RADIATION RESEARCH 177, 220–228 (2012)0033-7587/12 $15.00
Ó2012 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RR2746.1

Radiation Dose Associated with Renal Failure Mortality: A Potential
Pathway to Partially Explain Increased Cardiovascular Disease Mortality
Observed after Whole-Body Irradiation
Michael Jacob Adams,a,1 Eric J. Grant,b Kazunori Kodama,c Yukiko Shimizu,b Fumiyoshi Kasagi,e Akihiko Suyama,bRitsu Sakatab and Masazumi AkahoshidaDepartment of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; Departmentof b Epidemiology, c Chief Scientist, and d Department of Clinical Studies, Radiation Effects Research Foundation (RERF); and e Director, Institute ofRadiation Epidemiology, Radiation Effects Association

INTRODUCTION
Adams, M. J., Grant, E. J., Kodama, K., Shimizu, Y.,
Kasagi, F., Suyama, A., Sakata, R. and Akahoshi, M.
Radiation Dose Associated with Renal Failure Mortality: A
Potential Pathway to Partially Explain Increased Cardiovascular Disease Mortality Observed after Whole-Body Irradiation. Radiat. Res. 177, 220–228 (2012).

Numerous studies of various populations exposed towhole-body and chest irradiation have demonstrated thatthey are at increased risk of fatal cardiovascular disease(CVD) primarily due to increased myocardial infarctionmortality (1). These populations include patients treatedwith radiotherapy for Hodgkin’s disease (2–4), breast
cancer (5–8), and peptic ulcer disease (9), as well as some
but not all occupational cohorts (10–12), and atomic bomb
survivors (13–16). After 40 years of follow-up, evidence
began to emerge within the Adult Health Study (AHS), thelongitudinal clinical follow-up of atomic bomb survivors,that radiation dose was associated with increased incidenceof myocardial infarction (not just CVD mortality) among
those less than 40 years of age at the time of the bombing(17–19).
Recent work by the Radiation Effects Research Foundation has also demonstrated that radiation dose is associatedwith increased hypertensive heart disease mortality2 andwith increased systolic and diastolic blood pressure (20).
Studies of total-body irradiated (TBI) bone marrowtransplant survivors demonstrate that a linear relationshipexists between biologically effective radiation dose and riskof renal (kidney) failure (dysfunction) (21). These findings
suggest that the risk of cardiovascular disease in those
exposed to whole-body radiation may be mediated in partby damage to the kidney. The kidney is a key organ
involved with blood pressure regulation, and hypertension
is a well-known risk factor for myocardial infarction.
Chronic renal failure, regardless of the presence ofhypertension, is thought to add the same risk of future
myocardial infarction as having had a prior myocardial
infarction (22).
Thus we sought to evaluate whether the increased risk ofcardiovascular disease in those exposed to whole-bodyWhole-body and thoracic ionizing radiation exposure areassociated with increased cardiovascular disease (CVD) risk.
In atomic bomb survivors, radiation dose is also associatedwith increased hypertension incidence, suggesting thatradiation dose may be associated with chronic renal failure(CRF), thus explaining part of the mechanism for increased
CVD. Multivariate Poisson regression was used to evaluate
the association of radiation dose with various definitions ofchronic kidney disease (CKD) mortality in the Life Span
Study (LSS) of atomic bomb survivors. A secondary analysis
was performed using a subsample for whom self-reported
information on hypertension and diabetes, the two biggest
risk factors for CRF, had been collected. We found asignificant association between radiation dose and only ourbroadest definition of CRF among the full cohort. A
quadratic dose excess relative risk model [ERR/Gy2 ¼ 0.091(95% CI: 0.05, 0.198)] fit minimally better than a linear
model. Within the subsample, association was also observed
only with the broadest CRF definition [ERR/Gy2 ¼ 0.15 (95%
CI: 0.02, 0.32)]. Adjustment for hypertension and diabetes
improved model fit but did not substantially change the ERR/
Gy2 estimate, which was 0.17 (95% CI: 0.04, 0.35). We founda significant quadratic dose relationship between radiationdose and possible chronic renal disease mortality that issimilar in shape to that observed between radiation andincidence of hypertension in this population. Our results
suggest that renal dysfunction could be part of themechanism causing increased CVD risk after whole-body
irradiation, a hypothesis that deserves further study. Ó 2012 by
Radiation Research Society

1 Address for correspondence: Department of Community andPreventive Medicine, University of Rochester School of Medicine
and Dentistry, 265 Crittenden Blvd. CU 420644; Rochester, NY
14642-0644; e-mail: Jacob_Adams@URMC.Rochester.edu.

