Long-term consequences of cis-platinum-induced renal injuryA structural and functional study.код для вставкиСкачать
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 Dobyan, D.C., J. Levi, C . Jacobs, J. Kosek, and M.W. Weiner (1980) Mechanism of cis-platinum nephrotoxicity: 11. Morphologic observations. J. Pharmacol. Exp. Ther., 213:551-556. Dobyan, D.C., D. Hill, T. Lewis, and R.E. Bulger (1981)Cyst formation in rat kidney induced by cis-platinum administration. Lab. Invest., 45260-268. Dunnill, M.S., P.R. Millard, and D. Oliver (1977) Acquired cystic disease of the kidneys: A hazard of Iong-term intermittent maintenance of haemodialysis. J. Clin. Pathol., 302368-877. Fuhr, J., J. Kaczarcgyk, and C.D. Kruttgen (1955)Eine einfache Colorometrishe Method zur Inulinbestimmung fur Nieren-clearanceuntersuchungen bei Stoffwech-zelgesunden un Diabetikern. Klin. Wochensch., 33:729-735. Goldstein, M.H., and R. Safirstein (1981)Functional characteristics of chronic tubulo-interstitial disease after repeated doses of cisplatin. Abstr., 8th Int. Congr. Nephrol. Athens, p. 229. Gottlieb, J.A., and B. Drewinko (1975) Review of the current clinical status of platinum coordination complexes in cancer chemotherapy. Cancer Chemother. Rep., 59:621-628. Hard, G.C., and W.H. Butler (1971) Ultrastructural aspects of renal adenocarcinoma induced in the rat by dimethylnitrosamine. Cancer Res. 31:366-372. Huehson. M.D.. G.R. Hennipar. and J.F.A. McManus (1980) Atypical cysts, acquired renal cystic ’disease, and renal cell tumors & end stage dialysis kidneys. Lab. Invest., 42:475-480. Ishikawa, I., Y. Saito, 2. Onouchi, H. Kitada, S. Suzuki, S. Kurihara, T. Yuri, and A. Shinoda (1980) Development of acquired cystic disease and adenocarcinoma of the kidney in glomerulonephritic 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 200. 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. 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