Fenioie !.;2.- (‘l_ posed (rot
Total
(Submitted August 15, accepted September 28, 1956.)
ADDRESS: (M.P.S.) Department of Pediatrics, M. D. Anderson Hospital, Texas Medical Center,
lions-ton 25, Texas.
607
INCIDENCE
OF ABNORMAL
URINARY
FINDINGS
IN CHILDREN
EXPOSED
TO
THE
ATOMIC
BOMB
IN HIROSHIMA
By Margaret P. Sullivan, M.D., and Yasushi Takahashi, M.D.
Committee on Atomic Casualties, National Academi of Sciences-National Research Council, Waiiington, D.C.
S
INCE 1951 the United States AtomicBomb Casualty Commission has carried on i cotitinuing nledical survey of atomic
1)01111) survivors under the auspices of the
National Academy of Sciences-National Re-search Council, to determine whether there
ccun in the survivors post-radiation changes similar to those found in
expeni-Illental animals or in humans receiving
therapeutic doses of x-inradiation.
Post-radiation nel)hrltis has been reported in experimental animals,1 in humans
re-cei\’ing x-ray therapy for renal and other
tl)(lOI1liIlll tumors,9 1 4 and in mice exposed to an experimental nuclear detonation.
Such changes have not been reported in hu-iiians (‘XpOse(1 to 1t011lic radiation. Evidence of renal changes in children surviving the
atoniic l)laSt in Hiroshima is now being sought l)\’ al)l)raisal of urinary findings and l)\ otliei pertinent studies. The abnormal urinary findings in this group of children
(hiring the first 3 ‘ears of the continuing survey are sulilmanized in this progress re-port.
PATIENT MATERIAL AND METHODS
Selection of children exposed to the atomic
l)last within 2,500 m of the hvpocenter and
their controls for the continuing survey has been
previously described.16 The composition of the
sample studied is shown in Table I.
Participation in the program was on a volun-tary basis. Each child was examined within a month of his birthday. The clinical work-up consisted of medical and radiation histories,
physical examination, anthropometnic
measure-iiieiits, roentgenograms of the chest and left
wrist, blood (0U11t5 with determination of the
indices, routine urinalysis, serologic tests for
syphilis, and examination of stools for ova and
p1ra5iteS.
A vOi(led specimen of urine which contained singly or iii combination, protein, I + or more; 10 or more erythrocvtes per high power field;
or 10 or more leukocytes per high power field,
was considered to be abnormal. Microscopic counts were done on the urinary sedime;it after
centrifugation. Follow-up studies were
immedi-atelv undertaken on all patients showing ab-normalities in a voided specimen. Laboratory facilities were available for making urograms after the intravenous injection of radio-opaque material, for Add:s counts with determination of the specific gravity and total protein on the
specimen submitted, and for bacteriologic
studies including inoculation of guinea pigs.
In-est:gations ‘ere, in some cases, incomplete
TABLE I
AGE ANI) SEX OF (‘IIILoIIEN INVESTIGATEI)
FIIIST EXAMINATION 1951
.1!ale .lge in
---Years Er-
(‘on-po3e(l Irol
5 80 47 73 36 136
6 98 1 10 85 101 3!)4
7 13 2’ 18 3 76
H 104 100 99 1 10 413
9 i’2 9 2 9 (;
10 96 95 97 1() ‘I)O
11 109 96 117 109 431
H 114 99 1O2 93 408
13 91 86 93 Ii!) 359
14 78 78 75 77 311
15 60 68 43 73 ‘2
16 t0 78 75 61 294
17 40 .57 41 .5 193
18 54 47 3!) 43 153
due to lack of continued voluntary co-operation on the part of the patient. However, in many
instances it was possible to continue follow-up studies into 1954 and 1955. A number of the
children in the survey had been studied in 1949 and 1950 with particular emphasis on
hematologic data and/or data on growth and development and results of uninalyses on these patients date from 1949 or 1950.
Supplementary histories with particular
ref-erence to the urinary system were obtained in each case where abnormalities in the urine
were found. In most instances such histories
yielded no additional information due to the
traditional toilet customs of the country.
