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Urinary Tract Toxic Effects of Cancer Therapy
0022-534 7/84/1321-0001$02.00/0 THE JOURNAL OF UROLOGY
Vol.
Copyright© 1984 by The Williams & Wilkins Co.
Review Article URINARY TRACT TOXIC EFFECTS OF CANCER THERAPY ITZHAK D. GOLDBERG, MARC R GARNICK
AND
WILLIAM D. BLOOMER
From the Departments of Radiation Therapy and Medicine, Harvard Medical School, Joint Center for Radiation Therapy, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts, and Department of Radiotherapy, Mount Sinai School of Medicine, New York, New York
It is essential to preserve normal function of the urinary tract during and after treatment for cancer. Preservation has become increasingly difficult because cancer patients are exposed to a growing number of potential nephrotoxins with current modes of therapy. Antineoplastic and antimicrobial agents as well as radiation treatment can cause renal damage, and combined radiation therapy and chemotherapy may have synergistic toxic effects. In addition, tumor infiltration, obstructive uropathy and metabolic derangements associated with the primary tumor already may have compromised renal function before initiation of treatment. 1• 2 We discuss renal tolerance to irradiation and selected chemotherapeutic agents in terms of clinical signs and symptoms, pathophysiological findings and treatment. Ureteral and bladder injuries, which occur less frequently than renal injuries, also are discussed briefly.
phy and progressive interstitial fibrosis. There is a relative lack of inflammatory cell infiltrate. Physiological changes. Although renal function tests show no consistent changes with doses ~2,400 rad bilaterally early alterations (approximately 12 months after radiation) in glomerular filtration rate, renal plasma flow and tubular excretory capacity have been reported by Avioli and associates. 10 In their study glomerular filtration rate decreased transiently after 400 rad, was normal or slightly elevated after 1,625 rad and decreased with higher doses. Renal plasma flow decreased consistently after 400 to 750 rad. Tubular function as measured by para-aminohippurate was not reduced consistently until higher doses of radiation were delivered. Despite decreases in glomerular filtration rate and renal plasma flow to values as low as 40 per cent of control values all patients were normal clinically. Clinical syndromes. Acute radiation nephritis is characterized by signs and symptoms of renal and cardiovascular dysfunction, and is related temporally to exposure of the kidneys to therapeutic radiation. 5- 10 Unfortunately, there is no good clinical dose-response curve for radiation renal damage. The threshold dose appears to be >2,000 rad. However, the biologically effective radiation dose also is a function of the daily fraction size and over-all interval, the latter being far less important. Because of gut tolerance the daily fraction size administered to the kidneys is usually not >200 rad. Acute clinical changes occur 6 to 12 months after treatment and do not develop unless 2,300 to 2,500 rad have been delivered bilaterally to the entire kidney. Pedal edema, dyspnea on exertion, headache and nocturia are accompanied by hyperten sion, cardiac enlargement, anemia and proteinuria. The syndrome can progress to hypertensive encephalopathy and chronic renal failure, and is related pathophysiologically to the hypertension component. Patients who suffer malignant hypertension have a poor prognosis. The etiology of the hypertension may be related initially to alterations in the juxtaglomerular apparatus and increased vascular sensitivity, which perpetuate the cycles of hypertension and renal damage. 4 Normochromic, normocytic anemia may be present as part of this syndrome and is also a poor prognostic sign. 3 Although the initial manifestations of renal damage often are managed successfully the damage is probably irreversible. Of 20 patients with acute radiation nephritis reviewed by Luxton and Kunkler 6 of 8 with malignant hypertension died of the syndrome in 3 to 12 months, and 10 of the 20 patients eventually died. 7 The fatal cases showed a combination of hypertensive encephalopathy, left ventricular failure, congestive heart failure and uremia. The early deaths were caused by hypertensive disease and the later deaths by uremia. Full recovery rarely occurs after acute radiation nephritis and patients who survive the acute phase generally are left with decreased renal function that progresses to chronic radiation nephritis.
RENAL TOLERANCE TO RADIATION THERAPY
The response of the normal kidney to irradiation can be classified according to histologic and physiologic changes, and clinical sequelae. 3- 9 Although the majority of patients treated with radiation therapy in the abdominal and retroperitoneal areas do not manifest overt kidney damage clinically, sequential functional and pathological alterations do occur. Histological changes. Most animal and human data indicate that fractionated doses of 1,000 to 2,000 rad to the kidney in 2 to 3 weeks do not produce any sustained pathological abnormalities. 3 With doses of 2,300 to 2,500 rad in 4 to 5 weeks early histopathological changes can be detected and have been termed nephroglomeruloendotheliosis. 4 The changes are diffuse, and initially affect the endothelium and afferent arterioles of the glomerulus. Endothelial swelling accompanied by hyaline deposition in the intimal and medial layers of arterioles leads to swelling of glomerular capillaries, edema and, eventually, occlusive changes in the capillary loops. An occasional tubule may become atrophic but the major lesions involve the afferent arterioles and glomerular endothelium. Although most of the changes are reversible at these dose levels some nephrons are damaged permanently. These nephrons may be forerunners of the patchy parenchymal lesions seen in late radiation nephritis. The late histological manifestations ofradiation injury, many of which are related to the development of hypertension, resemble closely the changes associated with arteriolar nephrosclerosis, chronic glomerulonephritis and pyelonephritis. Late radiation nephrosclerosis constitutes a specific entity4 and is characterized by reduced renal parenchymal mass, capsular thickening and fibrosis associated with a pebbled renal surface. Vascular changes include prominent and sclerotic interlobular and arcuate arteries, hyalinization and occlusion of afferent arterioles, occlusion of glomerular capillary loops with hyalinization and prominent mesangial cells, and necrosis of efferent arterioles and interstitial capillaries with resulting tubular atro1
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GOLDBERG, GARNICK AND BLOOMER
The chronic form of radiation nephritis usually occurs after the patient has been asymptomatic for 6 to 18 months. However, some patients will have symptomatic renal failure without a latent interval. Chronic nephritis may be insidious, since a history of acute nephritis is not a prerequisite for chronic radiation nephritis. Clinical estimates of renal tolerance are based on previous findings in which changes were observed in patients who received large field abdominal irradiation for testicular malignancies. 5-7 When doses of 2,500 to 3,250 rad were delivered in 3 to 6 weeks bilaterally to the entire kidney 40 per cent of the patients had renal damage and 13 per cent died. Of those patients who survived with radiation nephritis the majority suffered chronic glomerulonephritis. Asymptomatic intermittent proteinuria can be observed years after renal irradiation. Standard renal function tests are often normal but such patients may have mildly impaired renal reserve and occasional elevation of the blood urea nitrogen (BUN). Although hypertension may be present it is not a necessary accompaniment. Some patients may be normotensive for years and complain only of lack of energy and nocturia. In the series of Luxton, 6 and Luxton and Kunkler7 9 of 24 patients with chronic radiation nephritis had normal blood pressure for an average of 8 years. Some patients who otherwise are asymptomatic may have a benign form of hypertension accompanied by variable proteinuria 6 to 12 months after irradiation. Although most of these patients do well a few may suffer malignant hypertension years later. Malignant hypertension can be fatal in a few weeks if hypertensive encephalopathy and brain stem hemorrhage develop. There may be associated papilledema, retinitis and an increase in BUN. However, in patients with known chronic radiation nephritis or benign essential hypertension malignant hypertension may develop insidiously. Treatment. Before dialysis or kidney transplantation came into general clinical practice the natural history of radiation nephritis was progressive renal failure and death. However, the majority of patients recovered but with varying degrees of residual hypertension and diminished renal function. If the hypertension is related to unilateral renal damage surgical removal of the diseased kidney may result in clinical improvement.1 The best treatment is prevention, that is adequate renal localization at the time of radiation treatment planning, and limitation of dose and volume. The threshold for irreparable damage to both kidneys resulting in a clinical syndrome of renal failure has not been defined clearly. 5-7 However, 2,000 rad in 10 fractions during 2 weeks generally is regarded as a safe treatment plan, although it is not uncommon to exceed this dose to 1 kidney in the treatment of upper abdominal malignancy. Provided the dose to 1 kidney is not >2,000 rad in 10 fractions the dose to the contralateral kidney is limited only by gastrointestinal tolerance. Since the kidney that received 2,000 rad will continue to function the injury to the contralateral kidney usually will not result in clinical manifestations of renal failure. Further definitions of renal tolerance are conjectural. Combined modality therapy. It presently is well known that actinomycin D and other chemotherapeutic agents enhance radiation damage in combined modality therapy. In several studies radiation nephritis occurred at lower radiation doses when chemotherapeutic agents were used concurrently. 11- 13 Although the increased toxicity could not be expressed quantitatively the oncologist should be aware of this potential danger with actinomycin D and other drugs. 14 URETERAL TOLERANCE
