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Long-term consequences of cis-platinum-induced renal injuryA structural and functional study.

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THE ANATOMICAL RECORD 212239-245 (1985)
Long-Term Consequences of Cis-Platinum-Induced
Renal Injury: A Structural and Functional Study
DENNIS C. DOBYAN
Renal Research Laboratory, University of Texas Medical School, Houston, TX 77225
ABSTRACT
Previous studies have shown that a single dose of the antitumor
drug, cis-platinum, causes renal cyst formation in rats 1-6 months after drug
injection. This observation led to a further evaluation of the long-term effects of cisplatinum on the kidney of the rat. Fisher 344 rats (N = 13) were given either a
single intraperitoneal injection of cis-platinum (6 mgkg body weight) or saline
(control) and 15 months later renal function and pathology were assessed. The
glomerular filtration rate and urinary osmolality in the cis-platinum-treated rats a t
15 months were significantly reduced compared to controls, 520
59 pl/min/gm
194 mOsm/kg HzO versus
kidney weight versus 799 f 100 ( P < .05) and 871
1471 f 162 ( P < .05), respectively. Renal injury was less marked and of a more
chronic type than to that originally described 6 months after cis-platinum. Morphometric evaluation of renal injury revealed cis-platinum-treated rats had greater numbers of abnormal proximal tubules (atrophic or hyperplastic) when compared to
control rats. Glomerular sclerosis and interstitial fibrosis were also more prevalent
in the animals injected with cis-platinum. In the inner stripe of the outer medulla,
numerous markedly dilated tubules filled with hyaline casts and lined by simple
squamous cells were present. To assess why cis-platinum exerts a chronic effect on
the kidney, total platinum levels were measured in different regions of the kidney
as a function of time after drug injection. Platinum levels were significantly elevated
in the cortex, outer and inner stripe regions, and in the inner medulla for as long as
1 month after cis-platinum treatment. By 2 months, however, the values were no
greater than controls. In summary, cis-platinum exerts a significant long-term
chronic effect on the structure and function of the rat kidney.
The administration of the antineoplastic agent cisdiamminedichloroplatinum I1 (cis-platinum) to rats produces a reproducible model of acute renal failure characterized by decreased glomerular filtration, impaired
urinary concentrating ability, and increased fractional
excretion of sodium (Choie et al., 1981; Safirstein et al.,
1981; Chopra et al., 1982). The major pathological lesion
which has been reported during acute platinum toxicity
is tubular necrosis of the S3 segment of the proximal
tubule located in the outer stripe region of the outer
medulla (Ward and Fauvie, 1976; Dobyan et al., 1980;
Choie et al., 1981; Chopra et al., 1982). Most investigations of cis-platinum-induced nephrotoxicity have concentrated on those alterations which occur during the
initiation and maintenance phases of this disease. In a
recent study, Dobyan and co-workers (1981) reported
that the administration of cis-platinum caused renal
cyst formation i n rats 1-6 months after a single intraperitoneal injection of the drug. In addition, Bulger and
Dobyan (1984) have recently described hyperplastic lesions of the proximal tubules and papillary epithelium
in the kidneys of rats subjected to a single dose of cisplatinum. These observations led to a further evaluation
of the long-term consequences of cis-platinum on the
structure and function of the rat kidney. In this study,
renal function was assessed and pathological changes
0 1985 ALAN R. LISS, INC.
were described and quantitated in the kidneys of rats 15
months after a single injection of cis-platinum. The total
tissue platinum levels were also assayed in specific regions of the kidney as a function of time after exposure
to the drug. The results suggest that animals treated
with cis-platinum and then examined over a year later
have significantly poorer renal function and a greater
number of pathological lesions compared to age-related
control rats. The observation of elevated platinum levels
in the cortex and outer and inner stripe regions of the
outer medulla for periods of up to 1 month after drug
treatment may help to explain the persistent nature of
cis-platinum-induced renal injury.
MATERIALS AND METHODS
Experiments were performed on male Fischer 344 rats
(Timco Breeding Laboratories, Houston, Texas). All animals were fed a diet of standard laboratory chow and
were allowed free access to water. The experimental
animals were given a single intraperitoneal injection of
cis-platinum (Bristol Laboratories, Syracuse, New York)
in a dose of 6 m g k g body weight. Control animals were
handled in a similar manner but were given vehicle
only. Renal function and structure were evaluated in
Received July 9,1984; accepted January 29,1985.
