Renal Sclerosis, "Post-Radiation Nephritis" Following upon Irradiation of the Upper Abdomen

13 Pages·2017·20.99 MB·English

RENAL SCLEROSIS, " POST-RADIATION NEPHRITIS"
FOLLOWING UPON IRRADIATION OF THE UPPER
ABDOMEN
By HELEN RUSSELL, M.D.
Consultant Pathologist at the Christie Hospital, Manchester
Introduction
The occurrence of renal sclerosis with hypertension following upon
irradiation of the upper abdomen suggested that in its study some
light might be thrown upon the development of renal disease and high
blood pressure syndromes. The exact date of irradiation and the
dose of exposure are known in such patients, and it was thought that in
them the process of renal disease might run a simple and straightforward
course of fairly uniform duration. This was not, however, found to
be the case, and a detailed study of fatal " post-radiation nephritis,
as well as of laboratory investigations of surviving patients, indicated
how variable the clinical picture and the duration of the disease could
be. It emphasised the importance of individual susceptibility and of
conditioning factors such as age, and pre-existing anatomical and
pathological abnormalities of the renal tract, and suggested the import-
ance of endocrine imbalance.
Injury to the kidney following upon irradiation has been reported
not infrequently, 2> 19 and in 1926 Hartman et al.4 showed that it could
be a useful method of inducing nephritis for experimental studies if1
animals. But there is little doubt that, because of the extremely slow
development of the clinical signs in man after radiotherapy, many cases
of very varying severity and duration may not have been recognised
in radiotherapeutic centres in the past.
Recently the radiological aspect of the subject has been dealt with
by Kunkler et al.6 working in this centre, and the clinical aspect by
Luxton,7 both of whom reported upon renal disease following abdominal
irradiation. This paper is concerned with the histology of six selected
cases in which clinical and post-mortem data are available. The first
four illustrate what is probably the most rapid and severe type of renal
disease caused by irradiation treatment. Among surviving cases there
are others known to have less severe lesions and which are running a
slower course.7
Details of Cases
No. 1. 3957/50. A man of 32 years.
History.?October 1949. Right orchidectomy was performed for semi-
noma testis, and in December of the same year he received X-ray treatment
to the abdomen ; the remaining testis was within the fields of exposure. I*
was estimated that the kidneys received 2700 r. over 37 days.6
RENAL SCLEROSIS 475
March 1950. Bilateral gynecomastia developed, and he was treated by
ls doctor for " endocrine disturbance." At that time the 17-ketosteroid
excretion was 19 mg./24 hr., and gonadotrophin (F.S.H.) was over 500 mouse
u*its on two occasions.
September 1950. Headaches developed and oedema of the feet: albumi-
nuria was found : the heart was enlarged and dilated and the haemoglobin
54 per cent. The blood pressure was 180/86, the blood urea 102 mg. per cent.,
and the sternal marrow was cellular, but many of the nucleated red cells
showed unusually fragmented nuclear material.
December 1950. He died, the last blood urea estimation being 240 mg.
Per cent.
Summary of partial post-mortem examination and histological report
V-Hate I? fig. ?There were petechial haemorrhages in many organs and
fusions into the serous cavities. No tumour or site of its absorption was
?und, and the lymphatic glands of the abdomen were inconspicuous. The
J^Pra-renal glands (weights 10-7 and 6-5 g.) contained cortical lipoid : the
^neys (weights 170 and 190 g.) were swollen and the cortices flecked with
^morrhages. The capsules and peri-renal tissues were sclerosed. The
bules of the left testis were atrophic and the Leydig cells inconspicuous.
Microscopic Examination (Plate II, fig. 1).?The kidneys showed a very
"use interstitial fibrosis in which every tubule was degenerate and separated
?m its neighbouring tube and capillaries by collagenous material. Many
, fiieruli were diseased but not so uniformly involved as the tubular paren-
yma. The large branches of the renal arteries were hypertrophied and a
e sclerotic, haline necrosis of afferent arterioles and of a few glomerular
u ts could be found.