Ureteral injuries secondary to radiation therapy are rare and usually occur as sequelae to treatment for cervical cancer. Ureteral injuries generally consist of strictur~s at the ureterovesical junction and occur 6 to 12 months after treatment. 15· 16 This site receives a high dose of irradiation when external beam irradiation has been combined with intracavitary radium ap-
plication. Sequential excretory urography at yearly intervals for 2 to 3 years should be obtained routinely in patients treated for cervical cancer to evaluate possible obstruction. The major differential diagnosis when ureteral obstruction is demonstrated in these patients is recurrent tumor. The rare diagnosis of radiation-induced injury often must be established by laparotomy. The simplest treatment for these injuries is a temporary ureteral stent but reimplantation or diversion may be necessary. Nephrostomy should be reserved for patients with renal pelvic distension, sepsis with hydronephrosis or advancing uremia. Urinary diversion in the face ofrecurrent tumor should be done only after careful assessment of the disability and life expectancy. BLADDER TOLERANCE
Acute radiation cystitis develops after external beam radiation doses of ~3,000 rad. Dysuria, frequency and nocturia are characteristic symptoms, while diffuse hemorrhage is rare. Cystoscopic findings vary with the severity of the reaction but hyperemia and occasional petechiae are early findings. These acute symptoms are usually self-limiting and are treated best symptomatically with phenazopyridine hydrochloride or oxybutynin hydrochloride, a reduction in daily dose fraction size or a short break in treatment. Chronic radiation cystitis develops 4 to 12 months after irradiation but longer intervals free of symptoms are not uncommon. Painless hematuria with or without hemorrhage is the classical presentation. The recurrence and severity of these late complications are not necessarily related to the severity of acute symptoms or the radiation dose (if <7,000 rad external beam irradiation or 10,000 mg. hours of radium exposure). 17 The incidence of late bladder injuries is <5 per cent in patients treated with radiation alone for cervical carcinoma. 15·17·18 Cystoscopy reveals tuft-like or tortuous blood vessels with erythema, bullous edema at sites of inflammation or bleeding ulceration. Otherwise, the epithelium usually is pale and atrophic, and has a fine telangiectatic pattern. Histologically, interstitial fibrosis and endarteritis obliterans are the predominant lesions. Hyalinization of the muscularis with fibrosis and vascular sclerosis also are common. Bladder contraction is more likely when an operation has been performed in conjunction with irradiation. 18· 19 RENAL TOLERANCE TO CHEMOTHERAPY
A variety of chemotherapeutic agents can be toxic to the kidney. 1· 20 As the list of new chemotherapeutic agents grows the clinician must monitor patients carefully for serious side effects. The common antineoplastic agents can induce renal injury by themselves and can act synergistically with radiation therapy. The concomitant presence of hypercalcemia, 21 hyperuricemia22 or urinary obstruction 23 may enhance renal damage further. A description of the more common chemotherapeutic agents follows. Cis-platinum. Cis-diamminedichloroplatinum (II) (cis-platinum) has a broad spectrum of antineoplastic activity. The compound has become a major component of combination chemotherapy programs. 24· 25 However, nephrotoxicity is the most serious side effect. Cis-platinum nephrotoxicity has been studied in a variety of small and large animals. 26 Morphologic alterations include degeneration of epithelial cells and necrosis of proximal tubules. Although glomerular damage is rare proteinuria is common. Physiologically, cis-platinum induces an uncoupling of the process of oxidative phosphorylation in mitochondria and disrupts the energy production of proximal tubular cells shortly after drug administration. 27 Additional abnormalities include defects in medullary accumulation of solutes that affect the ability to concentrate urine28 and lead to renal insensitivity to vasopressin in the collecting tubule. 29
URINARY TRACT TOXIC EFFECTS OF CANCER THERAPY
In pharmacologic studies an intravenous bolus of cis-platinum yields an a-half-life of 25 to 49 minutes, with a {3-half-life of 58 to 73 hours; 90 per cent of the drug binds to albumin, gamma globulin or transferrin. Urinary excretion accounts for 27 to 50 per cent of drug elimination, usually ~5 days after administration. Patients with renal insufficiency have a prolonged {3-half-life. Tissue distribution studies have shown that after cis-platinum administration the highest levels are seen immediately in the plasma and kidney, followed by the gonadal tissue. Levels in the renal medulla and renal cortex have persisted for >6 or 7 days in animal and human studies. 30-33 Renal biopsies in man show a variety of acute histopathological changes, such as renal cortical swelling, medullary congestion and focal, coagulative necrosis of the distal convoluted tubules and collecting ducts. 34 Dilatation of the convoluted segments in the distal tubule, atypical epithelial cells with syncytial nuclei and granular casts also have been noted. However, these changes are not pathognomonic for a specific lesion. Serial determinations of serum creatinine and glomerular filtration rate demonstrate transient decreases in glomerular filtration rate but full recovery usually occurs by day 21. 35 These studies were conducted after saline hydration had been instituted. When cis-platinum was introduced initially as a phase I agent nephrotoxicity seemed to be the dose-limiting side effect. The incidence of renal damage in patients receiving the drug was 50 to 100 per cent regardless of the dose of schedule. Renal biopsies revealed acute tubular necrosis, tubular degeneration and interstitial edema, and fatal acute renal failure occurred in some patients. From these early studies it was concluded that renal toxicity probably was cumulative. Furthermore, nephrotoxicity seemed to be most profound 3 weeks after drug administration. However, it later became evident that inadequate attention was paid to patient hydration. 20 In the early phase I studies when hydration was not monitored adequately the incidence of nephrotoxicity was 50 to 100 per cent, while in later studies with the use of adequate hydration the incidence ranged between 6 and 13 per cent. 35-44 Whether diuretics or mannitol infusion added to saline hydration alone is beneficial has not been determined adequately. A variety of hydration schedules have been used, including infusion of 3 to 6 1. normal saline per day with or without diuretics, such as mannitol or furosemide. Extracellular fluid volume expansion with saline hydration plus accompanying diuretic administration and rate of drug administration have contributed to a decreased incidence of nephrotoxicity. Many schedules appear equivalent in the ability to prevent nephrotoxicity provided that hydration status is monitored closely and adequate urinary output is maintained. 20 Some investigators suggest the addition of mannitol or loop diuretics to the hydration schedule. The prominent nephrotoxic effect of cis-platinum has been renal magnesium wasting. In 1 series of 44 evaluable patients, 7 of whom were followed prospectively, hypomagnesemia induced by cis-platinum occurred in 23, including 2 who required hospitalization because of symptoms. 45 Magnesium wasting is managed easily with oral magnesium chloride. Magnesium levels should be measured frequently in patients receiving cis-platinum. A variety of other pharmacologic agents have been studied to determine their usefulness in modulating the nephrotoxicity of cis-platinum. In pre-clinical animal studies probenecid, 46 the radioprotective agent WR 2721, 47 diethyldithiocarbamate 48 and sodium thiosulfate 49 • 50 all have shown some efficacy in diminishing renal damage. Methotrexate. Methotrexate, one of the most common chemotherapeutic agents, ordinarily is excreted by the kidneys. In the face of compromised renal function serum levels of methotrexate remain elevated and bone marrow depression, mucositis and dermatitis ensue. Nephrotoxicity is rare after conventional doses in patients with previously normal renal function.