240
D.C. DOBYAN
experimental or control groups 15 months after injection
of cis-platinum or saline.
At the time of study, the animal was anesthetized with
a n intraperitoneal injection of inactin (100 m g k g body
weight) and placed on a thermostatically heated table to
maintain the body temperature at 37°C. A tracheostomy was performed and the jugular vein, femoral artery, and bladder were catheterized with polyethylene
tubing (PE 50). The femoral artery was connected to a
pressure transducer attached to a recording polygraph
(Grass Instrument Company, Quincy, Massachusetts) for
blood-pressure monitoring. After the completion of surgery, a priming dose of inulin was injected into the
jugular vein, followed by a continuous infusion of saline
(0.03 mYmin) containing inulin in a sufficient quantity
to maintain plasma levels at 60-100 mg/dl. After a 90minute equilibration period, two 30-minute urine collections were begun for renal function determination. Arterial blood samples were obtained at the beginning,
midpoint, and end of each urine collection.
The concentration of inulin in plasma and urine was
determined by the anthrone method (Fuhr et al., 1955).
Sodium and potassium in plasma and urine were measured by flame photometry (Corning 480 Flame Photometer, Medfield, Massachusetts) and the osmolality was
measured by vapor-pressure osmometry (Wescor, Inc.,
Logan, Utah). Glomerular filtration rate and fractional
excretion of sodium were calculated using standard
formulae.
At the end of the clearance studies, the kidneys were
fixed by vascular perfusion using half-strength Karnovsky's fixative containing 2.5% glutaraldehyde and 2%
formaldehyde buffered in 0.14 M potassium phosphate
(pH 7.2-7.4). The kidneys were removed, weighed, and
processed for light microscopy.
P a r d i n sections were used for the quantitation of
pathological changes. Without prior knowledge of the
specimen under investigation, ten random pictures each
from the outer cortex and from the inner cortex were
taken at a magnification of 1 6 using
~
a Leitz-Wetzlar
photomicroscope with a Wild Photoautomat MPS 55
camera system. The area to be photographed (outer or
inner cortex) was first centered at low power and then
the 16x objective was rotated into position. After photographing each area the low-power objective was returned to the original position and the field was moved
a distance of approximately 2 mm (ocular reticle) for the
next photograph. Each negative was subsequently enlarged 7 . 5 ~to a final magnification of 2 5 0 ~ A
. multipurpose test system (Weibel et al., 1966) was used and it
consisted of discrete short test lines whose end points
were arranged in a regular triangular lattice using a n
array of nine rows of four test lines. This lattice contained 72 test points and 36 lines. Each point was classified into one of the following categories: 1) normal
proximal tubule; 2) normal distal tubule; 3) normal
glomerulus; 4) abnormal proximal tubule which included atrophic or hyperplastic tubules or those with
casts; 5 ) distal tubules with casts; 6) abnormal glomeruli
(sclerotic changes); 7) interstitium which included vessels, interstitial space, and inflammation; 8) inflammation (areas showing lymphocytic infiltration); and 9)
tubules which were unidentifiable. The total counts for
each categorv from all ten micromaphs were tabulated
and a siLg1e"value was express& f& the outer cortex
and for the inner cortex. Values expressed in this study
are means & SEM. Statistical comparisons between the
cis-platinum rats and the control group were performed
using the Wilcoxan rank sum test for two independent
samples.
Since cis-platinum exerts a long-term effect on the
structure of the kidney, total tissue platinum levels in
specific regions of the kidney were assayed to determine
the duration in which platinum remains within the renal
parenchyma. Total tissue platinum was measured 2
weeks, and 1,2, and 6 months after a single injection of
cis-platinum (6 m g k g body weight). For analysis of tissue platinum levels, the rats were anesthetized with
sodium pentobarbital (50 m g k g body weight) and the
kidneys were rapidly excised and placed in a petri dish
on ice. Transverse slices of kidney tissue were obtained
and the cortex, the outer stripe region of the outer medulla, the inner stripe region of the outer medulla, and
the inner medulla including the papilla were carefully
dissected into separate regions using a stereomicroscope. The tissue regions were subsequently homogenized in 2-cc cryogenic storage tubes using a Brinkman
PT-35 homogenizer equipped with a small sample probe
generator. The tissue homogenate was then rapidly frozen by immersing the tube into a container of liquid
nitrogen. After freezing, the tubes were immediately
placed into a lyophilizer flask and freeze-dried overnight
in a Labconco Bench Top Freeze-Dryer. Platimum determinations were made using a Kevex Ultra-Trace 0600
X-ray Fluorescence Spectrometer and the values are
expressed as pglgm dry weight. Results are expressed as
means SEM. Student's t-test (two-tailed) were used to
evaluate the significance between the experimental and
control groups.