^en-renal sclerosis was present and the subcapsular region of the kidney
??rtex
was rather more sclerosed than the juxta-medullary zone.
Comment.?This is a case of post-radiation nephritis who died one year
er treatment, with hypertension and uraemia. Endocrine imbalance and
^ere_ anaemia were observed, and the latter appears to have been related to
ective maturation of the red cells of the marrow, which, both during life
a at post-mortem examination, was found to be very cellular.
2- 0729/51. A man of 29 years.
History.?October 1949. Left orchidectomy was performed for seminoma
tlsj and in November of the same year radiotherapy was given to the abdomen,
e remaining testis was within the field of treatment. The kidneys received
r. over 35 days.
July 1950. Enlargment of the left mammary gland was noticed.
December 1950. The blood pressure was 170/100, the haemoglobin 35 per
? 5 albuminuria, achlorhvdria and blood urea level of 105 mg. per cent.
Were
recorded.
January 1951. The excretion of 17-ketosteroids was 13-0 mg./24 hr.,
j
Nonsteroids 0-67 mg./24 hr., gonadotrophic (F.S.H.) 32 mouse units, and
uteanising hormone was found.
1 arch 1951. He died of acute oedema of the lungs.
^ u?nmary of Post-mortem Examination and Histological Report (Plate II
eg.^' .2 and 3).?(Edema of the lungs, ascites, pericarditis and a left pleural
ke Sl0n were present. No tumour or site of its absorption was found. The
art weighed 450 g. The kidney was a symmetrical horshoe shaped organ
476 HELEN RUSSELL
weighing about 280 g. It had two healthy ureters, and two main renal arteries?
and three smaller ones which arose near the isthmus which they penetrated at
once. The peri-renal fat appeared to be reduced in quantity and peri-renal
sclerosis involving the supra-renal glands and the retro-peritoneal tissues 1*1
general was quite apparent.
Marrow of the sternum was cellular, that of the lumbar vertebrae less so
(this area was within the treatment fields), and no haemopoiesis was proceeding
in the marrow of the centre of the shaft of the femur.
Microscopic Examination?The kidney showed diffuse interstitial fibrosis;
the thickened capsule fusing with the peri-renal sclerotic tissue. Extensive
tubular degeneration was present. The large branches of the arteries were
hypertrophied, and arteriolar hyaline necrosis was noted in some glomerular
tufts and also in the pancreas and testis (Plate III, fig. 2).
The tubules of the right testis were atrophied, and the Leydig cells were
quite conspicuous. The basophilic cells of the pituitary were also conspicuous-
The sternal marrow, which was cellular, showed a shift to the left in the granular
series, and many degenerate forms among the nucleated red cells.
PLATE I
Fig. 1. Case i.?" Post-radiation nephritis " with some peri-renal fibrosis.
Fig. 2. Case 6.?To show the dense peri-renal sclerosis related to the kidney pelves and
breaking down para-aortic metastases.
The supra-renal glands contained cortical lipoid. The mammary gland
enlargment was a hyperplastic overgrowth of both gland ductules and the
supporting stroma.
Comment.?This is apparently a case of post-radiation nephritis or sclerosis
who survived for 16 months after treatment. It is unlikely that the symmetric^
horse-shoe kidney was a conditioning factor in any way. Achlorhydria
severe anaemia were present: it is not possible to say whether this is related
to changes in the intestinal tract from exposure to irradiation.
No. 3. 2071/51. A man of 25 years.
History.?For one year before laparotomy he had complained of palia
in the loins.
June 1950. At operation an inoperable retro-peritoneal tumour was foui^
in the upper para-aortic region of the abdomen. Biopsy material showed a
malignant tumour, probably an embryonal carcinoma of nephro-genital ridge
origin. Clinically the testes appeared to be healthy.
September 1950. He was treated by abdominal irradiation and the teste5
were not included in the fields of exposure. The dose was approximate!)
3000 r. over 30 days to the kidneys.
March 1951. He became breathless and complained of aching lim^3'
The heart was dilated and enlarged and the haemoglobin 34 per cent. The
blood pressure was 190/95, the blood urea 1x0 mg. per cent., and albuminuria
and retinitis were found. A test meal gave a normal analysis.