2 Y. Shimizu, K. Kodama and N. Nishi, Circulatory diseasemortality in atomic bomb survivors 1950–2003. Presented at theThirteenth International Congress of Radiation Research, San
Francisco, 2007.

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RADIATION DOSE ASSOCIATED WITH RENAL FAILURE MORTALITY

221

FIG. 1. Relationship between radiation and heart disease in atomic bomb survivors (solid lines) and potential biological mechanisms explaining
the relationships (dashed lines). Also shown is the relationship that we hoped to demonstrate in this study (dash/dotted lines).

radiation might be mediated at least in part through chronic
renal dysfunction. We indirectly explored this main
hypothesis by evaluating the association between radiation
exposure from the atomic bomb and kidney diseasemortality, in particular chronic renal failure mortality.
Figure 1 illustrates the relationship between radiation andheart disease as demonstrated in the atomic bomb survivors(solid lines) and potential biological mechanisms explaining
the relationships (dashed lines). This figure also illustrates
the relationship (dash/dotted arrows) that we hope todemonstrate in this research study. If radiation exposure
increases the incidence of chronic renal failure, this should
lead to higher chronic renal failure mortality and increased
mortality from both hypertensive heart disease andmyocardial infarction, as previously observed in atomic
bomb survivors. However, the relationship is not as simple
as a one-way relationship from kidney disease to myocardial infarction risk, because there are many overlapping risk
factors for myocardial infarction and chronic kidney disease(CKD). Thus our secondary aim was to evaluate whether
overlapping risk factors potentially explained or confounded the relationship between radiation and kidney diseasemortality.
The most significant overlapping modifiable risk factors
for myocardial infarction and kidney disease are hypertension and diabetes mellitus (23). In fact, Yamada et al.
demonstrated a significant quadratic dose–response rela-tionship between radiation dose and hypertension as well as
myocardial infarction incidence in atomic bomb survivors
clinically followed between 1958 and 1998 (19). Althoughother overlapping risk factors exist such as dyslipidemia,
they are much less important than hypertension and diabetes
in terms of kidney disease risk (22, 23). Therefore, weconcentrated on adjusting our analysis on the two mostimportant modifiable risk factors for kidney disease as well
as age.
METHODS
Study Population
The Life Span Study (LSS) cohort consists of 120,321 registeredresidents of Nagasaki and Hiroshima at the time of the atomic
bombings and who were still residents of these two cities when thecohort was established between 1950 and 1953 (24). It contains a vast
majority of the survivors who were within 2.5 km of the hypocentersat the time of the bombings, a random sample of age- and sex-matched
controls who were 2.5 to 10 km from the hypocenter who received
small to negligible radiation doses, and 26,580 residents who were outof the city at the time of bombing (24). Like other recent reports on
non-cancer mortality, our analyses used only the cohort members withestimated radiation doses and who were within 10 km of the
hypocenter of the bombs (16).
Subjects in the LSS were never formally recruited for participation,and therefore a formal informed consent was not initially acquired.
Mail survey subjects agree to their inclusion by returning thequestionnaire. Any subject can withdraw from the overall study via

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ADAMS ET AL.

TABLE 1
Definition of Renal Failure Codes By Increasing Sensitivity/Decreasing Specificity
DiseaseDefinite chronic renal failure
Chronic renal failure þ hypertensive
kidney disease
Probable chronic renal failurea
Possible chronic renal failureb

ICD-10 (1998–2003)

ICD-9 (1979–1997)

N18
N18, I12, I13585
585, 403, 404

N18, I12, I13, N03, N04, N11
N18, I12, I13, N03, N04, N11, N05, N12, N19585, 403, 404, 581, 582
585, 403, 404, 581, 82, 583, 586