RESULTS
There were no differences noted in either total body
weight or in total kidney weight between the control
rats and those given cis-platinum. A summary of renal
functional parameters for the control and experimental
groups is shown in Table 1. The glomerular filtration
rate in pllmidgm kidney weight and the urinary osmolality in mOsm/kg H20 were significantly reduced from
control values of 799 100 and 1,471 160 to respective values of 520 & 59 and 871 k 194 in the cisplatinum-treated rats (P< .05).
The kidneys from the control rats were essentially
normal and similar to those of younger rats; however, a
number of morphological changes consistent with agerelated nephrosis could be identified. These changes
which were not particularly prominent varied among
the control animals. The proximal tubules were largely
normal but a few atrophic or hyperplastic proximal tubules were observed. Hyaline casts (Fig. 1)could be occasionally identified in the distal segments of the nephron
particularly in the inner stripe region of outer medulla.
A few foci of chronic inflammation were also seen in the
control kidneys.
In general, animals receiving the single injection of
cis-platinum and then examined 15 months later had a
significantly greater number of pathological lesions
compared to the age-related controls (Fig. 2). Renal injury was evident in all regions of the cortex and outer
stripe although it appeared to be qualitatively greater
in the inner cortical and outer stripe regions. A sum-
+
LONG-TERM EFFECTS OF CIS-PLATINUMON KIDNEY
241
TABLE 1. Summary of renal function 15 months after cis-platinum administration'
Control
(N = 5)
Cis-platinum
CTJ
BP
(mm
Hg)
Bodywt.
(gm)
Kidneywt.
(gm)
Hct
392 f 10
3.5 k 0.2
124 f 3 47 f 2
391 f 16
3.3 & 0.1
123 k 3
(%)
46 k 1
GFR
pl/min/gmKwt.
799
100
520 f 59*
FENa
(%)
Uosm
mOsm/kg
H20
0.1 k 0.1 1,471 +_ 162
0.1
0.1
871 k 194*
= 4)
'Values are means f SEM. Abbreviations are: BP, blood pressure; Hct, hematocrit; GFR, glomerular filtration rate;
FENa, fractional sodium excretion; Uosm, urinary osmolality.
* P < .05.
TABLE 2. Summary of morphologic quantitation of outer and inner cortical regions of the kidney in
control and cis-platinum-treated rats'
Outer cortex
CP
(N = 7 )
Pvalue
51.6 f 2.8
12.4 k 0.8
42.7 k 4.7
6.6 f 1.3
< .05
8.4 f 0.3
0.3 + 0.1
0.3 f 0.1
0.1 f 0.1
7.5 k 1.4
5.3 f 1.6
1.2 rt 0.8
1.0 f 0.4
0.5 f 0.1
19.9 k 2.6
7.3 f 3.0
29.2 f 2.7
Control
(N = 5)
Proximal tubules, normal
Distal tubules, normal
Glomeruli, normal
Proximal tubules, abnormal
Distal tubules with casts
Glomeruli, abnormal
Inflammation
Interstitium, total
NS
Control
(N = 5)
Inner cortex
CP
(N = 7)
50.6 4.3
9.4 f 0.4
37.4 k 3.1
5.9 k 1.3
< .05
NS
8.9 f 0.9
0.5 + 0.3
0.1 k 0.1
0.1 f 0.1
8.6 k 0.9
5.3 i: 1.0
1.3 + 0.5
1.0 k 0.3
< .01
< .05
1.2 k 0.7
23.4 f 5.3
8.5 k 3.5
34.2 f 3.0
NS
< .05
Pvalue
< .05
NS
NS
< .01
NS
< .05
< .01
< .05
'Values are means + SEM and represent percentage of outer or inner cortex occupied by each component. Abnormal
proximal tubules include atrophic, hyperplastic, or tubules with casts. Total interstitium refers to vessels, interstitial
space, and inflammation.
mary of the morphometric analysis of the kidneys from
the control and experimental groups is shown in Table
2. Cis-platinum-treated rats had significantly fewer
proximal and distal tubules which were considered t o be
normal when compared to the control group. In agreement with this was the observation that cis-platinum
rats had a greater number of abnormal proximal tubules
in both the outer and inner cortical regions. These abnormal tubules consisted of atrophic tubules with markedly thickened basement membranes, basophilic
hyperplastic tubules, and tubules which contained casts
(Figs. 3,4). Some proximal tubules appeared to be filled
with large vacuoles and had a foamy appearance Wig.