June 1951. He died with signs and symptoms of sub-acute nephritis a#
hypertension.
Summary of Post-mortem Examination and Histological Report (Plate 1;'
fig. 3).?Effusions were present in all the serous cavities and a metastas15
PLATE I
I 2 3 4 5 ( 7 8 9 10 II 12 0 14 15 s
CENTIMETERS
?ii^l^mLAiltAaUl?tJ{iatoiiiijyiJiialiainiilii}uMaiiji( iiila>iliitiaMiHiliiiiliiiiMi( ilinjij
PLATE II
*r
**' J r - J'' ~ -
/. ?,.. ..^^g
RENAL SCLEROSIS 477
was found in the para-oesophageal glands in the chest. The heart weighed
375 g. and was hypertrophied and dilated. The tumour was a lobulated mass
which lay between the kidneys, and the kidneys, peri-renal tissues and
Neoplasm were glued together in dense fibrous tissue and fixed to the
front of the vertebrae. The renal vessels on the right side were embedded
ln the growth and there was some hydronephrosis on that side caused by pres-
sure on the upper part of the ureter. The kidney parenchyma on both sides
appeared to be diminished in quantity, the capsules srtipped quite easily and
the cortices were pale and mottled, and streaked with petechial haemorrhages.
The supra-renal glands were not obviously diseased, the seminal vesicles were
hyperplastic and distended with secretion.
Microscopic Examination.?There was diffuse interstitial fibrosis of the
kidneys with some degree of atrophy of all the tubules. The glomeruli were
less widely damaged than the tubules, but arteriolar necrosis was easily found,
and many of the tufts showed some fibrosis. The large branches of the renal
arteries were hypertrophied. Both testes were oedematous, the tubules atrophic
and the Leydig cells very conspicuous. A section of marrow from the sternum
was cellular and showed some macro-cvtosis of the red cell series, and marrow
from the shaft of the femur was much the same in appearance.
PLATE II
^IG- I. Case i.?Kidney cortex x 10. Periodic acid-Schiff stain.
^IG-2. Case 2.?Kidney cortex X io. Same stain. Dense peri-renal sclerosis present.
^IG- 3- Case 2.?Detail of cortex X 70. Same stain.
^IG-4- Case 3.?Kidney cortex X 10. Same stain.
^IG-
5- Case 4.?Detail of kidney cortex X 70. Hsematoxylin and eosin.
Comment.?This patient died nine months after exposure to irradiation
and showed a severer degree of peri-renal sclerosis than the two previous cases.
This is usually noticed when breaking down tumour tissue is mixed up in
the reaction. The anaemia was not associated with achlorhydria, and in the
Presence of cellular marrow may be due to some defect of maturation of the
red cells. The testicular atrophy may be a sign of systemic stress, or dis-
turbance of the circulation.
4* 3646/50. A man of 46 years.
History. July 1948. Right orchidectomy for seminoma testis.
November 1948. He received treatment by abdominal irradiation and the
iefr testis was within the fields of exposure. The dose was estimated at 2700 r.
OVer 25 days.
August 1950. He became ill but continued to go to sea until he was very
When admitted finally his heart was dilated, the haemoglobin 39 per cent.,
the blood pressure 210/115, the blood urea 154 Per cent. and retinitis
and albuminuria were found. He died five days after admission in December
*95o.
Summary of Post-mortem Examination and Histological Report. There
Was oedema of the lungs and pleural effusions, and the heart was enormously
hypertrophied and dilated, weighing 650 g. No tumour or site of its absorption
Was found.
The kidneys weighed 170 g. right, and 125 g- left respectively, and no gross
VOL. LX NO. T 2 2 H
478 HELEN RUSSELL
peri-renal sclerosis was seen. There was less peri-renal fat on the right side
than on the left. The capsules stripped easily but the cortical parenchyma
was obviously diseased and the large branches of the renal arteries showed
some sclerosis. The supra-renal glands weighed 8-5 g. and 8-9 g. and their
cortices were laden with lipoids.