3
However, in 1 series of 13 patients with advanced cancer conventional doses resulted in elevated BUN levels in 5 patients.51 Of these 5 patients 2 died of persistent azotemia. At autopsy 1 patient had direct renal tubular damage characterized by extensive necrosis of the convoluted tubular epithelium. In the past higher doses of methotrexate were used routinely in patient management (1 to 7.5 gm./M. 2). 52 Currently, high dose methotrexate is approved for advanced nonHodgkin's lymphoma and may be used for other tumors. Nephrotoxicity is a prominent side effect of high doses of methotrexate and occasionally has limited the usefulness of the drug. Although the exact pathogenesis of methotrexate-induced renal failure has not been delineated fully several mechanisms have been proposed, including precipitation of the antifole in the renal tubules, a direct toxic effect of methotrexate on renal tubules and a direct effect on glomerular filtration rate. 20 In earlier clinical studies that evaluated the effects of high doses of methotrexate the hydration and extracellular fluid volume of patients were not assessed well. A survey of several early studies shows that serum creatinine was >50 per cent above baseline values in 60 per cent of the patients 24 hours after administration of high doses of the drug. Of 33 patients in these studies 3 died of acute renal failure. 53 Postmortem examination of kidneys demonstrated bilateral renal enlargement, methotrexate precipitation in the tubules and native methotrexate within the renal parenchymal tissue (see figure). When vigorous urinary alkalization and hydration programs were used the incidence of nephrotoxicity was much less. Only 17 per cent of the patients had serum creatinine increases of 50 to 100 per cent above baseline and only 3 per cent had
Kidney biopsy from patient treated with 3 gm./M. 2 methotrexate followed by citrovorum factor rescue who suffered dehydration and acute renal failure. Tissue demonstrates methotrexate precipitation in renal tubule. Fluorescent rabbit antimethotrexate antibody stain. Reprinted with permission. 1
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GOLDBERG, GARNICK AND BLOOMER
increases > 100 per cent above baseline. Most programs with high dose methotrexate use saline hydration as well as urinary alkalization to a pH >7. A critical evaluation of the relative merits of hydration versus alkalization is lacking. The Dana Farber Cancer Institute in Boston has had extensive experience with high doses of methotrexate. Moderate or severe nephrotoxicity developed in only 7 per cent of the patients. 52 Our over-all treatment plan to prevent methotrexate-induced renal toxicity includes 1) basal glomerular filtration rate and serum creatinine, 2) vigorous patient hydration with 3 to 5 I. 5 per cent dextrose in water containing 60 mEq./ I. sodium bicarbonate to obtain a urinary pH of 7.0 (hydration generally begins 12 to 14 hours before infusion and continues for 2 to 3 days afterward), 3) repeat serum creatinine determination 24 hours after methotrexate infusion, 4) continuation of citrovorum factor at regular doses if serum creatinine is ~50 per cent above the baseline level, which usually indicates renal toxicity, until the methotrexate level decreases to <7.5 X 10-7 M. (hydration and alkalization should be maintained during this period) and 5) maintenance of hydration and alkalization in addition to increase of citrovorum factor 10-fold from 15 to 150 mg. every 3 hours if serum creatinine increases to ~100 per cent (acute renal failure). 2° Consideration also should be given to the addition of thymidine. 54 These supportive measures should be continued until the serum methotrexate level is <10-8 M. and serum creatinine is normal, which can take 30 to 60 days. A more detailed discussion of biochemical rescue techniques is available in the literature. 20 Nitrosoureas. Streptozotocin: The nitrosourea streptozotocin has been used for a variety of malignancies, such as metastatic islet cell carcinoma of the pancreas and carcinoid tumors. 55 · 56 Pre-clinical studies of animal toxicity have shown that nephrotoxicity is a prominent side effect and that streptozotocin may induce renal tumors in several species. 57 - 59 A variety of nonspecific pathological changes also have been noted, including vacuolization and periodic acid, Schiff positivity in the proximal tubular cells, and mitochondrial disruption. 56 Several renal and metabolic abnormalities have been reported after the use of streptozotocin in man and some appear to be related to the dose and schedule of administration. Nephrotoxicity is the principal side effect that limits the usefulness of this drug. Fanconi's syndrome, hypophosphatemia, glycosuria, proteinuria, renal tubular acidosis, hypokalemia and nephrogenic diabetes insipidus occur fairly frequently. 20 ·60 Hypophosphatemia and proteinuria usually are the first manifestations of renal toxicity and, when they occur, renal status must be examined before additional doses of the drug are administered. However, most worrisome is the development of azotemia, elevated serum creatinine and diminished creatinine clearance, which occur in 20 to 40 per cent of the patients treated during a prolonged interval. Life-threatening or fatal renal failure has occurred in approximately 5 per cent of the patients reported on in the literature. In patients who died acute tubular necrosis was demonstrated at autopsy. Although a variety of schedules have been used with varying success the most common method consists of 1.5 gm./M. 2 (body surface area) per week or 0.5 gm./M. 2 for 5 days, repeated every 6 weeks. Streptozotocin is not recommended in patients with preexisting renal dysfunction. 1- (2 - chloroethyl)- 3 - (4 - methylcyclohexyl) -1- nitrosourea (methyl-CCNU): Methyl-CCNU recently has been identified as a potential nephrotoxin in children61 · 62 and adults 63 who have been treated for a variety of neoplasms. In 1 study the development of chronic renal failure was reported in 6 children who received >1,500 mg./M. 2 methyl-CCNU, which usually was given within 17 months. 62 In a review from the Mayo Clinic nephrotoxicity was reported in 2.1 per cent of 857 consecutively studied adults treated with methyl-CCNU either as a single agent or in combination chemotherapy programs. 63 The major manifestation of methyl-CCNU nephrotoxicity is