Notes. Corresponding 4-digit codes for subcategories used when appropriate. Bolded codes represent the conditions that are added on top of thestricter conditions from the stricter categories above.
a
Also includes other chronic kidney disease conditions.
b
Also includes kidney disease and renal failure of unspecified length.
written request. The study design, analysis and procedures performed
for this paper were approved by the Radiation Research Effects
Foundation Independent Review Board, the Human Investigation
Committee.
Individual doses to multiple organs have been carefully estimatedusing the improved DS02 dosimetry system, primarily on the basis ofpeople’s location and shielding at the time of the bombings (25). We
estimated risks by using the weighted DS02 dose estimate of exposure
to the urinary system. Weighted doses sum the c-ray dose plus 10
times the smaller neutron dose to allow for the greater biologicaleffectiveness of neutrons.
In summary, for atomic bomb survivors to be eligible for inclusionin this analysis, they had to be in the LSS cohort, had to have a urinary
system DS02 dose estimate, and had to be within one of the cities at
the time of the bombing.
Data Sources and Variables
Data on demographics, dosimetry, mortality status and causes ofdeath were obtained from the LSS database. Follow-up of vital status
for this analysis began October 1, 1950 and ended December 31,
2003. Mortality data, including causes of death, were collected fromthe nationwide obligatory family registration system in Japan (koseki),a system that is virtually 100% complete. Underlying and contributing
causes of death were classified according to the ICD-7 (International
Classification of Diseases, 7th revision) through ICD-10 as appropriate for year of death.
The strongest correlation between heart disease and kidney disease
is between coronary heart disease and chronic renal failure. Although
not well defined today, we choose to call our outcome of interest
chronic renal failure (CRF), because we believe the association
between disease processes in the kidney and CVD is due primarily toeffects on the kidney’s filtering function and to distinguish ouroutcome from the strict definition of chronic kidney disease (CKD) as
defined in 2002. In that year, U.S. national guidelines defined CKD as
abnormal kidney/renal function for 3 months or greater below a certain
threshold of normal that results from a chronic disease process (23).
The condition then called chronic renal failure or end stage kidneydisease was defined as stage 5 CKD in these guidelines, but it should
be reemphasized that our use of the term ‘‘CRF’’ refers to the whole
spectrum of non-acute renal dysfunction. In addition, for most of theperiod of follow-up, there was no standard test to screen for renal
dysfunction, let alone a standard cut-off level to define renal failure.
Therefore, there may be significant misclassification of chronic renal
failure with other types of kidney disease. As a result we defined CRF
using four different definitions of increasing sensitivity and decreasing
specificity. Table 1 illustrates how we defined these outcomes by ICD
revision period: chronic renal failure, chronic renal failure þ
hypertensive kidney disease, probable chronic renal failure, andpossible chronic renal failure, with this last category also including
kidney pathologies of indeterminate length. Additionally, cardiovascular disease is the leading cause of death in individuals with chronic

renal failure (26), which is often asymptomatic until its end stages.
Thus cardiovascular disease may often have been coded mistakenly as
the underlying cause of death. Therefore, we performed secondary
analyses to evaluate all causes of death listed on the death certificate aswell as for each definition of our outcome.
Covariate Data
Hypertension and diabetes status information was obtained fromquestionnaires sent to different but overlapping subsets of LSS
subjects in 1965, 1978 and 1991 (27, 28). For the first survey, acategorical yes/no variable was created from the text answer for eachof these conditions. For the last two surveys, the presence of acondition was queried using a checkbox; we considered a blankcheckbox as a negative answer. Once positive for a risk factor, anindividual was coded as having the risk factor until death or censoring,unless the subject reported not having the risk factor on two
subsequent surveys after the first positive response in which casethey were coded as never having the risk factor.
Statistical Analysis
We constructed detailed summary tables of number of deaths andperson-years stratified by dose, city, sex and 5-year intervals of age at
exposure, attained age and follow-up time. We divided subjects into
urinary system weighted dose categories of 0–, 0.005–, 0.01–, 0.02–,
0.04–, 0.06–, 0.08–, 0.10–, 0.15–, 0.20–, 0.25–, 0.30–, 0.50–, 0.75–,
1.00–, 1.50–, 2.00–, 2.50–, 3.00– and 3.50 Gy. We created separate
tables for each of the four definitions of our outcome. We also createda second set of four tables to evaluate whether diabetes andhypertension affected the relationship between radiation dose andkidney disease mortality, because data on these factors were available
only in the subset of the entire LSS cohort that returned at least one of
the above questionnaires.
We used Poisson regression methods for grouped survival data to
describe the dependence of risk on radiation dose and to evaluate thevariation of dose–response effects with respect to city, sex, age at
exposure, time since exposure and attained age (29), essentially thesame methods used previously to examine mortality from cancer inthis cohort (24). Time at risk was calculated for each subject starting at
the initiation of the LSS and ending at loss of follow-up or death. We
used SAS version 9.1 and the Epicure software package (30) (Datab
and Amfit modules) to create the summary tables and performstatistical analysis. We based significance tests on a two-sided alpha of,0.05 and calculated 95% confidence intervals for excess relative risk
estimates, when P values were ,0.10.
The primary models evaluated are excess relative risk (ERR)
models of the formk0 ðc; s; a; age atbÞ½1 þ ERRðd; s; age atb; age;
where k0(*) is a log-linear parametric model of the baseline renal