Microscopic Examination.?There was widespread interstitial fibrosis in
the kidneys, with a slight tendency to the formation of more dense wedges of
sclerosis such as are seen in arterio-sclerotic organs. On the whole the
glomerular damage was less than the tubular. The medium sized arteries
were sclerotic to some extent, and hyaline necrosis was noted in some glomerular
tufts. The right kidney showed a slightly more advanced stage of disease than
the left (Plate II, fig. 5).
No abnormality was seen in the pituitary. Marrow of the sternum was very
cellular, showing a shift to the left in the granular series of cells, and many
breaking down nuclei in the red cell series. Marrow from the lumbar vertebrse
was less cellular (it was within the irradiation fields of treatment) and the
marrow from the centre of the shaft of the femur was inactive, (Plate III?
fig. 1).
PLATE III
Fig. 1. Case 4.?Marrow of sternum X 250. Hematoxylin and eosin.
Fig. 2. Case 2.?Atrophic testis X 60, to show arteriolar necrosis which was found in extra-
renal sites in this patient. Hsematoxylin and eosin.
Fig. 3. Case 5.?Kidney X 70 showing interstitial oedema and widening of the glomeruli.
Fig. 4.?Normal kidney X 70 to compare with preceding photograph. Hsematoxylin and eosin-
Fig. 5. Case 6.?Right kidney X 70 conditioned by chronic obstruction of the ureter.
Hsematoxylin and eosin.
Fig. 6. Case 6.?Left kidney X 70 showing less advanced disease. Hsematoxylin and eosin.
Comment.?This patient was much older than the preceding three. He
died two years after treatment and it is likely that he might have survived
longer if he had not been with the fishing fleet to within two weeks of death-
It may be said that the kidneys were conditioned by pre-existing arterial
disease but it is more difficult to say whether this might be beneficial or harmful-
X-radiation appears to be particularly injurious to young tissues, and some
degree of arterial sclerosis might diminish sensitivity to vascular injury.
The preceding four cases were examples of chronic nephritis with
hypertension following upon X-ray treatment and the histological
studies in all were made in the last stages of the disease. The records
of the pathology department of the Christie Hospital were therefore
searched back for ten years in an attempt to find histological material
from patients who had died soon after exposure to treatment and in
which the earlier stages of the nephritis might be detected. The two
following cases were the only records which were found and considered
relevant.
No. 5. 2280/44. A man of 33 years.
History.?There was complaint of a few weeks' abdominal pain. Orchi-
dectomy and laparotomy were performed in July 1944. The tumour
was a seminoma and retroperitoneal metastases were present.
PLATE III
*,4*^ w-
e *
*
*
RENAL SCLEROSIS 479
From 5th August to 14th September of the same year he received X-ray
treatment of the abdomen.
Dose.?The serial strip technique was used and the kidneys received approxi-
mately 1500 r. over 8 days.
He died of pulmonary embolism on 14th September (Plate III, fig. 3).
Summary of Post-mortem Examination and Histological Report and
Comment.?Metastases were found in the liver and lungs and the retro-peri-
toneal mass was breaking down, its veins were clotted and the extension of
"this clot into the vena cava had been the source of the embolus. The kidneys
Appeared to be healthy, but as there was some clot in the left renal vein the
nght kidney was selected for examination. It showed some degree of inter-
stitial oedema and general capillary dilatation tending to separate the tubules
and capillaries from one another, and also dilatation of the glomerular vessels
and widening of the whole glomerular structure. In Plate III it is shown
beside a healthy kidney photographed at the same magnification. This picture
maY be the early stage of a chronic and diffuse hypersemia with some degree
^ circulatory stasis which is characteristic of irradiation reactions in general,
t is not possible to predict whether it is an irreversible stage of that process.
^?"
3450/52. A woman of 45 years.
History.?March 1952. A malignant ovarian cyst was removed, and
Post-operative irradiation was given to the abdomen. It was estimated that the
'ianeys received between 2000 and 2500 r. over 30 days.
May 1952. Her blood pressure was 125/80.