a decrease in renal size. Pathologically, the most prominent renal changes consist of glomerular sclerosis with thickening of the glomerular basement membrane and severe nephron loss. Other changes include interstitial fibrosis and cellular infiltration. The lesion of nitrosourea nephrotoxicity may resemble that of radiation nephropathy but the clinical syndromes are different. Although recommendations regarding the use of nitrosoureas cannot be made with certainty, it seems prudent to limit the use of methyl-CCNU to doses <1,200 mg./M. 2 and to treatment courses of <1 year. Obviously, patients who undergo such therapy should have serial renal ultrasound examinations and periodic determinations of renal function. Therapy should be terminated at the first sign of decrease in renal size. 1,3 Bischloro (2 chloroethyl)-1-nitrosourea seems to have similar nephrotoxic effects as methyl-CCNU. Limited data are available for chloroethyl cyclohexylnitrosourea. Other agents. Recent studies have suggested a possible association between mitomycin C and subsequent nephrotoxicity. Patients on chronic therapy with mitomycin C, especially those on combination programs that contain a nitrosourea, should be followed closely for the development of nephrotoxicity. 64 Other renal-related toxicities of mitomycin C include a symptom complex consistent with the hemolytic uremic syndrome. 65 Mithramycin has caused nephrotoxicity when used as an anticancer agent in patients with germ cell carcinoma of the testis. 66 Renal function also should be monitored carefully in patients receiving low doses of mithramycin for the management of malignant hypercalcemia, since abnormalities in renal function may occur even with these lower doses. Azacytidine has been associated with renal tubular dysfunction, and a spectrum of proximal and distal tubular abnormalities.67 However, a clear relationship between this drug and the development of nephrotoxicity has not been well established. Other agents, such as doxorubicin hydrochloride 68 and cancer immunotherapy with Corynebacterium parvum, and interferon, have been associated with a spectrum of renal abnormalities in case reports. REFERENCES 1. Garnick, M. B. and Mayer, R. J.: Acute renal failure associated with neoplastic disease and its treatment. Sem. Oneal., 5: 155, 1978. 2. Richie, J.P. and Garnick, M. B.: Primary renal and ureteral cancer. In: Cancer and the Kidney. Edited by R. E. Rieselbach and M. B. Garnick. Philadelphia: Lea & Febiger, pp. 662-706, 1982. 3. Maier, J. G.: Effects of radiations on kidney, bladder and prostate. Front. Rad. Ther. Oneal., 6: 196, 1972. 4. White, D. C.: The histopathologic basis for functional decrements in late radiation injury in diverse organs. Cancer, suppl. 2, 37: 1126, 1976. 5. Kunkler, P. B., Farr, R. F. and Luxton, R. W.: The limit of renal tolerance to x-rays: an investigation into renal damage occurring following the treatment of tumours of the testes by abdominal baths. Brit. J. Rad., 25: 190, 1952. 6. Luxton, R. W.: Radiation nephritis. Quart. J. Med., 22: 215, 1953. 7. Luxton, R. W. and Kunkler, P. B.: Radiation nephritis. Acta Rad., 2: 169, 1964. 8. Rubenstone, A. I. and Fitch, L. B.: Radiation nephritis. A clinicopathologic study. Amer. J. Med., 33: 545, 1962. 9. Levitt, W. M.: Radiation nephritis. Brit. J. Ural., 29: 381, 1957. 10. Avioli, L. V., Lazor, M. Z., Cotlove, E., Broce, K. C. and Andrews, J. R.: Early effects of radiation on renal function in man. Amer. J. Med., 34: 329, 1963. 11. Sagerman, R.H.: Radiation nephritis. J. Ural., 91: 332, 1964. 12. Cassady, J. R., Tefft, M., Filler, R. M., Jaffe, N., Paed, D. and Hellman, S.: Considerations in the radiation therapy of Wilms' tumor. Cancer, 32: 598, 1973. 13. Arneil, G. C., Harris, F., Emmanuel, I. G., Young, D. C., Flatman, G. E. and Zachary, R. B.: Nephritis in two children after irradiation and chemotherapy for nephroblastoma. Lancet, 1: 960, 1974. 14. Churchill, D. N., Hong, K. and Gault, M. H.: Radiation nephritis following combined abdominal radiation and chemotherapy
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57. 58. 59.
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Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer, 33: 1219, 1974. Talley, R. W., O'Bryan, R. M., Gutterman, J. U., Brownlee, R. W. and McCredie, K. B.: Clinical evaluation of toxic effects of cisdiamminedichloroplatinum (NSC-119875)-phase I clinical study. Cancer Chemother. Rep., 57: 465, 1973. Wiltshaw, E. and Kroner, T.: Phase II study of cis-dichlorodiammineplatinum(II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat. Rep., 60: 55, 1976. Chary, K. K., Higby, D. J., Henderson, E. S. and Swinerton, K. D.: Phase I study of high-dose cis-dichlorodiammineplatinum(II) with forced diuresis. Cancer Treat. Rep., 61: 367, 1977. Merrin, C., Beckley, S. and Takita, H.: Multimodal treatment of advanced testicular tumor with radical reductive surgery and multisequential chemotherapy with cis platinum, bleomycin, vinblastine, vincristine and actinomycin D. J. Urol., 120: 73, 1978. Einhorn, L. H. and Donohue, J.: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann. Intern. Med., 87: 293, 1977. Garnick, M. B., Canellos, G. P., Richie, J. P. and Stark, J. J.: Sequential combination chemotherapy and surgery for disseminated testicular cancer: cis-dichlorodiammineplatinum(II), vinblastine, and bleomycin remission-induction therapy followed by cyclophosphamide and adriamycin. Cancer Treat. Rep., 63: 1681, 1979. Young, R. C., Von Hoff, D. D., Gormley, P., Makuch, R., Cassidy, J., Howser, D. and Bull, J. M.: cis-Dichlorodiammineplatinum(II) for the treatment of advanced ovarian cancer. Cancer Treat. Rep., 63: 1539, 1979. Rosoff, A. H., Slayton, R. E. and Perlia, C. P.: Preliminary clinical experience with cis-diamminedichloroplatinum (II) (NCS 119875, CACP). Cancer, 30: 1451, 1972. Schilsky, R. L. and Anderson, T.: Hypomagnesemia and renal magnesium wast'ing in patients receiving cisplatin. Ann. Intern. Med., 90: 929, 1979. Ross, D. A. and Gale, G. R.: Reduction of the renal toxicity of cisdichlorodiammineplatinum(II) by probenecid. Cancer Treat. Rep., 63: 781, 1979. Yuhas, J.M. and Culo, F.: Selective inhibition of the nephrotoxicity of cis-dichlorodiammineplatinum(II) by WR-2721 without altering its antitumor properties. Cancer Treat. Rep., 64: 57, 1980. Borch, R. F. and Pleasants, M. E.: Inhibition of cis-platinum nephrotoxicity by diethyldithiocarbamate rescue in a rat model. Proc. Natl. Acad. Sci., 76: 6611, 1979. Howe!, S. B. and Taetle, R.: Effect of sodium thiosulfate on cisdichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia. Cancer Treat. Rep., 64: 611, 1980. Howe!, S. B., Pfeifle, C. E., Wung, W. E. and Olshen, R. A.: Intraperitoneal chemotherapy with cisplatin (DDP). Proc. Amer. Soc. Clin. Oncol., abstract C-107, 1: 27, 1982. Condit, P. T., Chanes, R. E. and Joel, W.: Renal toxicity of methotrexate. Cancer, 23: 126, 1969. Frei, E., III, Blum, R. H., Pitman, S. W., Kirkwood, J. M., Henderson, I. C., Skarin, A. T., Mayer, R. J., Bast, R. C., Garnick, M. B., Parker, L. M. and Canellos, G. P.: High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity. Amer. J. Med., 68: 370, 1980. Pitman, S. W. and Frei, E., III: Weekly methotrexate-calcium leucovorin rescue: effect of alkalinization on nephrotoxicity; pharmacokinetics in the CNS; and use in CNS non-Hodgkin's lymphoma. Cancer Treat. Rep., 61: 695, 1977. Ensminger, W. D. and Frei, E., III: The prevention of methotrexate toxicity by thymidine infusions in humans. Cancer Res., 37: 1857, 1977. Weiss, R. B.: Streptozocin: a review of its pharmacology, efficacy, and toxicity. Cancer Treat. Rep., 66: 427, 1982. Schein, P., Kahn, R., Gorden, P., Wells, S. and DeVita, V. T.: Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature. Arch. Intern. Med., 132: 555, 1973. Arison, R. N. and Feudale, E. L.: Induction of renal tumour by streptozotocin in rats. Nature, 214: 1254, 1967. Rakieten, N., Gordon, B. S., Cooney, D. A., Davis, R. D. and Schein, P. S.: Renal tumorigenic action of streptozotocin (NSC85998) in rats. Cancer Chemother. Rep., 52: 563, 1968. Myerowitz, R. L., Sartiano, G. P. and Cavallo, T.: Nephrotoxic and cytoproliferative effects of streptozotocin: report of a patient with multiple hormone-secreting islet cell carcinoma. Cancer,