RESU LTS
During the first 3 years of the continuing
survey, 128 exposed children and 95
con-trol children showed abnormal urinary find-ings. These children were divided into the
following mutually exclusive categories, as shown in Table II : 1. Clinical history of
nephritis. 2. Isolated abnormality-no ab-normality demonstrable in immediate fol-low-up study or thereafter. 3. Brief,
transi-tory urinary abnormalities without history of renal disease-changes present during follow-up period but absent by time of next annual examination. 4. Abnormalities pres-ent for as long as 1 year-changes present through follow-up period and on next an-nual examination but not thereafter. 5. Abnormalities present for a period longer
than 1 year-changes still present in follow-up period following next annual
examina-tion.
Examination of the data showed a higher incidence of urinary abnormalities among
the exposed group as compared to the
con-trol group. This difference was statistically
significant (p < .05). When sex was
con-sidered, the higher incidence among the
ex-posed group occurred predominantly among the girls, and this difference was sufficiently
great to influence the pooled data. Protein
and increased numbers of leukocytes were found frequently in voided specimens from both exposed and control girls and
con-tributed greatly to the difference in mci-dence found between the sexes. No
sig-nificant difference in the incidences of ab-normal urinary findings between exposed
and control groups was demonstrable among the boys (p>O.3O).
The data were further examined to see
whether or not the urinary findings with serious clinical implications were more fre-quent among the exposed children than
among the control children. Of the 128
chil-dren in the exposed group who showed
ab-normal urinary findings, 28 with either a
history of nephritis or abnormalities persist-ing for longer than 1 year could be
con-sidered to have findings of actual or poten-tially serious nature. In the group of 95
control children, 22 could be classified as
showing serious findings. When statistically
compared, however, no significant
differ-ences could be demonstrated, the incidence
of serious abnormalities being almost iden-tical in the two groups (p > 0.80).
The amount of radiation received by a
TABLE II
NUMBER OF ChILDREN IN STUDY GROUP WITh HISTORY OF NEPHRITIB AND URINARY
ABNORMALITIES OF Vutious DURATION
Mate Female
Exposed Control Exposed Control
History of nephritis Isolated abnormality
Transitory abnormalities
Abnormalities for 1year
Abnormalities for longer than 1year
3 (.8%) 24 (.8%) 14 (1 .3%)
(.48%) (.48%)
4 (.40%) 19( 1.9%)
9 (.91%) 4 (.40%)
6 (.60%)
(.0%)
37 (3.8%) 1 (I .%)
8 (.81%)
is (1 .8%)
(.0%)
6 (.6%) 8 (.81%) 7 (.7%) 10 (1.0%)
ARTICLES 609
survivor of an atomic bomb is uncertain
even though the distance from the
hypo-center has been accurately determined in each case giving an estimate of the possible
maximum dosage. For example, Wilson’s
curves indicate that an unshielded survivor at 1500 m from the hypocenter in Hiroshima was exposed to approximately lO slow neutrons/cm’ and a gamma ray dosage of
100 r.1’ In most instances partial or com-plete shielding afforded by geographic
con-tours on concrete structures makes
calcula-tion of the actual dosage received most difficult. Therefore, symptoms developed by a survivor in the post-radiation period were
chosen as an index to degree of exposure.
The data were then examined to determine
whether the occurrence of significant
radia-tion symptoms* was more frequent in those
children who had urinary findings of a more serious nature. Data from a previous study have shown that approximately 15.5% of the
entire group of exposed children enrolled
in the study gave histories of one on more significant radiation symptoms. In the group with abnormal urinary findings,
approxi-mately 24% gave histories of significant radi-ation symptoms. This difference in mci-dence, however, was not statistically signifi-cant (p > 0.10).