RADIATION DOSE ASSOCIATED WITH RENAL FAILURE MORTALITYTABLE 1
Extended
ICD-8 (1969–1978)

ICD-7 (1950–1968)

792
792, 403, 404

792
792, 446, 442

792, 403, 404, 581, 582,
792, 403, 404, 581, 582, 583

792, 446, 442, 592,
592, 792, 446, 442, 592, 591, 593

disease mortality rate, in the absence of radiation exposure, depending
upon city (c), sex (s), attained age (age) and age at time of bombing(age_atb). The excess rate depends upon dose, allowing for the effectof city (c), sex (s), attained age (age) and age at time of bombing(age_atb).
We compared the relative fitness of several different models of the
ERR term. These included a linear model of dose [q(d) ¼ bd] with andwithout thresholds, a linear-quadratic model [q(d) ¼ bd þ cd2], and apurely quadratic model [q(d) ¼ cd2 ] using likelihood ratio tests fornested models and the Akaike information criterion for non-nested
models (31).
A similar analytic approach was taken to evaluate whether radiationdose was independently associated with cause-specific kidney diseasemortality after also adjusting for hypertension and diabetes in the LSS.
Terms were included to evaluate both the direct association of each on
kidney disease mortality and whether each modified the association ofradiation dose on kidney disease mortality. If either factor appeared tobe significant at P , 0.10, we performed stratified analysis based onthat factor. This may be particularly important for hypertension,
because it is both a cause and consequence of chronic renal failure.
Thus, if dose was only significantly associated with kidney diseasemortality in those with hypertension, this would potentially suggestthat hypertension is somewhere in the pathway between radiation
exposure and kidney disease mortality. If stratified analyses were notsignificantly different by strata, then only multivariate analyses werereported. Finally, the demographic information of the subsample of the
LSS included in this analysis was also compared to those not included
to evaluate whether the subsample was representative of the cohort asa whole.
0

RESULTSA total of 86,609 survivors with a total of 3,296,595
person-years of follow-up were included in the analysis of
our first aim, the evaluation of the association between theestimated atomic bomb radiation dose and CRF mortality.
Of the survivors, 41.2% were male (Table 2); 67.5% werefrom Hiroshima. The median urinary weighted dose was
7.81 mGy (range: 0–3860 mGy), while the mean was
117.56 mGy (SD 315.5 mGy). As Table 3 illustrates, 214
deaths had an underlying cause of death of chronic renal
failure for a rate of 6.5 per 100,000 person-years, and 908
deaths had CRF listed anywhere on the death certificate fora rate of 27.5 per 100,000 person-years. After adjusting forcity, sex, attained age and age at time of bombing, theexcess relative risk per Gy (ERR/Gy) estimate for CRF as
the underlying cause was 0.38 (P ¼ 0.33) and as any causeof death was 0.26 (P ¼ 0.19), so neither was statisticallysignificant. Neither the quadratic nor the linear-quadratic
dose models fit the data better than the linear models.

223

TABLE 2
Characteristics of 86,609 LSS Survivors Analyzed in Aim 1:
Overall CRF Mortality
Subjects (%)(N ¼ 86,609)

Person-yearsa (%)(PY ¼ 3,296,595)

GenderMale
35,687 (41.2)
1,281,734 (38.9)
Female50,922 (58.8)
2,014,861 (61.1)
City
Hiroshima
58493 (67.5)
2,197,930 (66.7)
Nagasaki
28116 (32.5)
1,098,665 (33.3)
Age at time of bombing Median: 27.37 years Range: 0–91.5 years
Urinary dose (mGy)Median: 7.81
Range: 0–3860
aFollow-up from 01/01/1950 until 12/31/2003.