August 1952. She complained of pain in the back. The blood pressure
'Vas *85/100, the haemoglobin 75 per cent., the blood urea 23 mg. per cent.,
and there was a trace of albumen in the urine. She died in November 1952.
Summary of Post-mortem Examination and Histological Report (Plate I,
g. 2).?There were multiple metastases in the liver, a deposit in the second
mbar vertebra, and tumour emboli in the lungs. In the abdomen a para-
aortic mass of semi-necrotic tumour was bound down around the kidneys in
ense fibrous tissue. The left kidney was comparatively healthy but showed
?arly sub-capsular fibrosis of the cortex. The right kidney was hydro-
^ephrotic, the ureter being almost closed in its upper third on that side and the
lnterstitial sclerosis of the kidney cortex was advanced. The large branches
?f the renal arteries on both sides were arterio-sclerotic to some extent (Plate III,
5 and 6).
Comment.?This patient was in middle life and probably had some degree
?f arterial disease before the final illness. It is difficult to decide in
SUch a complicated picture how much renal damage may be attributed to
?xP?sure to irradiation and how much to peri-renal sclerosis and hydro-
nePhrosis. It emphasises how easily post-radiation injury to the kidney may
Pass unnoticed. The case was accepted clinically as being at a stage of post-
radiation nephritis when she died of multiple metastases.
Discussion
From the present-day knowledge of the histological effects of
irradiation
on the human body, it is considered likely that whatever
histological damage may be induced in the kidney by irradiation, it
vol. lx. no. 12 2 h 2
480 HELEN RUSSELL
will follow the same series of changes as are seen in irradiation of other
parts of the body. It cannot be assumed that irradiation will have any
specific effects upon kidney structure ; rather the specificity will lie
in the characteristics of renal anatomy and physiology, being, as it is,
a compact, firmly encapsulated organ, of closely packed parenchyma
and blood vessels, with a capacity of both exo- and endo-crine secre-
tion, and having a remarkable hsemodynamic mechanism under
complex vasomotor and hormonal control.
It is generally accepted to-day that in exposure to irradiation two
processes may overlap one another.16 On the one hand there is a
local effect, and on the other a systemic reaction of shock or stress of
varying degree. In experimental work exposure to irradiation has
been suggested as the ideal method of inducing non-specific shock with
all the changes which are characteristic of stress and which are mediated
by the pituitary and supra-renal secretions. The usual clinical means of
assessing these reactions is by detecting changes in the circulating
mesenchymal cells, and there is little doubt that the haematological
changes recorded in exposures of varying kinds depend upon the
degree in which either the local, or the general systemic reaction, or
both participate ; as well as upon individual differences in mesenchymal
sensitivity.
In our experience of irradiation effects upon many tissues it has
appeared that the reacting mesenchyme, which includes the vascular
and lymphatic apparatus, the marrow and the scattered tissue histio-
cytes, the system in fact which keeps the body alive from day to day,
is that which is most sensitive to atomic energy as well as to many
other noxious agencies.13, 14 Atomic energy sharing with many other
chemical and physical agents the capacity to destroy life if given m
sufficient dosage. Any injury to reacting mesenchyme which leads to
permanent closure of capillaries and destruction of local histiocytes,
may shorten the life of the tissue involved. The importance of general-
ised mesenchymal damage from any cause, is that it may shorten the
span of life of the individual, whereas the importance of local mesen-
chymal damage depends upon its site. The serious effects of local
mesenchymal damage to the whole organism is nowhere better
illustrated than in disease of the kidney.
The local histological effects of irradiation have been known for
many years, and in their final stages can best be described as comparable
to a histological process of premature ageing of the tissues. Non-
specificity is on the whole the outstanding characteristic of the changes
and they appear to be due to a slow failure of the reacting mesenchyme
to carry out its full function. The skin is the tissue in which the effects
of irradiation can be easily seen 17 as well as examined histologically-
With comparatively small exposures to the skin a red lesion may be
seen in a few hours, and it fades slowly over many days. With larger
doses oedema and thickening of the area are more marked, and the
slowly fading reaction changes finally, after months, into an atrophic