5.)
In greater than 50%of the animals which received cisplatinum, renal cysts could still be identified. These
ranged from microcysts to cysts which had cross-sectional diameters of several millimeters (Fig. 6 ) . Hyperplastic cysts or solid nodules derived from altered
proximal tubular epithelium as well as hyperplastic lesions of the renal papillary epithelium were also observed in the animals receiving cis-platinum Wig. 7).
These proliferative lesions have been previously described in detail elsewhere (Bulger and Dobyan, 1984).
There were numerous markedly dilated tubules filled
with hyaline casts and lined by simple squamous epithelial cells in the inner stripe region of the outer medulla
(Fig 8). Casts were also present in the distal tubules
located in the cortex. Many of the tubules within the
inner medulla, including both thin limbs of Henle and
collecting ducts, had calcium-containing accumulations
within their lumens (Fig. 9).
There was a greater number of glomeruli which appeared abnormal in the cis-platinum rats. These were
generally glomeruli which exhibited either focal or total
sclerosis of the capillary tuft. The percentage of interstitial area (vessels, interstitial space, and inflammation)
was significantly greater (see Table 2) in the cis-platinum-treated rats when compared to the control animals.
The major reason for the increase in interstitial volume
within the cis-platinum group was the large amount of
chronic inflammation seen in this group of rats. There
were large foci of chronic inflammatory cells, particularly lymphocytes, as well as large areas of interstitial
fibrosis in the kidneys of the cis-platinum-treated rats
(Fig. 10).
To determine the duration in which platinum remains
in the kidney, the platinum levels were determined in
the different regions of the kidney as a function of time
after injection of a single dose of the drug. The results of
these measurements are shown in Table 3. Platinum
levels were significantly elevated in the cortex and outer
and inner stripe regions of the outer medulla for as long
as 1 month after drug administration. It was elevated
in the inner medullary zone for as long as 2 weeks after
cis-platinum administration.
DISCUSSION
Cis-platinum is an important antineoplastic chemotherapeutic agent used for the treatment of a variety of
solid tumors (Lippman et al., 1973; Gottlieb and Drewinko, 1975; Wittes et al., 1977). The principal limiting
factor in the use of this drug in clinical situations is
renal toxicity. Most experimental models examining cis-
242
Fig. 1. Light micrograph showing the cortex of the kidney of a n agerelated control rat. The majority of tubules appear normal. Note the
casts in the distal portions of the nephron (C). Hematoxylin and eosin.
x 130.
Fig. 2. Light micrograph showing the cortex of the kidney of a cisplatinum-treated rat. Note the increase in interstitium, hyperplastic
proximal tubules, and casts (C) in the distal tubules. Hematoxylin and
eosin. X130.
Fig. 3. Light micrograph showing atrophic proximal tubules from a
rat kidney 15 months after cis-platinum administration. The basement
membranes (arrows) are markedly thickened. Hematoxylin and eosin.
XSOO.
Fig. 4. Light micrograph showing an altered proximal tubule from
the kidney of a rat 15 months after cis-platinum. A mitotic figure is
apparent (arrow). Hematoxylin and eosin. ~ 8 0 0 .
Fig. 5. Light micrograph showing proximal tubules whose cell cytoplasm is filled with clear vacuoles from the kidney of a rat 15 months
after cis-platinum. Hematoxylin and eosin. x 350.
Fig. 6. Light micrograph showing a large cyst (C) in the kidney of a
rat 15 months after cis-platinum. Hematoxylin and eosin. x50.
LONG-TERM EFFECTS OF CIS-PLATINUM ON KIDNEY
Fig. 7. Light micrograph showing two small cysts (arrows) in the
kidney of a rat 15 months after cis-platinum. Hematoxylin and eosin.
x 130.
Fig. 8. Light micrograph showing the inner stripe region of the outer
medulla from the kidney of a rat 15 months after cis-platinum. Note
243
Fig. 9. Light micrograph showing the papilla from the kidney of a
rat 15 months after cis-platinum. Note the apparent calcium accumulations (arrows) in the lumens of the tubules. Hematoxylin and eosin.
the large number of casts filling the lumens of tubules lined by simple
squamous epithelial cells. Hematoxylin and eosin. x 50.
x260.