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38: 1550, 1976. 60. Sadoff, L.: Effects of streptozotocin in a patient with islet cell carcinoma. Diabetes, 18: 675, 1969. 61. Avner, E. D. and lngelfinger, J. R.: Special considerations in the pediatric patient. In: Cancer and the Kidney. Edited by R. E. Rieselbach and M. B. Garnick. Philadelphia: Lea & Febiger, sect. I, chapt. 9,pp. 275-302, 1982. 62. Harmon, W. E., Cohen, H. J., Schneeberger, E. E. and Grupe, W. E.: Chronic renal failure in children treated with methyl CCNU. New Engl. J. Med., 300: 1200, 1979. 63. Nichols, W. C. and Moertel, C. G.: Nephrotoxicity of methyl CCNU. New Engl. J. Med., 301: 1181, 1979. 64. Ratanatharathorn, V., Baker, L. H., Cadnapaphornchai, P., Rosenberg, B. F. and Vaitkevicius, V. K.: Clinical and pathologic
65. 66. 67. 68.
study of mitomycin C nephrotoxicity. In: Mitomycin C: Current Status and New Developments. Edited by S. K. Carter and S. T. Crooke. New York: Academic Press, p. 219, 1979. Pavy, M. D., Wiley, E. L. and Abeloff, M. D.: Hemolytic-uremic syndrome associated with mitomycin therapy. Cancer Treat. Rep., 66: 457, 1982. Kennedy, B. J.: Metabolic and toxic effects of mithramycin during tumor therapy. Amer. J. Med., 49: 494, 1970. Peterson, B. A., Collins, A. J., Vogelzang, N. J. and Bloomfield, C. D.: 5-Azacytidine and renal tubular dysfunction. Blood, 57: 182, 1981. Burke, J. F., Jr., Laucius, J. F., Brodovsky, H. S. and Soriano, R. Z.: Doxorubicin hydrochloride-associated renal failure. Arch. Intern. Med., 137: 385, 1977.
Vol.
Copyright© 1984 by The Williams & Wilkins Co.
Review Article URINARY TRACT TOXIC EFFECTS OF CANCER THERAPY ITZHAK D. GOLDBERG, MARC R GARNICK
AND
WILLIAM D. BLOOMER
From the Departments of Radiation Therapy and Medicine, Harvard Medical School, Joint Center for Radiation Therapy, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts, and Department of Radiotherapy, Mount Sinai School of Medicine, New York, New York
It is essential to preserve normal function of the urinary tract during and after treatment for cancer. Preservation has become increasingly difficult because cancer patients are exposed to a growing number of potential nephrotoxins with current modes of therapy. Antineoplastic and antimicrobial agents as well as radiation treatment can cause renal damage, and combined radiation therapy and chemotherapy may have synergistic toxic effects. In addition, tumor infiltration, obstructive uropathy and metabolic derangements associated with the primary tumor already may have compromised renal function before initiation of treatment. 1• 2 We discuss renal tolerance to irradiation and selected chemotherapeutic agents in terms of clinical signs and symptoms, pathophysiological findings and treatment. Ureteral and bladder injuries, which occur less frequently than renal injuries, also are discussed briefly.
phy and progressive interstitial fibrosis. There is a relative lack of inflammatory cell infiltrate. Physiological changes. Although renal function tests show no consistent changes with doses ~2,400 rad bilaterally early alterations (approximately 12 months after radiation) in glomerular filtration rate, renal plasma flow and tubular excretory capacity have been reported by Avioli and associates. 10 In their study glomerular filtration rate decreased transiently after 400 rad, was normal or slightly elevated after 1,625 rad and decreased with higher doses. Renal plasma flow decreased consistently after 400 to 750 rad. Tubular function as measured by para-aminohippurate was not reduced consistently until higher doses of radiation were delivered. Despite decreases in glomerular filtration rate and renal plasma flow to values as low as 40 per cent of control values all patients were normal clinically. Clinical syndromes. Acute radiation nephritis is characterized by signs and symptoms of renal and cardiovascular dysfunction, and is related temporally to exposure of the kidneys to therapeutic radiation. 5- 10 Unfortunately, there is no good clinical dose-response curve for radiation renal damage. The threshold dose appears to be >2,000 rad. However, the biologically effective radiation dose also is a function of the daily fraction size and over-all interval, the latter being far less important. Because of gut tolerance the daily fraction size administered to the kidneys is usually not >200 rad. Acute clinical changes occur 6 to 12 months after treatment and do not develop unless 2,300 to 2,500 rad have been delivered bilaterally to the entire kidney. Pedal edema, dyspnea on exertion, headache and nocturia are accompanied by hyperten sion, cardiac enlargement, anemia and proteinuria. The syndrome can progress to hypertensive encephalopathy and chronic renal failure, and is related pathophysiologically to the hypertension component. Patients who suffer malignant hypertension have a poor prognosis. The etiology of the hypertension may be related initially to alterations in the juxtaglomerular apparatus and increased vascular sensitivity, which perpetuate the cycles of hypertension and renal damage. 4 Normochromic, normocytic anemia may be present as part of this syndrome and is also a poor prognostic sign. 3 Although the initial manifestations of renal damage often are managed successfully the damage is probably irreversible. Of 20 patients with acute radiation nephritis reviewed by Luxton and Kunkler 6 of 8 with malignant hypertension died of the syndrome in 3 to 12 months, and 10 of the 20 patients eventually died. 7 The fatal cases showed a combination of hypertensive encephalopathy, left ventricular failure, congestive heart failure and uremia. The early deaths were caused by hypertensive disease and the later deaths by uremia. Full recovery rarely occurs after acute radiation nephritis and patients who survive the acute phase generally are left with decreased renal function that progresses to chronic radiation nephritis.