Table 3 also illustrates similar data for the three othersecondary definitions of our outcome. Only the broadest
category, possible CRF listed as an underlying or acontributory cause of death (number of events ¼ 2436),
approached significance in the adjusted model, with an
ERR/Gy of 0.135 (95% CI: 0.008–0.30). The quadratic
dose multivariate model fit the data as well [Akaike
information criterion (AIC) difference ¼ 0.891] with ERR/
Gy2 term of 0.091 (95% CI: 0.05–0.198).
A total of 49,970 unique subjects (57.7% of the LSS
cohort) provided information on hypertension and diabetes
through the three self-report surveys. They make up oursample for aim 2, the evaluation of the association between
the estimated atomic bomb radiation dose and CRF
mortality including adjustment for hypertension anddiabetes. This sample provides 2,372,139 person-years offollow-up (72% of entire cohort). For each alternative
definition of our outcome, Table 4 shows the number ofdeaths, the mortality rate per 100,000 person-years, the
ERR/Gy estimates from the adjusted linear model, and the Pvalue of whether the estimate was significantly different
from zero. Models were adjusted for city*sex (a combined
variable of sex and city with four categories), age at time of
the bombing, attained age, hypertension and diabetes.
Number of deaths (and rates) ranged from 140 with anunderlying cause of CRF (5.9 per 100,000 person-years)
and 466 deaths with CRF listed anywhere on the deathcertificate (19.6 per 100,000 person-years) to 417 deaths
with an underlying cause of possible CRF (rate 17.6. per
100,000 person-years) and 1171 with possible CRF
anywhere on the death certificate (rate 49.4. per 100,000
person-years). Only the outcome of possible CRF as any
cause of death demonstrated a significant dose effect. The
adjusted linear model revealed an ERR/Gy of 0.27 (P ¼
0.033), though the quadratic dose–effect model fit the data
nonsignificantly better (AIC difference ¼ 0.896), with an
ERR/Gy2 of 0.17 (P ¼ 0.031) (Table 4, Fig. 2). The linear
model explains 34 excess deaths (2.98%) of the 1171
possible CRF deaths, while the quadratic dose model
explains only 18 excess deaths (1.55%). The addition of the224

ADAMS ET AL.

TABLE 3
Aim 1: CRF Mortality: Number of Events, Rate and Adjusted Excess Relative Risk Estimates
Underlying cause of death
Chronic renal failure
CRF or HKD
Probable CRF
Possible CRF

All listed causes of death

NumberRate (per 100K PY)

ERR/GyP value

NumberRate (per 100K PY)

ERR/GyP value

214
448
765
1105

6.5
13.5
23.2
33.5

0.13
0.22
0.10
0.09

.0.50
0.27
0.50
0.46

908
1137
1456
2436

27.5
34.5
44.2
73.9

0.075
0.126
0.096
D: 0.135
D2: .091

.0.50
0.27
0.34
(0.008–0.30)(0.005–0.198)

Notes. N ¼ 86,609 survivors (100% of cohort); PY ¼ 3,296,595 (100% of cohort). CRF: chronic renal failure; HKD: hypertensive kidneydisease. Baseline models adjust for city*sex, attained age and age_at time of bombing (latter two variables continuous), using the estimated,weighted radiation dose to urinary system from the atomic bomb. All models linear regression except where noted. D ¼ ERR/Gy estimate fromadjusted linear model; D2 ¼ ERR/Gy estimate from adjusted model of quadratic dose.

TABLE 4
Aim 2: CRF Mortality Adjusted for Hypertension and Diabetes: Number of Events, Rate and Adjusted Excess Relative
Risk Estimate
Underlying cause of death
Chronic renal failure
CRF or HKD
Probable CRF
Possible CRF

All listed causes of death

NumberRate (per 100K PY)

ERR/GyP value

NumberRate (per 100K PY)

ERR/GyP value

140
195
255
417

5.9
8.2
10.8
17.6

0.38
0.28
0.30
0.08

0.33
0.28
0.28
.0.50

466
514
590
1171

19.6
21.7
24.9
49.4

0.26
0.29
0.24
D: 0.27
D2: 0.17

0.19
0.13
0.16
0.033
0.031

Notes. N ¼ 49,970 survivors (57.7% of cohort); PYR ¼ 2,372,139 (71.96% of cohort). CRF: chronic renal failure; HKD: hypertensive kidneydisease; CKD: chronic kidney disease. Baseline models adjust for city*sex, hypertension, diabetes, attained age and age_at time of bombing (lattertwo variables continuous), using the estimated, weighted radiation dose to urinary system from the atomic bomb. All models linear regression
except where noted. D ¼ ERR/Gy estimate from adjusted linear model; D2 ¼ ERR/Gy estimate from adjusted model of quadratic dose.

