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Nephrotoxicity Induced by Cancer Chemotherapy With Special Emphasis on Cisplatin Toxicity

F Ries. MD, and J. Klastersky, MD .
Renaliailure in cancer patients Is a common problem in oncology; this complicatlon is frequently multlfactorial In origih. Several antineoplastlc agents are potentially nephrotoxlc; previous renal impairment as well aa comblnr. tlons with other nephrotoxic drugs may Increase the risk of nephrotoxiclty during administration of chemotherapy. Methotrexate-related renal damage most frequently occula with hlghdose therapy and can be a v o l d d by t o m alkaline diuresis and administration of follnlc acid. Renal dysfunction secondary to semustlne (CHACNU) 1 8 clearly related t o cumulative doses in excess to 1,200 mglma; the onset may be delayed and renal failure progreu despite drug discontinuation. Streptozotocin is also nephrotoxic and may cause proteinuria and renal tubular acidosis; progressive renal failu-dicted by a close monitoring of protelnuria and preventd by drug discontinuance. Mltomycin-associatedrenal failure frequently presents with sign8 of microanglopathlc hemolytic anemia; renal failure is usually delayed but occasionally, It may be rapidly progressive despite drug dlscontlnu. ance. Clsplatin nephrotoxicity is clearly dose-related and used to be considered dose llmltlng. Renal I n s u f f l c l e n ~ ~ can be prevented by hydration and forced dlsuresis; i n addltlon, hyperhydratlon with mannltol-Induced 8allne dluresis may allow administration of high doses and thus circumvent the dose-limiting effect of clsplatln-Induced renal toxicity. Cisplatin-induced renal magnesium wasting occurs frequently and should be supplemented. C?!-;.r approaches to reduce c~splatin nephrotoxicity are currently under investigation and are diacusOed. 9 1986 by the National Kldney Foundaton, Inc. INDEX WORDS: Nephrotoxic drugs; chemotherapy; renal failure; cisplatln; methotrexate; mltomycin; semustine; streptozotocin; cancer.

INCE THE KIDNEY is highly susceptible to toxic injury by a multitude of different drugs. it is not surprising that several antineoplastic agents may exert potent nephrotoxicity. In cancer patients. however, one must always be aware of additive or synergistic efiects that may potentiate chemotherapy-induced nephrotoxicity. Cancer patients are frequently treated with nephrotoxic antibiotics (eg, aminoglycosides or amphotericin B). They may suffer from radiation-induced nephrotoxicity. or present with hypercalcemia. hyperuricemia. lysozymuria. cancer-related microangiopathic hemolysis. or disseminated intravascular coagulopathy. These patients also may present with immune complex-mediated glomerulopathy or paraprotein-'felated nephropathy, and with amyloidosis as well as minimal-change nephritis. They may have direct infiltration of the kidney by tumdr cells as well as an obstructive nephropathy caused by lower urinary tract invasion and compression. Different radiologic investigations with iodine
From rhe Senice de Midedne lnrtrnr er Laboraroire d ' l n \.esrigarion Clinique H. 7hgnon. Cenrre des Tumeurs de I'Universire Ljbre de Bturelles. lr~srirurJules Border. B n u elles. Address reprinr rcquesrs ro F: Ries. MD. Imrirur Jules Border. I Rue Heger- order. IWO Bnuelles. Belgique. C 1986 bv rhe National Kidt~e;Fou&iion. Inc. 02 n-6386/86/08os-oo14soj.

contrast media may be potentially harmful to the kidney; cancer patients frequently suffer from urinary tract infections. It is. therefore, important to take into account every potentially harmful effect when looking for chemotherapy-related nephrotoxicity. The agents whose potential for nephrotoxicity has been clearly established will be discussed i: the following review. These are methotrexate. :.. . platin. semustine (methyl-CCNU), streptozotocrn. mithramycin. mitomycin C, and azacytidine. Cisplatin nephrotoxicity will be reviewed in greater detail. In addition. the reader is informed that the problem of chemotherapy-related nephrotoxicity has been analyzed in several review articles.'.'
METHOTREXATE

0010

Methotrexate (MTX), an inhibitor of folate synthesis. is one of the earliest and one of the most used agents in cancer chemotherapy. Used for more than 30 years. MTX has shown activity in great number of tumors. such as leukemia. !I phoma. choriocarcinoma, osteosarcoma. and mors of the breast, h e d and neck, and lung." Since MTX is excreted primarily by the kidney. any changes in renal function will have an effect on hfTX plasma levels arid MTX clearance, with subsequent exposuro of the whole organism to per-'