RENAL TOLERANCE TO RADIATION THERAPY
The response of the normal kidney to irradiation can be classified according to histologic and physiologic changes, and clinical sequelae. 3- 9 Although the majority of patients treated with radiation therapy in the abdominal and retroperitoneal areas do not manifest overt kidney damage clinically, sequential functional and pathological alterations do occur. Histological changes. Most animal and human data indicate that fractionated doses of 1,000 to 2,000 rad to the kidney in 2 to 3 weeks do not produce any sustained pathological abnormalities. 3 With doses of 2,300 to 2,500 rad in 4 to 5 weeks early histopathological changes can be detected and have been termed nephroglomeruloendotheliosis. 4 The changes are diffuse, and initially affect the endothelium and afferent arterioles of the glomerulus. Endothelial swelling accompanied by hyaline deposition in the intimal and medial layers of arterioles leads to swelling of glomerular capillaries, edema and, eventually, occlusive changes in the capillary loops. An occasional tubule may become atrophic but the major lesions involve the afferent arterioles and glomerular endothelium. Although most of the changes are reversible at these dose levels some nephrons are damaged permanently. These nephrons may be forerunners of the patchy parenchymal lesions seen in late radiation nephritis. The late histological manifestations ofradiation injury, many of which are related to the development of hypertension, resemble closely the changes associated with arteriolar nephrosclerosis, chronic glomerulonephritis and pyelonephritis. Late radiation nephrosclerosis constitutes a specific entity4 and is characterized by reduced renal parenchymal mass, capsular thickening and fibrosis associated with a pebbled renal surface. Vascular changes include prominent and sclerotic interlobular and arcuate arteries, hyalinization and occlusion of afferent arterioles, occlusion of glomerular capillary loops with hyalinization and prominent mesangial cells, and necrosis of efferent arterioles and interstitial capillaries with resulting tubular atro1
2
GOLDBERG, GARNICK AND BLOOMER
The chronic form of radiation nephritis usually occurs after the patient has been asymptomatic for 6 to 18 months. However, some patients will have symptomatic renal failure without a latent interval. Chronic nephritis may be insidious, since a history of acute nephritis is not a prerequisite for chronic radiation nephritis. Clinical estimates of renal tolerance are based on previous findings in which changes were observed in patients who received large field abdominal irradiation for testicular malignancies. 5-7 When doses of 2,500 to 3,250 rad were delivered in 3 to 6 weeks bilaterally to the entire kidney 40 per cent of the patients had renal damage and 13 per cent died. Of those patients who survived with radiation nephritis the majority suffered chronic glomerulonephritis. Asymptomatic intermittent proteinuria can be observed years after renal irradiation. Standard renal function tests are often normal but such patients may have mildly impaired renal reserve and occasional elevation of the blood urea nitrogen (BUN). Although hypertension may be present it is not a necessary accompaniment. Some patients may be normotensive for years and complain only of lack of energy and nocturia. In the series of Luxton, 6 and Luxton and Kunkler7 9 of 24 patients with chronic radiation nephritis had normal blood pressure for an average of 8 years. Some patients who otherwise are asymptomatic may have a benign form of hypertension accompanied by variable proteinuria 6 to 12 months after irradiation. Although most of these patients do well a few may suffer malignant hypertension years later. Malignant hypertension can be fatal in a few weeks if hypertensive encephalopathy and brain stem hemorrhage develop. There may be associated papilledema, retinitis and an increase in BUN. However, in patients with known chronic radiation nephritis or benign essential hypertension malignant hypertension may develop insidiously. Treatment. Before dialysis or kidney transplantation came into general clinical practice the natural history of radiation nephritis was progressive renal failure and death. However, the majority of patients recovered but with varying degrees of residual hypertension and diminished renal function. If the hypertension is related to unilateral renal damage surgical removal of the diseased kidney may result in clinical improvement.1 The best treatment is prevention, that is adequate renal localization at the time of radiation treatment planning, and limitation of dose and volume. The threshold for irreparable damage to both kidneys resulting in a clinical syndrome of renal failure has not been defined clearly. 5-7 However, 2,000 rad in 10 fractions during 2 weeks generally is regarded as a safe treatment plan, although it is not uncommon to exceed this dose to 1 kidney in the treatment of upper abdominal malignancy. Provided the dose to 1 kidney is not >2,000 rad in 10 fractions the dose to the contralateral kidney is limited only by gastrointestinal tolerance. Since the kidney that received 2,000 rad will continue to function the injury to the contralateral kidney usually will not result in clinical manifestations of renal failure. Further definitions of renal tolerance are conjectural. Combined modality therapy. It presently is well known that actinomycin D and other chemotherapeutic agents enhance radiation damage in combined modality therapy. In several studies radiation nephritis occurred at lower radiation doses when chemotherapeutic agents were used concurrently. 11- 13 Although the increased toxicity could not be expressed quantitatively the oncologist should be aware of this potential danger with actinomycin D and other drugs. 14 URETERAL TOLERANCE
Ureteral injuries secondary to radiation therapy are rare and usually occur as sequelae to treatment for cervical cancer. Ureteral injuries generally consist of strictur~s at the ureterovesical junction and occur 6 to 12 months after treatment. 15· 16 This site receives a high dose of irradiation when external beam irradiation has been combined with intracavitary radium ap-
plication. Sequential excretory urography at yearly intervals for 2 to 3 years should be obtained routinely in patients treated for cervical cancer to evaluate possible obstruction. The major differential diagnosis when ureteral obstruction is demonstrated in these patients is recurrent tumor. The rare diagnosis of radiation-induced injury often must be established by laparotomy. The simplest treatment for these injuries is a temporary ureteral stent but reimplantation or diversion may be necessary. Nephrostomy should be reserved for patients with renal pelvic distension, sepsis with hydronephrosis or advancing uremia. Urinary diversion in the face ofrecurrent tumor should be done only after careful assessment of the disability and life expectancy. BLADDER TOLERANCE
Acute radiation cystitis develops after external beam radiation doses of ~3,000 rad. Dysuria, frequency and nocturia are characteristic symptoms, while diffuse hemorrhage is rare. Cystoscopic findings vary with the severity of the reaction but hyperemia and occasional petechiae are early findings. These acute symptoms are usually self-limiting and are treated best symptomatically with phenazopyridine hydrochloride or oxybutynin hydrochloride, a reduction in daily dose fraction size or a short break in treatment. Chronic radiation cystitis develops 4 to 12 months after irradiation but longer intervals free of symptoms are not uncommon. Painless hematuria with or without hemorrhage is the classical presentation. The recurrence and severity of these late complications are not necessarily related to the severity of acute symptoms or the radiation dose (if <7,000 rad external beam irradiation or 10,000 mg. hours of radium exposure). 17 The incidence of late bladder injuries is <5 per cent in patients treated with radiation alone for cervical carcinoma. 15·17·18 Cystoscopy reveals tuft-like or tortuous blood vessels with erythema, bullous edema at sites of inflammation or bleeding ulceration. Otherwise, the epithelium usually is pale and atrophic, and has a fine telangiectatic pattern. Histologically, interstitial fibrosis and endarteritis obliterans are the predominant lesions. Hyalinization of the muscularis with fibrosis and vascular sclerosis also are common. Bladder contraction is more likely when an operation has been performed in conjunction with irradiation. 18· 19 RENAL TOLERANCE TO CHEMOTHERAPY