FIG. 2. Excess relative risk of possible chronic renal failure by dose. Black line is the linear model; dashed line is the quadratic model. Models
adjusted for city*sex, age_atb, attained age, HTN and diabetes. City*sex is a single combined variable of city and sex with 4 categories (males in
Hiroshima is the baseline group). Age_atb ¼ age at time of bombing ¼ age at exposure

quadratic term to the linear model did not improve thestatistical fit by the AIC.
The parameter estimates and their 95% confidence
intervals for all variables in both the linear and quadratic
dose multivariate models of possible CRF as a cause ofdeath are shown in Table 5. As expected, diabetes andhypertension each nearly doubled the risk of possible CRF
mortality in both models. Male sex also nearly doubled therisk, though city had little effect. Each decade of aging
increased the risk of possible CRF death by 4.25 times.
These parameter estimates remained remarkably steady no

225

RADIATION DOSE ASSOCIATED WITH RENAL FAILURE MORTALITYTABLE 5Results Aim 2: Multivariate Model Parameters for Possible CRF All Listed Causes of Death
LinearRR
Baseline risk
City*sexa
Hiroshima*female
Nagasaki*male
Nagasaki*female
Age at time of bombing (per decade)Age (per decade)
Diabetes
Hypertension
Dose (ERR/Gy)aQuadratic

95% CI

RR

0.066 per million PY
0.54
0.89
0.43
0.73
4.25
1.91
1.96
0.27

95% CI
0.067 per million PY

0.47–0.62
0.72–1.08
0.35–0.52
0.69–0.79
3.98–4.57
1.65–2.19
1.74–2.21
0.05–0.54

0.55
0.89
0.43
0.74
4.26
1.91
1.96
0.17

0.47–0.63
0.72–1.09
0.35–0.52
0.69–0.79
3.98–4.57
1.65–2.19
1.74–2.21
0.03–0.35

Baseline group for comparison is males in Hiroshima.

matter which definition of kidney failure or disease wemodeled (data not shown).
Unfortunately, the subcohort for aim 2 is less male
(57.6% compared to 60.4%, P , 0.001), contains a higher
percentage of Hiroshima survivors (69.5% compared to
64.9%, P , 0.001), had lower median age at time ofbombing (18.4 compared to 43.9 years, P , 0.001), and had
a higher median urinary dose (8.74 mGy compared to 6.37
mGy) than those who were not included in the survey(Supplementary Table A, http://dx.doi.org/10.1667/
RR2746.1.S1). Thus this subcohort is not representativeof the LSS cohort as whole. As the earliest survey occurredin 1965, it is not surprising that those who participatedwould have been younger than the overall population of thetwo cities at the time of the bombings. We sought toevaluate the potential for selection bias in our results bycomparing our results in just those who were less than 30
years of age at the time of the bombing (Table 6a). In thesame multivariate linear model adjusting for city*sex,
attained age and age at time of bombing, the ERR/Gyestimate was 0.28 (95% CI: 0.02–0.61) in those younger
than 30 in the full LSS and 0.55 (95% CI: 0.15–1.06) inthose younger than 30 in the subcohort analyzed for aim 2.
Adjusting for hypertension and diabetes slightly increases

the ERR/Gy by about 12% to 0.62 (95% CI: 0.20–1.16).
Similarly, when using the multivariate quadratic dosemodel, the ERR/Gy estimate nearly doubles in the aim 2
subsample and increases by about 12% when adjusted for
hypertension and diabetes. Similar results are also seen
when we do not restrict the analysis by age at exposure(Table 6b).
DISCUSSION

We found evidence that radiation dose is associated withincreasing chronic renal disease mortality even thoughestimated exposure in all individuals was less than 4 Gy andthe median dose was 7.81 mGy. The strongest evidence fora radiation effect came from the subsample of the LSS
cohort who also answered survey questions. Their ERR/Gy
based on the linear model prior to adjusting for known
chronic renal disease risk factors equaled 0.237 (95% CI:
0.02, 0.49) compared to 0.135 (95% CI: 0.008, 0.30) in
the LSS as a whole. A quadratic dose model fit the data as
well, if not minimally better, in both the subsample and the
LSS as a whole and gave statistically significant ERR/Gy2
estimates of 0.15 (95% CI: 0.02, 0.32) and 0.09 (95% CI:
0.005, 0.20), respectively.