Case histories of exposed children who had had nephritis or who showed persistent albuminuria and hematunia by routine
urinalysis or Addis count and who had
major radiation symptoms are briefly
sum-marized:
A.M. (MF No. 400210, a microcephalic fe-male, was born on February 15, 1946. She had
been exposed at 700 m in utero at a fetal age of 16 to 20 weeks. In the post-radiation period the mother experienced 100% epilation as well as purpura, oropharyngeal lesions, slight fever and diarrhea. The patient was first seen by
members of the Atomic Bomb Casualty
Com-mission in August, 1950. In addition to the
microcephaly there was mental retardation, bi-lateral internal strabismus and bilateral
con-* Major or significant radiation symptoms
in-cluded epilation, oropharyngeal lesions and
pur-pura.
genital dislocation of the hips. Urinalysis
re-vealed a specific gravity of 1.008 and the
re-action for protein was 4+ . There were 5 to 10 erythrocytes and 0 to 3 leukocytes in a
high-power field, as well as occasional casts. The concentration of nonprotein nitrogen in the blood was 60.1 mg/100 ml. A urogram oh-tamed after intravenous administration of
opaque material was unsatisfactory. Another
urinalysis performed in February, 1951,
re-vealed a specific gravity of 1.010 and a 3+ reaction for protein. There were no erythrocytes and no more than 5 leukocytes in a high-power field as well as occasional hyaline casts and fat globules. The child expired on January 21, 1952, and the cause of death listed on the death certificate was “Marasmus. Infantile
paralysis.”
T.K. (MF No. 294355), a male, was born on
April 22, 1940. He had been exposed at 900 m. In the post-radiation period he had expeni-enced 100% epilation as well as purpura,
oro-pharyngeal lesions and diarrhea. In April, 1951,
the patient was believed by his local physi-cian to have acute nephnitis with generalized edema, pulmonary edema and oliguria. He was
first seen by members of the Atomic Bomb
Casualty Commission in May, 1951. Urinalysis revealed a specific gravity of 1.014 with a
“trace” reaction for protein. There were 2 to 18 erythrocytes and an occasional leukocyte in a
high-power field, but no casts. The blood pressure was normal. Another urinalysis
per-formed in 1952 was normal. Two additional
uninalyses were done in 1953 and another in
1954 and all revealed a trace of protein. The examiners at the Atomic Bomb Casualty
Com-mission found no elevation in the blood
pres-sure.
N.O. (MF No. 273852), a female, was born on October 20, 1940. She had been exposed at
1200 m. In the post-radiation period she had experienced severe epilation and diarrhea. She was first seen by members of the Atomic Bomb Casualty Commission in October, 1951.
Un-nalysis at that time revealed a specific gravity
of 1.017 and the reaction for protein was 1+.
There were 40 to 50 erythrocytes and 1 to 3
leukocytes in a high-power field. The blood
in a high-power field. Routine and acid-fast
cultures showed no growth. The concentration of nonprotein nitrogen in the blood was 19.2 mg, 100 ml. A urogram obtained after intra-venous administration of opaque material showed no al)normalities. In May, 1954, the
specific gravity of the urine was 1.010 and there was a “trace” reaction for protein. There were 75 to 108 erythrocvtes in a high power field. The l)lOOd pressure remained normal. The patient’s three sisters, who were not exposed
to atomic bomb radiation, were also known to have albuminunia and hematunia. The entire
family had been extensively studied in a
hos-1)ital in Hiroshima.
M.W. (MF No. 215219), a female, was born
OH February 17, 1933. She had been exposed at
1700 m. During tile post-radiation period there
vas slight epilation. In 1949 she was first cx-irnined by members of the Atomic Bomb Cas-tialty Commission and no abnormalities were
found. A further examination in 1951 was also
normal. In February, 1952, however, a urinalysis
revealed a specific gravity of 1.025 with a 1+
ieaction for 1)rtei11. There were 200 erythro-cvtes 10(l 0 to 2 leukocvtes in a high-power
field. The specimen collected for Addis count had a specific gravity of 1 .020 with a normal
reaction for protein. There were 5,000,000
ervthrocvtes, 4,000,000 leukocvtes and 10,000
casts. The 1)lOOd pressure was 124/76. In May,
1954, another urinalysis revealed a specific
gravity of 1.024 with a “trace” reaction for protein. There were 36 to 72 erythrocytes and
4 to 16 leukocvtes in a high-power field. The patient refused further studies.