A variety of chemotherapeutic agents can be toxic to the kidney. 1· 20 As the list of new chemotherapeutic agents grows the clinician must monitor patients carefully for serious side effects. The common antineoplastic agents can induce renal injury by themselves and can act synergistically with radiation therapy. The concomitant presence of hypercalcemia, 21 hyperuricemia22 or urinary obstruction 23 may enhance renal damage further. A description of the more common chemotherapeutic agents follows. Cis-platinum. Cis-diamminedichloroplatinum (II) (cis-platinum) has a broad spectrum of antineoplastic activity. The compound has become a major component of combination chemotherapy programs. 24· 25 However, nephrotoxicity is the most serious side effect. Cis-platinum nephrotoxicity has been studied in a variety of small and large animals. 26 Morphologic alterations include degeneration of epithelial cells and necrosis of proximal tubules. Although glomerular damage is rare proteinuria is common. Physiologically, cis-platinum induces an uncoupling of the process of oxidative phosphorylation in mitochondria and disrupts the energy production of proximal tubular cells shortly after drug administration. 27 Additional abnormalities include defects in medullary accumulation of solutes that affect the ability to concentrate urine28 and lead to renal insensitivity to vasopressin in the collecting tubule. 29
URINARY TRACT TOXIC EFFECTS OF CANCER THERAPY
In pharmacologic studies an intravenous bolus of cis-platinum yields an a-half-life of 25 to 49 minutes, with a {3-half-life of 58 to 73 hours; 90 per cent of the drug binds to albumin, gamma globulin or transferrin. Urinary excretion accounts for 27 to 50 per cent of drug elimination, usually ~5 days after administration. Patients with renal insufficiency have a prolonged {3-half-life. Tissue distribution studies have shown that after cis-platinum administration the highest levels are seen immediately in the plasma and kidney, followed by the gonadal tissue. Levels in the renal medulla and renal cortex have persisted for >6 or 7 days in animal and human studies. 30-33 Renal biopsies in man show a variety of acute histopathological changes, such as renal cortical swelling, medullary congestion and focal, coagulative necrosis of the distal convoluted tubules and collecting ducts. 34 Dilatation of the convoluted segments in the distal tubule, atypical epithelial cells with syncytial nuclei and granular casts also have been noted. However, these changes are not pathognomonic for a specific lesion. Serial determinations of serum creatinine and glomerular filtration rate demonstrate transient decreases in glomerular filtration rate but full recovery usually occurs by day 21. 35 These studies were conducted after saline hydration had been instituted. When cis-platinum was introduced initially as a phase I agent nephrotoxicity seemed to be the dose-limiting side effect. The incidence of renal damage in patients receiving the drug was 50 to 100 per cent regardless of the dose of schedule. Renal biopsies revealed acute tubular necrosis, tubular degeneration and interstitial edema, and fatal acute renal failure occurred in some patients. From these early studies it was concluded that renal toxicity probably was cumulative. Furthermore, nephrotoxicity seemed to be most profound 3 weeks after drug administration. However, it later became evident that inadequate attention was paid to patient hydration. 20 In the early phase I studies when hydration was not monitored adequately the incidence of nephrotoxicity was 50 to 100 per cent, while in later studies with the use of adequate hydration the incidence ranged between 6 and 13 per cent. 35-44 Whether diuretics or mannitol infusion added to saline hydration alone is beneficial has not been determined adequately. A variety of hydration schedules have been used, including infusion of 3 to 6 1. normal saline per day with or without diuretics, such as mannitol or furosemide. Extracellular fluid volume expansion with saline hydration plus accompanying diuretic administration and rate of drug administration have contributed to a decreased incidence of nephrotoxicity. Many schedules appear equivalent in the ability to prevent nephrotoxicity provided that hydration status is monitored closely and adequate urinary output is maintained. 20 Some investigators suggest the addition of mannitol or loop diuretics to the hydration schedule. The prominent nephrotoxic effect of cis-platinum has been renal magnesium wasting. In 1 series of 44 evaluable patients, 7 of whom were followed prospectively, hypomagnesemia induced by cis-platinum occurred in 23, including 2 who required hospitalization because of symptoms. 45 Magnesium wasting is managed easily with oral magnesium chloride. Magnesium levels should be measured frequently in patients receiving cis-platinum. A variety of other pharmacologic agents have been studied to determine their usefulness in modulating the nephrotoxicity of cis-platinum. In pre-clinical animal studies probenecid, 46 the radioprotective agent WR 2721, 47 diethyldithiocarbamate 48 and sodium thiosulfate 49 • 50 all have shown some efficacy in diminishing renal damage. Methotrexate. Methotrexate, one of the most common chemotherapeutic agents, ordinarily is excreted by the kidneys. In the face of compromised renal function serum levels of methotrexate remain elevated and bone marrow depression, mucositis and dermatitis ensue. Nephrotoxicity is rare after conventional doses in patients with previously normal renal function.
3
However, in 1 series of 13 patients with advanced cancer conventional doses resulted in elevated BUN levels in 5 patients.51 Of these 5 patients 2 died of persistent azotemia. At autopsy 1 patient had direct renal tubular damage characterized by extensive necrosis of the convoluted tubular epithelium. In the past higher doses of methotrexate were used routinely in patient management (1 to 7.5 gm./M. 2). 52 Currently, high dose methotrexate is approved for advanced nonHodgkin's lymphoma and may be used for other tumors. Nephrotoxicity is a prominent side effect of high doses of methotrexate and occasionally has limited the usefulness of the drug. Although the exact pathogenesis of methotrexate-induced renal failure has not been delineated fully several mechanisms have been proposed, including precipitation of the antifole in the renal tubules, a direct toxic effect of methotrexate on renal tubules and a direct effect on glomerular filtration rate. 20 In earlier clinical studies that evaluated the effects of high doses of methotrexate the hydration and extracellular fluid volume of patients were not assessed well. A survey of several early studies shows that serum creatinine was >50 per cent above baseline values in 60 per cent of the patients 24 hours after administration of high doses of the drug. Of 33 patients in these studies 3 died of acute renal failure. 53 Postmortem examination of kidneys demonstrated bilateral renal enlargement, methotrexate precipitation in the tubules and native methotrexate within the renal parenchymal tissue (see figure). When vigorous urinary alkalization and hydration programs were used the incidence of nephrotoxicity was much less. Only 17 per cent of the patients had serum creatinine increases of 50 to 100 per cent above baseline and only 3 per cent had
Kidney biopsy from patient treated with 3 gm./M. 2 methotrexate followed by citrovorum factor rescue who suffered dehydration and acute renal failure. Tissue demonstrates methotrexate precipitation in renal tubule. Fluorescent rabbit antimethotrexate antibody stain. Reprinted with permission. 1
4
GOLDBERG, GARNICK AND BLOOMER