Fig. 10. Light micrograph showing an area of chronic inflammation
in the kidney of a rat 15 months after cis-platinum. Hematoxylin and
eosin. ~ 1 3 0 .
platinum nephrotoxicity have centered on the acute effects of this drug on the kidney. Safirstein and colleagues (1981) and Chopra and co-workers (1982)
reported marked decreases in both whole kidney and
single nephron filtration rates, depression in urinary
concentrating ability, and an increase in the fractional
excretion of sodium 3-5 days after cis-platinum administration. Acute tubular necrosis of the pars recta segment of the proximal tubule located in the outer stripe
of the medulla was the principal pathological finding
after cis-platinum treatment (Ward and Fauvie, 1976;
Dobyan et al., 1980; Choie et al., 1981; Chopra et al.,
1982). The initiation and maintenance phases of cis-
platinum-induced acute renal failure are usually followed by a recovery phase which lasts 1-4 weeks and is
characterized by a recovery in renal function, although
not complete, and tubular regeneration.
Evidence has been presented by a number of investigators showing that cis-platinum administration can
also cause chronic damage to the kidneys. Dobyan and
co-workers (1982) examined the kidneys of rats 1-6
months after the injection of a single dose of cis-platinum and reported injury characterized by tubular atrophy, nephron loss, cyst development, and severe nuclear
atypia. Choie and co-workers (1981) showed that repeated injections of cis-platinum for periods of up to 11
244
D.C. DOBYAN
TABLE 3. Regional distribution of platinum in the kidney following cis-platinum
administration’
Cortex
Control
(N = 4)
2 Weeks post CP
(N = 7)
4 Weeks post CP
(N = 8)
2 Months post CP
(N = 9)
6 Months post CP
(N = 6)
Outer medulla
Outer stripe
Inner stripe
Inner
medulla
3.6 + 0.5
4.4 f 0.4
43.8 k 6.9*
32.5 & 4.7*
23.6 _+ 4.4**
9.0
20.5 f 3.9***
12.1 k 2.8*
7.0 f 1.1
20.4
+ 7.2***
4.3 _+ 0.3
3.4 k 0.7
+ 1.0*
5.6 k 1.8
7.4 f 2.2
5.3 f 1.5
2.8
5.2 k 1.6
5.0
+ 2.1
2.2 k 0.5
3.1 _+ 1.2
jr
0.6
’Values are means k SEM. The concentrations of platinum in selected zones of the kidney are expressed
as pg/gm dry weight. Fisher 344 rats received a single intraperitoneal injection of 6 mgkg body weight
of cis-platinum(CP).
*P < .005 **P< .01; ***P < ,025when compared to control values.
weeks resulted in massive tubular dilation in the corticomedullary region of the kidney, interstitial fibrosis,
glomerular fibrosis, and thickening of the tubular basement membranes. Goldstein and Safirstein (1981) also
showed that repeated injections of this drug produced a
model of tubulo-interstitial disease characterized by reduced glomerular filtration, renal blood flow, and urinary concentrating ability. More recently, Bulger and
Dobyan (1984) described the development of hyperplastic lesions of the proximal tubular epithelium and of the
papillary epithelium in rat kidneys at 6 and 15 months
after cis-platinum injection. This present study documents and quantitates structural and functional changes
in the kidneys 15 months after a single injection of cisplatinum. Glomerular filtration rate and urinary osmolality were markedly depressed and the extent of pathological lesions was significantly greater in animals
injected with platinum compared to age-related controls.
These pathological changes involved all areas of the
cortex and outer stripe regions implying more extensive
damage than at previous time intervals when injury
was largely confined to the corticomedullary zone (Dobyan et al., 1981; Choie et al., 1981). It appears then
that cis-platinum induces chronic renal injury which is
associated with marked structural and functional impairment. This is of particular relevance to patients
receiving cis-platinum thereapy for treatment of various
malignancies.
The reason for the chronicity of cis-platinum toxicity
may possibly be explained by the fact that the kidney
represents the major storage depot and the prinicpal
excretory organ for cis-platinum. Litterst and co-workers (1976, 1977) showed that after a n intravenous dose
of cis-platinum greater than 50%of the dose is excreted
into the urine within 4 hours and by 48 hours 80%had
been eliminated. Despite this rapid removal by the kidney, Litterst and co-workers (1976) and Choie and colleagues (1981) could still detect platinum in the kidneys
of rats for up to 14 days after drug administration.