H.S. (MF No. 400062), a female, was born
on December 8, 1939. She had been exposed at 1800 m. During the post-radiation period she had experienced incomplete epilation and bloody diarrhea. She was first seen by
physi-cians at the Atomic Bomb Casualty Commission
in November, 1951. Examination of her heart
revealed a grade three apical systolic murmur without signs of cardiac enlargement or other abnormalities. Urinalysis performed at this time did not reveal any abnormality. In December, 1952, the specific gravity of the urine was 1.015 and the reaction for protein was 1+ and there were 1 to 7 erythroctes in a
high-power field. In December, 1953, the specific
gravity was 1.010 with a “trace” reaction for protein. There were no more than 3
erythro-cytes in a high-power field and no more than
1 hvaline cast in a low-power field. The blood pressure was 120/80. In March, 1954, another
urinalysis revealed a specific gravity of 1.020
with a “trace” reaction for protein. There were 6 or fewer erythrocytes in a high-power field. The specific gravity on the urine collected for
Addis count was normal as was the content of
protein. Two million erythrocytes were present.
Acid-fast cultures showed no growth. In June,
1954, a urogram obtained after intravenous
administration of opaque material revealed slight pelvic enlargement on the right and
poor visualization on the left.
S.M. (MF No. 215296), a female, was bonn on June 13, 1937. She had been exposed at 1900 m and during the post-radiation period had experienced 75% epilation, oropharyngeal lesions, bloody diarrhea, fever and vomiting.
She was first seen by members of the Atomic
Bomb Casualty Commission in June, 1951. At
that time urinalysis revealed a specific gravity of 1.005 with a “trace” reaction for protein. No more than 1 erythrocyte and 4 or fewer leuko-cvtes were present in a high-power field. One
i-ear later the specific gravity of the urine was 1.014 and the reaction for protein was 1+.
There were 0 to 5 erythrocvtes and 5 to 15
leukocytes in a high-power field, with occa-sional clumps of cells. There were rare hyaline
and finely granular casts in a low-power field. In February, 1954, the urinalysis showed a specific gravity of 1.013 with a 1 + reaction for protein. There were no more than 2
leuko-cytes in a high-power field and no more than 1 finely granular cast in a low-power field. Routine and acid fast cultures showed no
growth. The specific gravity on the urine
col-lected for Addis count was normal as was the
content of protein. There were 5,000,000
eryth-rocytes, 4,000,000 leukocytes and 10,000 casts
present. In November, 1954, the urinalysis was
normal.
DISCUSSION
In their experiments on rats Bennett et al.8 found that late survivors who had
re-ceived 800 to 1200 n developed a clinical
syndrome characterized by apparent re-covery from acute irradiation effects; a latent period of good health; gradual onset of arteriosclerosis, nephrosclerosis, and
insuffi-ARTICLES
ciency or vascular accidents. Furth et al.’
have reported significant shortening of life
span in mice exposed to an experimental nuclear detonation, due to neoplasia and
(legenenative changes including
nephro-sclerosis. Hursh, Van Slyke and CasanetV
have found a 19% shortening of life span in
rats surviving 60 (lays after a single 600 r (loSe of x-irra(liation.
It is difficult to deduce from the
expeni-nients in animals the latent period which
could be expected in humans receiving a single dose of x-inradiation before the
char-actenistic renal changes might appear. The
pathologic changes described by Bennett et a!., were found in those who survived for
100 to 540 days. The clinical findings
re-l)Onted in this study apply to patients seen 6, 7, ifl(l 8 years after exposure. If dosages
were comparable and the latent periods
as-sumed to be proportional to life expectancy
(
rat-3 years, human-GO years), clinicalchanges could well have been expected (Inning the period of this study. However,
through 1953 no significant statistical
dif-ference was found between the incidence of urinary abnormalities of an actual or
Pte11tially serious nature in the exposed
111(1 control groups in this study.