increases > 100 per cent above baseline. Most programs with high dose methotrexate use saline hydration as well as urinary alkalization to a pH >7. A critical evaluation of the relative merits of hydration versus alkalization is lacking. The Dana Farber Cancer Institute in Boston has had extensive experience with high doses of methotrexate. Moderate or severe nephrotoxicity developed in only 7 per cent of the patients. 52 Our over-all treatment plan to prevent methotrexate-induced renal toxicity includes 1) basal glomerular filtration rate and serum creatinine, 2) vigorous patient hydration with 3 to 5 I. 5 per cent dextrose in water containing 60 mEq./ I. sodium bicarbonate to obtain a urinary pH of 7.0 (hydration generally begins 12 to 14 hours before infusion and continues for 2 to 3 days afterward), 3) repeat serum creatinine determination 24 hours after methotrexate infusion, 4) continuation of citrovorum factor at regular doses if serum creatinine is ~50 per cent above the baseline level, which usually indicates renal toxicity, until the methotrexate level decreases to <7.5 X 10-7 M. (hydration and alkalization should be maintained during this period) and 5) maintenance of hydration and alkalization in addition to increase of citrovorum factor 10-fold from 15 to 150 mg. every 3 hours if serum creatinine increases to ~100 per cent (acute renal failure). 2° Consideration also should be given to the addition of thymidine. 54 These supportive measures should be continued until the serum methotrexate level is <10-8 M. and serum creatinine is normal, which can take 30 to 60 days. A more detailed discussion of biochemical rescue techniques is available in the literature. 20 Nitrosoureas. Streptozotocin: The nitrosourea streptozotocin has been used for a variety of malignancies, such as metastatic islet cell carcinoma of the pancreas and carcinoid tumors. 55 · 56 Pre-clinical studies of animal toxicity have shown that nephrotoxicity is a prominent side effect and that streptozotocin may induce renal tumors in several species. 57 - 59 A variety of nonspecific pathological changes also have been noted, including vacuolization and periodic acid, Schiff positivity in the proximal tubular cells, and mitochondrial disruption. 56 Several renal and metabolic abnormalities have been reported after the use of streptozotocin in man and some appear to be related to the dose and schedule of administration. Nephrotoxicity is the principal side effect that limits the usefulness of this drug. Fanconi's syndrome, hypophosphatemia, glycosuria, proteinuria, renal tubular acidosis, hypokalemia and nephrogenic diabetes insipidus occur fairly frequently. 20 ·60 Hypophosphatemia and proteinuria usually are the first manifestations of renal toxicity and, when they occur, renal status must be examined before additional doses of the drug are administered. However, most worrisome is the development of azotemia, elevated serum creatinine and diminished creatinine clearance, which occur in 20 to 40 per cent of the patients treated during a prolonged interval. Life-threatening or fatal renal failure has occurred in approximately 5 per cent of the patients reported on in the literature. In patients who died acute tubular necrosis was demonstrated at autopsy. Although a variety of schedules have been used with varying success the most common method consists of 1.5 gm./M. 2 (body surface area) per week or 0.5 gm./M. 2 for 5 days, repeated every 6 weeks. Streptozotocin is not recommended in patients with preexisting renal dysfunction. 1- (2 - chloroethyl)- 3 - (4 - methylcyclohexyl) -1- nitrosourea (methyl-CCNU): Methyl-CCNU recently has been identified as a potential nephrotoxin in children61 · 62 and adults 63 who have been treated for a variety of neoplasms. In 1 study the development of chronic renal failure was reported in 6 children who received >1,500 mg./M. 2 methyl-CCNU, which usually was given within 17 months. 62 In a review from the Mayo Clinic nephrotoxicity was reported in 2.1 per cent of 857 consecutively studied adults treated with methyl-CCNU either as a single agent or in combination chemotherapy programs. 63 The major manifestation of methyl-CCNU nephrotoxicity is
a decrease in renal size. Pathologically, the most prominent renal changes consist of glomerular sclerosis with thickening of the glomerular basement membrane and severe nephron loss. Other changes include interstitial fibrosis and cellular infiltration. The lesion of nitrosourea nephrotoxicity may resemble that of radiation nephropathy but the clinical syndromes are different. Although recommendations regarding the use of nitrosoureas cannot be made with certainty, it seems prudent to limit the use of methyl-CCNU to doses <1,200 mg./M. 2 and to treatment courses of <1 year. Obviously, patients who undergo such therapy should have serial renal ultrasound examinations and periodic determinations of renal function. Therapy should be terminated at the first sign of decrease in renal size. 1,3 Bischloro (2 chloroethyl)-1-nitrosourea seems to have similar nephrotoxic effects as methyl-CCNU. Limited data are available for chloroethyl cyclohexylnitrosourea. Other agents. Recent studies have suggested a possible association between mitomycin C and subsequent nephrotoxicity. Patients on chronic therapy with mitomycin C, especially those on combination programs that contain a nitrosourea, should be followed closely for the development of nephrotoxicity. 64 Other renal-related toxicities of mitomycin C include a symptom complex consistent with the hemolytic uremic syndrome. 65 Mithramycin has caused nephrotoxicity when used as an anticancer agent in patients with germ cell carcinoma of the testis. 66 Renal function also should be monitored carefully in patients receiving low doses of mithramycin for the management of malignant hypercalcemia, since abnormalities in renal function may occur even with these lower doses. Azacytidine has been associated with renal tubular dysfunction, and a spectrum of proximal and distal tubular abnormalities.67 However, a clear relationship between this drug and the development of nephrotoxicity has not been well established. Other agents, such as doxorubicin hydrochloride 68 and cancer immunotherapy with Corynebacterium parvum, and interferon, have been associated with a spectrum of renal abnormalities in case reports. REFERENCES 1. Garnick, M. B. and Mayer, R. J.: Acute renal failure associated with neoplastic disease and its treatment. Sem. Oneal., 5: 155, 1978. 2. Richie, J.P. and Garnick, M. B.: Primary renal and ureteral cancer. In: Cancer and the Kidney. Edited by R. E. Rieselbach and M. B. Garnick. Philadelphia: Lea & Febiger, pp. 662-706, 1982. 3. Maier, J. G.: Effects of radiations on kidney, bladder and prostate. Front. Rad. Ther. Oneal., 6: 196, 1972. 4. White, D. C.: The histopathologic basis for functional decrements in late radiation injury in diverse organs. Cancer, suppl. 2, 37: 1126, 1976. 5. Kunkler, P. B., Farr, R. F. and Luxton, R. W.: The limit of renal tolerance to x-rays: an investigation into renal damage occurring following the treatment of tumours of the testes by abdominal baths. Brit. J. Rad., 25: 190, 1952. 6. Luxton, R. W.: Radiation nephritis. Quart. J. Med., 22: 215, 1953. 7. Luxton, R. W. and Kunkler, P. B.: Radiation nephritis. Acta Rad., 2: 169, 1964. 8. Rubenstone, A. I. and Fitch, L. B.: Radiation nephritis. A clinicopathologic study. Amer. J. Med., 33: 545, 1962. 9. Levitt, W. M.: Radiation nephritis. Brit. J. Ural., 29: 381, 1957. 10. Avioli, L. V., Lazor, M. Z., Cotlove, E., Broce, K. C. and Andrews, J. R.: Early effects of radiation on renal function in man. Amer. J. Med., 34: 329, 1963. 11. Sagerman, R.H.: Radiation nephritis. J. Ural., 91: 332, 1964. 12. Cassady, J. R., Tefft, M., Filler, R. M., Jaffe, N., Paed, D. and Hellman, S.: Considerations in the radiation therapy of Wilms' tumor. Cancer, 32: 598, 1973. 13. Arneil, G. C., Harris, F., Emmanuel, I. G., Young, D. C., Flatman, G. E. and Zachary, R. B.: Nephritis in two children after irradiation and chemotherapy for nephroblastoma. Lancet, 1: 960, 1974. 14. Churchill, D. N., Hong, K. and Gault, M. H.: Radiation nephritis following combined abdominal radiation and chemotherapy
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