. normal group (n ¼ 121) adjusted for age, gender, and smoking and drinking habits.
used with adjustment for age, gender, and smoking and drinking
habits to evaluate the association between renal dysfunction and CVD
risk factors (Table 2) We used logistic regression analysis was usedwith adjustment for age, gender, and smoking and drinking habits toevaluate the association between CKD and CVD risk factors (Table 3).
We used GLM analysis with adjustment to evaluate the association
between renal dysfunction and radiation dose (Table 4) and usedlogistic or ordinal logistic regression analysis to evaluate theassociation between renal dysfunction/CKD and radiation dose (Table5). We considered P , 0.05 as significant.

RESULTS

Table 1 shows the distribution of risk factors in the 4 renal
dysfunction groups and in the anthropometric indexes andvariables relating to renal dysfunction. Almost all the CVD
risk factors relating to blood pressure, lipid metabolism, andglucose metabolism deteriorated with renal dysfunction but
medication history was not taken into account, which could
have led to some measurement error. The Hb level was low
in the severe renal dysfunction group, while the adiponectinlevel was high. HOMA-IR was significantly high in thesevere renal dysfunction group. Additionally, ba-PWV
increased with renal dysfunction, while ba-PWV significantly decreased with renal dysfunction when age, gender,and smoking and drinking habits were incorporated into theanalysis (data not shown).
Serum adiponectin levels were low in subjects with DM(8.94 6 4.81 lg/mL) vs. those without DM (10.72 6 5.63
lg/mL) (P , 0.001), in subjects with hyperlipidemia (9.95
6 5.41 lg/mL) vs. subjects without hyperlipidemia (10.97
6 5.63 lg/mL) (P , 0.001), and in subjects with MetS
(8.37 6 5.05 lg/mL) vs. those without MetS (10.98 6 5.53
lg/mL) (P , 0.001), while they tended to increase withrenal dysfunction and were significantly elevated in subjects
with severe renal dysfunction.
Table 2 shows the prevalence and odds ratio of
hypertension, DM, hyperlipidemia, and MetS by renal
dysfunction. Prevalence of hypertension, hyperlipidemia,
and MetS increased with renal dysfunction. Odds ratios ofhypertension, DM, hyperlipidemia, and MetS are shown forthe mild, moderate, and severe renal dysfunction groups
using the normal group as a reference. Hypertension and
DM were associated with only severe renal dysfunction,
while hyperlipidemia and MetS were associated with mildto-severe renal dysfunction.
The odds ratios of hypertension, DM, hyperlipidemia and
MetS, with the combined normal and mild renal dysfunction
TABLE 4
Mean Radiation Doses for Three Levels of Renal
Dysfunction

TABLE 3
Odds Ratio (95% Confidence Interval) of Cardiovascular Disease (CVD) Risk Factors for Chronic
Kidney Disease
CVD risk factor

Odds ratio (95% CI )P

Hypertension
Diabetes mellitus
Hyperlipidemia
Metabolic syndrome

1.57 (1.12–2.20)
1.79 (1.23–2.61)
1.55 (1.12-–2.14)
1.86 (1.32–2.63)

0.009
0.002
0.008
,0.001

Note. P, compared with combined normal and mild renal
dysfunction groups (n ¼ 807) adjusted for age, gender, and smoking
and drinking habits.

Renal
dysfunctionnmGy (mean 6 SD)

PPa

Normal–mildModerate
Severe584149
13503.2 6 720.7
572.8 6 769.6
1199.3 6 1034.4

0.279,0.001

0.278,0.001

P; v.s. combined normal and mild renal dysfunction groups (n ¼584) adjusted for age, gender, and smoking and drinking habits.
Pa; v.s. combined normal and mild renal dysfunction groups
adjusted for age, gender, and smoking and drinking habits,
hypertension, diabetes mellitus, hyperlipidemia and metabolic syndrome.

50

SERA ET AL.

TABLE 5
Odds Ratio (95% Confidence Interval) of Radiation Dose for Chronic Kidney Disease (CKD)
Renal dysfunctionn

Not adjusted OR/Gy (95%CI)

P

Adjusteda OR/Gy (95%CI)

Pa

Normal–mildModerate
SevereCKD (moderate þ severe)

584
149
13
162

1
1.13 (0.90–1.44)
2.25 (1.36–3.78)
1.26 (1.01–1.57)

0.295
0.002
0.040*

1
1.15 (0.89–1.48)
3.19 (1.63–6.25)
1.29 (1.01–1.63)

0.293,0.0010.038*

Notes. Reference was the combined normal and mild renal dysfunction group. CKD; chronic kidney disease.
aAdjusted for age, gender, and smoking and drinking habits, hypertension, diabetes mellitus, hyperlipidemia and metabolic syndrome.
*Analyzed with ordinal logistic regression model.