Further-more, there was no significant statistical
difference in the incidence of one or more
significant radiation symptoms between the exposed group as a whole and exposed
children showing urinary changes of a more
serious nature. Follow-up studies are in-(licate(l as the 19% life shortening
percent-age derived by Hunsh et a!., if applicable to
human survivors of the atomic bomb, might
indicate that such changes could appear at
a later date in the group of children studied.
SUMMARY AND CONCLUSIONS
Urinary abnormalities have been studied
in 2,031 boys (1,039 exposed, 992 control)
and 1,963 girls (985 exposed, 978 control)
in Hiroshima, Japan, as a part of the con-tinuing medical survey being carried on by the Atomic Bomb Casualty Commission from 1951 through 1953.
A history of nephnitis was given by .28%
of exposed boys, .49% of control boys, .20%
of exposed girls, and .20% of control girls.
Isolated abnormalities were found in 2.3%
of exposed boys, 1.9% of control boys, 3.8% of exposed girls and 2.6% of control girls.
Brief, transitory urinary changes without
further evidence of urinary tract disease
were found in 1.3% of exposed boys, .91% of
control boys, 1.2% of exposed girls and .81% of control girls. Abnormalities were present for as long as 1 year in .48% of exposed
boys, .40% of control boys, .81% of exposed girls, and .72% of control girls. There was no evidence of permanent damage in the
22 children in this group of 24 with
ade-quate follow-up studies. Chronic renal
dis-ease, active or inactive, was suspected in .48% of exposed boys, .60% of control boys, 1.8% of exposed girls and 1.0% of control girls who showed urine abnormalities for
longer than 1 year.
Case summaries have been presented in
relation to six exposed children with his-tories of nephnitis or with albuminunia and hematunia who had experienced one or
more of the major radiation symptoms after the bombing.
There was no statistical difference in the
incidence of nephnitis or urinary abnon-malities of a serious nature between the
exposed and control groups. There was no statistical difference in the incidence of
major radiation symptoms when the entire
exposed group was compared with exposed children showing urinary findings of a serious nature.
The above data should be considered a
progress report. The urinary findings in this study group should be reviewed in the
future to determine whether on not renal damage has occurred in children exposed
to the atomic bomb
in
Hiroshima.REFERENCES
1. Hartman, F. W., Bolliger, A., and Doub,
H. P.: Experimental nephritis produced
by irradiation. Am.
J.
M. Sc., 172:487,1926.
2. Bolliger, A., and Laidley,
J.
W. S.:exposed to a measured amount of un-filtered rays of medium wave length.
M.
J.
Australia, 1 : 136, 1930.3. Bolliger, A., and Earlam, M. S. S. :
Expeni-mental renal disease produced by x-rays;
production and functional study of stand-ardized lesion. M.
J.
Australia, 1:340, 1930.4. Earlam, NI. S. S., and Bolliger, A. : Ex-perimental renal disease produced by x-rays; late results of irradiation. M.
J.
Australia, 1:826, 1932.5. O’Hare,
J.
P., Altnow, H., Christian, T. D.,Calhoun, A. W., and Sosman, M. C.: Chronic nephritis produced by x-ray. Boston M. & S.
J.,
194:43, 1926.6. Warren, S. : Effects of radiation on normal
tissues. VII. Effects of radiation on the
urinary system. Arch. Path., 34:1070,
1942.
7. Page, I. H. : Production of nephritis in dogs
by roentgen rays. Am. J. M. Sc., 191:
251, 1936.
8. Bennett, L. R., Chastain, Sarah M., Flint,
J. S., Hansen, R. A., and Lewis, A. E.:
Late effects of roentgen irradiation;
studies on rats irradiated under anoxic anoxia. Radiology, 61 :411, 1953.
9. Doub, H. P., Hartman, F. W., and Boffiger, A. : Relative sensitivity of the kidney to
irradiation. Radiology, 8: 142, 1927. 10. Mertz, H. 0., Howell, R. D., and
Hend-ricks,
J.
W. : Limitations of irradiationof solid renal tumors in children. J. Urol., 46:1103, 1941.
11. Dean, A. L., and Abels,
J.