TABLE 6
Excess Relative Risk Dose Parameters for Possible CRF: All Listed Causes
Linear (dose)a: Age , 30 at time of bombing
Full LSS (n ¼ 86, 609) adjusted for city*sex, attained age, age_at time of bombing
Aim 2 sample (n ¼ 49,970) adjusted for city*sex, attained age, age at timeof bombing
Aim 2 sample (n ¼ 49,970) adjusted for hypertension and diabetes as wellb: All ages at time of bombing
Full LSS (n ¼ 86,609) adjusted for city*sex, attained age, age_at time of bombing
Aim 2 sample (n ¼ 49,970) adjusted for city*sex, attained age, age_at timeof bombing
Aim 2 sample (n ¼ 49,970) adjusted for hypertension and diabetes as wellNote. Bolded ERR/Gy estimates are significantly different than no radiation effect.

Quadratic (dose)2

ERR/Gy95% CI

ERR/Gy95% CI

0.28

0.02–0.60

0.14

0.009–0.341

0.55
0.62

0.15–1.06
0.20–1.16

0.26
0.29

0.04–0.59
0.05–0.63

0.135

0.008–0.30

0.09

0.005–0.20

0.237
0.271

0.02–0.49
0.05–0.54

0.15
0.17

0.02–0.32
0.04–0.35

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ADAMS ET AL.

A dose-associated increased risk of kidney failure
mortality has not been reported previously in the LSS
cohort. However, a significant radiation-associated increasein kidney and ureteral stones was first observed in men but
not women with the follow-up of the AHS ending in 1998
(19). Frequent stone formation may be a sign of decreased
kidney function and may also increase the risk of kidney
failure, as shown by Gillen et al. (32). Yamada et al. also
noted a significant quadratic dose relationship for hypertension and for myocardial infarction incidence in those lessthan 40 years of age at the time of the bombing (19). In fact,
Sasaki et al. first reported significant relationships between
radiation dose and rise in both systolic and diastolic bloodpressure, potentially quadratic in nature, even after
accounting for aging and smoking (20). There is aninteresting similarity between our finding of a quadratic
dose relationship between radiation and kidney disease andtheir findings. Our study results and prior results from the
RERF cited above suggest that there truly is a relationshipbetween radiation dose and kidney function and that part ofthe effect of radiation on cardiovascular health is via kidney
function. Although we attempted to validate that by looking
at the radiation dose relationship with deaths caused by bothcardiovascular and renal failure, there were far too few
events to do this (n ¼ 416).
We are aware of only a limited number of studies that
attempted to evaluate the association between radiation doseand kidney health, and none that analyzed the association
between dose and chronic renal failure mortality. A recent
review of 14 studies, including all the studies we foundindependently, evaluating bone marrow transplant (BMT)
survivors treated with total-body irradiation and renal
failure as measured by serum creatinine, proteinuria, anemia
and hypertension found a significant linear relationshipbetween biologically effective radiation doses above 16 Gy
and kidney failure (20). Unfortunately, it is difficult tocompare the BMT population to atomic bomb survivors.
First, biologically effective doses are used to measureradiation exposure in cancer patients while weighted doses
were used in the atomic bomb survivors. Cancer patients
also receive a cumulative dose that is usually at least 10
times greater than those of the atomic bomb survivors, andthe dose received is fractionated over multiple treatments. In
addition, cancer survivors are often treated with various
other therapies toxic to the kidneys, which may confoundthe association between radiation and renal failure.
Admittedly, the evidence for an association between
radiation dose and kidney disease mortality is limited to theleast specific definition of possible CRF listed anywhere on
the death certificate. This most sensitive category of
possible CRF actually includes kidney disease and renal
failure of unspecified length (but not acute conditions) as
well as a variety of chronic kidney conditions, only one ofwhich is chronic renal failure. However, the ability to detect
renal failure, especially chronic renal failure, has changed
drastically over the years this cohort has been followed. In