Tissue levels of platinum were measured in different
regions of the kidney as a function of time after drug
exposure in the present study. Platinum could be detected in the cortical and outer stripe region for as long
as 1 month after drug administration. This retention of
platinum by the kidney may account for the long-term
pathological effects seen in this and other studies. It
should be noted, however, that by 2 months there was
no increase in platinum levels in spite of continued
toxicity.
The mechanism by which platinum is sequestered by
the kidney, and in particular the S3 segment of the
proximal tubule, is only now being evaluated. Safirstein
and colleagues (1984) recently demonstrated that renal
tissue slices accumulate platinum in vitro to up to fivefold above medium concentration. This uptake was energy dependent and could be partially inhibited by drugs
which compete for the transport of organic bases. These
same investigators (1984) used autoradiography and
showed that platinum was preferentially localized in the
pars recta segment of the proximal tubule, the principal
site of acute injury in the kidney. On the basis of these
studies, they suggested that cis-platinum accumulation
in the proximal tubule may in part be through the
organic base transport system of the kidney.
In this study, renal cysts were observed in greater
than 50% of the animals which were treated with cisplatinum (four of seven). At 15 months, however, the
number of cysts was not as large as seen a t 6 months
(Dobyan et al., 1981). The extent of total injury to the
kidney, such as nephron loss, atrophic and hyperplastic
tubules, and chronic inflammation, however, was considerably more extensive and correlated with declining
renal function a t 15 months. A number of recent studies
evaluating chronic dialysis patients as well as renal
transplant recipients have suggested that acquired cystic disease may be regarded as a premalignant condition. Dunnill and co-workers (1977), Ishikawa and coworkers (1980),and Hughson and colleagues (1980)have
reported a significantly high incidence of adenomas and
adenocarcinomas in patients with acquired cystic disease after long-term hemodialysis. In this respect, it is
interesting to note that Bulger and Dobyan (1984) reported hyperplastic nodules which were apparently derived from altered proximal tubular epithelium 6 and
15 months after cis-platinum administration. These lesions were markedly similar to tumors produced by a
variety of carcinogenic agents such as N-(4’-fluoro-4biphenyl) acetamide, aflatoxin B l , dimethylnitrosamine, and lead acetate (Boyland et al., 1962; Riopelle
and Jasmin, 1969; Hard and Butler, 1971; McGiven and
LONG-TERM EFFECTS OF (XLPLATINUM ON KIDNEY
Ireton, 1972; Merkow et al., 1973; Dees et al., 1976,
1980). It is tempting to suggest that cis-platinum may
be mutagenic and that cyst formation in this experimental model may predispose to the development of tumors.
In this regard, Choie and colleagues (1980) measured
the subcellular localization of platinum in rat kidneys
and showed a significantly higher affinity for nuclei and
microsomes. Since cis-platinum is known to interact with
DNA in various mammalian cells presumably through
intra- and interstrand chain crosslinking (Zwelling et
al., 19791, it seems plausible to suggest that this drug
may affect normal macromolecular synthetic processes
such as normal DNA replication. It is interesting to note
that Safirstein and colleagues (1984) have shown that
cis-platinum can induce bacterial mutagenesis.
In summary, cis-platinum can lead to significant
chronic renal injury characterized by reduced renal
function and marked alterations in structure. The observation of cystic lesions and hyperplastic nodules raises
the possibility that this antineoplastic drug may be
mutagenic.
245
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ACKNOWLEDGMENTS
chronic hemodialysis patients. Clin. Nephrol., 14:l-6.
A.J., C. Helson, and I.H. Krakoff (1973)Clinical trials of cisThis work was supported in part by a grant from the Lippman,
diamminedichloroplatinum 11. Cancer Chemother. Rep., 57:191National Institutes of Health (AM26134) and by a grant
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from the American Cancer Society PDT-771.’The author Litterst, C.L., T.E. Gram, R.L. Dedrick, R.L. Leroy, and A.M. Guarino
(1976) Distribution and deposition of platinum following I.V.
would like to thank Ms. Linda S. Magill and Ms. Lena
administration of cis-diamminedichloroplatinum(m to dogs. CanWallach for their excellent technical and secretarial
cer Res. 36:2340-2344.
assistance.
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