C. : Study bythe newer renal function tests of an unusual case of hypertension following irradiation of one kidney and the relief of the patient by nephrectomy.
J.
Urol.,52:497, 1944.
12. Zuelzer, W. W., Palmer, H. D., and New-ton, W. A., Jr. : Unusual
glomenulone-phnitis in young children; probably
radiation nephritis; report of 3 cases.
Am. J. Path., 26:1019, 1950.
13. Smith, W. G., and Williams, A. W. : In-radiation nephnitis. Lancet, 269:175,
1955.
14. Grossman, B. J.: Radiation nephnitis.
J.
Pediat., 47:524, 1955.15. Furth, J., Upton, A. C., Christenberry,
K. W., Benedict, W. H., and Moshman,
J.:
Some late effects in mice of ionizing radiation from an experimental nuclear detonation. Radiology, 63:562, 1954.16. Sutow, W. WI.: Summary of medical
studies on Hiroshima children exposed to the atomic bomb (Project PE-18,
1951-1953). Report to ABCC, April 30, 1954.
17. Wilson, R. R. : Nuclear radiation at
Hiro-shima and Nagasaki. Radiation Research, 4:349, 1956.
18. Hursh,
J.
W., Van Slyke, Florence, and Casarett, G. :Effect of single vs. divided doses of x-irradiation on survival of rats. Report UR-317, University of Rochester, 1954.SUMMARIO
IN INTERLINGUA
Incidentia
de Anormal
Constatationes
Urinari in Juveniles Exponite al Bomba Atomic de Hiroshima
Datos relative a alterationes renal post-radiational in juveniles supervivente al explo-sion atomic de Hiroshima esseva collegite per comparar le incidentia de anormal constata-tiones urinani durante un peniodo de tres annos in 2024 juveniles exponite al radiation atomic intra un distantia de 2.500 m ab le hypocentro con le incidentia de tal constatationes in 1977 juveniles de controlo qui non esseva a Hiro-shima al tempore del bombardamento. Speci-mens de urina esseva considerate como anonmal quando iios contineva, individualmente o in
combination, (a) proteina de 1 + o supra,
(b) 10 0 supra 10 erythrocytos in un campo a
alte potentia, e/o (c) 10 o supra 10 leucocytos in un campo a alte potentia.
Un historia de nephritis esseva presentate per 0,28% del pueros exponite, 0,49% del pueros de controlo, 0,20% del pueras exponite, e 0,20% del pueras de controlo. Isolate anormalitates urinari esseva trovate in 2,3% del pueros expomte, 1,9% del pueros de controlo, 3,8% del puenas exponite, e 2,6% del pueras de controlo. Breve tnansitoni alterationes urinani sin maul-festationes additional de morbo del vias uninari esseva trovate in 1,3% del pueros exponite, 0,91% del pueros de controlo, 1,2% del pueras exponite, e 0,81% del puenas de controlo.
Anormalitates esseva presente durante periodos
de usque a un anno in 0,48% del pueros exponite, 0,40% del pueros de controlo, 0,81% del pueras exponite, e 0,72% del pueras de controlo. Nulle prova de lesiones penmanente esseva trovate in 22 del 24 juveniles in iste
gruppo pro qui adequate studios de
consecu-lion esseva obtenite. Chronic morbo renal,
active o inactive, esseva suspicite in 0,48% del pueros expomte, 0,60% del pueros de controlo,
controlo in qui anormalitates urinari habeva
habite un duration de plus que un anno.
Nulle statisticamente significative differentia esseva trovate inter le incidentia de nephritis o anormalitates uninani de serie natura in le
gruppos de pueros e pueras exponite e le mci-dentia de tal conditiones in le gruppos de
controlo. Nulle statisticamente significative differentia in le incidentia de major symptomas
radiational esseva constatate quando le integre gruppo de pueros e pueras exponite esseva comparate con Ic exponite pueros e puenas qui
monstrava anormalitates urinani de natura
senie. Le datos urinani constatate in iste gruppo
de subjectos deberea esser re-investigate in le
futuro pro determinar si 0 non lesiones renal
ha occunnite in juveniles exponite al bomba