fact, a consensus definition of CKD and its diagnosis was
not reached until 2002 (23). Thus the use of CKD or CRF asa cause of death on the death certificate in our cohort was
likely not consistent throughout time and does notcorrespond with this current consensus definition. Nevertheless, it is unlikely that there is bias associated with
exposure level since personal physicians diagnosing thiscondition, or others filing out the death certificate, wereunlikely to have known an individual’s dose from theatomic bomb.
The finding that ERR/Gy estimates increased when we
adjusted for hypertension and diabetes was somewhat
surprising and should be interpreted in light of the large
confidence intervals around these estimates. We would haveexpected that as independent risk factors for kidney disease
they would have explained some of the absolute risk in thispopulation. In addition, prior findings from atomic bomb
survivors between radiation dose and increased risk ofhypertension, hypertensive heart disease mortality, CVD
incidence and mortality, and known associations in thegeneral public between blood pressure, kidney failure andheart disease suggest that hypertension is part of themechanism between radiation and kidney disease mortality.
For both reasons, we would have expected that adjusting for
hypertension would have decreased the size of association
between radiation and kidney disease mortality as it would
reflect only that part truly independent of blood pressure.
One limitation of our study that could possibly explain
this odd finding is that we relied on self-report. However,when we evaluated the association between hypertension
and diabetes on kidney disease mortality, they eachincreased the risk as expected. Furthermore, when wevalidated the self-reported conditions against the mostrecent clinic visits in those who participated in both theclinically followed AHS and the questionnaires, the positive
predictive value of self-reported hypertension for truly
having diastolic blood pressure and/or systolic bloodpressure in the hypertensive range was 82.5% and thenegative predictive value was 72%. Data were not available
to validate self-reported diabetes. Another limitation of ourstudy is the reliance on death certificate data that may not be
accurate, especially for contributing causes of death anddiseases that tend to be asymptomatic like kidney disease
until their end stages. And as mentioned previously, thedefinitions and diagnosis of CKD and CRF have changed
over time, although they were likely to be similar amongst
physicians within each community at a particular time. Allof these limitations would have likely affected all survivors
the same regardless of dose, which would have led to nondifferential bias and decreased our ability to find asignificant association when one was truly present rather
than increase the risk of finding an association when one
was not really present.
In conclusion, our results suggest, but do not prove, that
there is a positive association between radiation dose andkidney disease mortality at doses under 3 Gy. The

RADIATION DOSE ASSOCIATED WITH RENAL FAILURE MORTALITY

relationship is likely mediated through blood pressure, butthere also appears to be a component independent of bloodpressure. While our study cannot address this independent
component, it may be related to inflammation, which is oneof the mechanisms of atherosclerotic cardiovascular in thegeneral population (33) and has been noted to be elevated ina dose-dependent manner among atomic bomb survivors(34). As relationships between radiation dose and bloodpressure, presence of hypertension, cardiovascular diseasemortality and incidence of myocardial infarction in those,40 years old at exposure have already been reported, ourfindings further suggest that part of the risk of cardiovascular disease, particularly myocardial infarction risk, ismediated by renal dysfunction. Given the importance of
cardiovascular disease as a cause of mortality in those
exposed to whole-body radiation and therapeutic radiation
to the chest, our results suggest that future studies shouldseek to better measure kidney function over time andevaluate its association with the incidence and mortality ofcardiovascular events, especially myocardial infarction.
ACKNOWLEDGMENTS
We acknowledge the assistance of James Dolan, M.D., in preparing Fig.
1. Dr. Adams greatly acknowledges the assistance and support of Evan
Douple and Roy Shore in encouraging his research fellowship at theRadiation Effects Research Foundation. The corresponding author also
thanks his chair, Susan Fisher, for supporting his pursuit of this research
fellowship. Finally, Dr. Adams thanks the RERF for its direct financial
support and the career development financial support of the U.S. National
Heart Lung and Blood Institute (NHLBI Grant K-23 HL070930). The
Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki,
Japan, is a private, non-profit foundation funded by the Japanese Ministryof Health, Labour and Welfare (MHLW) and the U.S. Department ofEnergy (DOE), the latter in part through the National Academy of
Sciences (DOE Award DE-HS0000031). This publication was supported
by RERF Research Protocol(s) RP no. A11-08.
Received: July 27, 2011; accepted November 7, 2011; published online:
December 11, 2011

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