groups used as the reference, show that all 4 conditions
were significantly associated with CKD (Table 3).
Compared with combined normal and mild renal
dysfunction groups, the severe renal dysfunction group
had received a significantly higher dose of A-bombradiation (Table 4), and radiation dose was significantly
associated with both CKD and severe renal dysfunction
with or without adjustment for age, gender, and smoking
and drinking habits, hypertension, DM, hyperlipidemia and
MetS (Table 5).
DISCUSSION

In this study, we found radiation dose to be significantly
associated with CKD (moderate/severe renal dysfunction) andwith severe renal dysfunction in A-bomb survivors, with orwithout adjustment for age, gender, and smoking and drinking
habits, hypertension, DM, hyperlipidemia and MetS. Ourfindings suggest that CKD is involved in the mechanism(s)linking radiation exposure with CVD risk factors.
When we assessed the association of hypertension, DM,
hyperlipidemia and MetS with renal dysfunction, odds ratios
representing these associations increased along with thedeterioration of renal functions from mild to severe dysfunctions, although significance was not observed for DM.
However, when we compared the clinical setting of CKD,
including moderate and severe, to the reference group
including normal and mild, hypertension, DM, hyperlipidemia
and MetS were significantly associated with CKD, which was
the same as that reported for non A-bomb survivors (21,).
PWV, a marker of aortic wall stiffness, predicts
cardiovascular events (29), and vascular function andarterial compliance are impaired in patients with CKD(30). Thus, PWV is associated inversely with GFR inpatients with non-dialysis-dependent renal insufficiency(31, 32). Also, in hypertensive patients, GFR .60 ml/
min/1.73 m2 correlates inversely with aortic PWV (33). In
the present study, ba-PWV was inversely associated witheGFR and it increased with renal dysfunction when no
adjustment was made. Our finding that both PWV andeGFR were closely related to age, and that the association
between ba-PWV and renal dysfunction disappeared when
age was incorporated into the analysis (data not shown) wasin agreement with a previous study (34).

Serum adiponectin levels reportedly decrease in patientswith hypertension (35), DM (36), dyslipidemia (37, 38), or
MetS (39), which is in agreement with the results of thepresent study. On the other hand, we also found that elevatedserum adiponectin levels are seen in patients with moderate
renal dysfunction (17, 40). Further studies are necessary to
explain the association we found between elevated serum
adiponectin level and severe renal dysfunction.
The prevalence of systemic CVD risk factors such as
hypertension, DM and hyperlipidemia, as well as the levelof inflammatory markers, increases with radiation dose in
A-bomb survivors (7, 11, 14, 15). The clustering ofsystemic CVD risk factors suggests the possibility that
MetS plays a role. In line with this, we previously reported
that fatty liver, a surrogate marker of MetS, clusters with
CVD risk factors (16), predicts IHD (17), and is associatedwith A-bomb radiation dose (13). Since aortic calcification
and retinal arteriosclerosis also increase with radiation dose
(9), it is reasonable to think that a general rather than aregional atherosclerotic process is involved in the development of CVD in A-bomb survivors. Thus, we think that themechanism(s) that induces MetS is stimulated, leading to
the clustered systemic CVD risk factors, general atherosclerosis, and CVD, although that mechanism(s) has yet to
be clarified.
High-dose radiation therapy induces renal injury, leading
to renovascular hypertension (41), and high levels of Abomb radiation induce ureter and renal calculi in men (12),but the effect of low-to-moderate dose radiation on thekidney has not been elucidated. In the present study, lowdose radiation was significantly associated with CKD andsevere renal dysfunction independently of hypertension,DM, hyperlipidemia and MetS, suggesting that A-bombradiation affects the kidney directly. Prospective studies areneeded to clarify how the association between low-doseradiation and CVD may be mediated by CKD.
ACKNOWLEDGMENTS
The Radiation Effects Research Foundation (RERF), Hiroshima andNagasaki, Japan, is a private, nonprofit foundation funded by the Japanese
Ministry of Health, Labour and Welfare (MHLW), and the U.S.
Department of Energy (DOE), the latter in part through DOE Award
DE-HS0000031 to the National Academy of Sciences. The present study
was supported by grant number 15590570 from the Japanese Ministry of
Education, Culture, Sports, Science and Technology. This publication was

CHRONIC KIDNEY DISEASE IN ATOMIC BOMB SURVIVORS

based on RERF Research Protocol RP 2–75. The views of the authors do
not necessarily reflect those of the two governments.
Received: November 11, 2011; accepted: July 29, 2012; published online:
November 13, 2012

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