368

American Jourri6l of IOdn6y 3iseases. Vol Vlli. No 5 (November). 1986: pp 368-379

EPHROTOXICITY OF CYTOSTATICS

.,

(IV) .~ y elevated concentrations of the d r ~ g . ~ . ~ . ~ or oral bicarbonate a d m i n i ~ t r a t i o n(2) A rise of serum creatinine value from baseline pretreatliferating or cycling cells. since those of the ment value may identify patients at risk for addie marrow and gastrointestinal tract are most tional renal damage. For these patients, adminisusceptible to the toxic effects of MTX and intoxtration of leucovorin rescue as well as vigorous with MTX secondary to renal failure, prihydration and alkalinization should be considresult in marrow hypoplaiia and severe muered.9 (3) Monitoring of serum MTX levels is of cositis. Apart from causing important systemic toxicity, high plasma concentrations of MTX are primordial importance and identifies patients needing additional rescue measures. Leucovorin also nephrotoxic per se, and renal failure has been rescue should be provided until MTX serum levels implicated in 20% of the deaths associated with fall below lo-' m o l / ~17-19 i . iiP '-/dl highdose MTX administrati~n.~ In patients with established nephrotoxicity, W'" qeveral mechanisms may contribute to MTXleucovorin rescue treatment may counteract the :r~atedrenal failure: precipitation of MTX in renal tubules, direct antimitotic effect on renal cytotoxic effects of MTX. Leucovorin (tetrahydrofolate), inhibitins MTX activity by competitubular cells, and possibly, alteration of glomeruIar filtration rate (GFR). Among these mechation. is administered in high-dose MTX programs at conventional doses of 15 mg, repeated at regular nisms, tubular precipitation producing obstructive renal failure is the best known and the most widely intervals12; since MTX concentrations are someaccepted. MTX solubility has been shown to times extremely high in MTX-induced renal change with urinary pH, and the drug was shown failure, the doses of leucovorin rescue should be to be two to ten times more soluble at pH 6.9 than appropriately i n c r e a ~ e dLowering of MTX levels .~ at pH 5.7.9.'0 Precipitation of the drug may occur by means of peritoneal dialysis, hemodialysis. or hemoperfusion seems to be of marginal v a l ~ e . ~ ~ - ~ ~ in concentrated and acid urine resulting in renal ~ b u l a obstruction by an amorphous yellow mater Since, in most cases. patients are not oliguric or rial; this has been shown at autopsy examinations anuric in MTX-related renal failure, high fluid inof MTX-treated patients dying from acute renal take with alkalinization should always be mainf a i l ~ r eThe amorphous material was identified as .~ tained. Apart from vigorous hydration, alkalinizaMTX by immunofluorescent techniques. The risk tion. and administration of leucovorin during of tubular MTX precipitation can be minimized by high-dose MTX therapy, care should be taken to < hydration as well as alkalinization. I - ' ) Since hyavoid the drug in patients who suffer from pre: dration and alkalinization programs have been inliminary renal insufficiency or to postpone its use troduced into clinical practice, the incidence of rein patients who are dehydrated; urine acidifying agents and salicglate derivatives should be avoided : nal toxicity has decreased dramatically. 3ther observations suggest that MTX might inbefore and during MTX treatment. Good knowledge and careful application of these efficient 2ce renal failure without tubular precipitation be1 cause oliguria or anuria are rarely found. and true measures for prevention of MTX-related nephroobstructive nephropathy has only been reported in toxicity have been associated with the near disap<. a few case repc~rts.~ Since MTX reaches high conpearance of this potentially harmful complication. centrations for prolonged periods in h e urine, reSEMUSTINE (METHYL-CCNU) nal tubular epithelialcells undergoing renewal or repair could be potentially susceptible to this conSemustine. like the other nitrosourea comcentration by time effect of the drug. l 4 pounds. is a highly lipid-soluble drug that has t some clinical activity in neoplasms of the brain. A high-dose MTX-related decrease in GFR was gastrointestinal tract. as well as malignant melaobserved in pediatric and adult patients,I5.l6 but the pathogenetic mechanism of this phenomenon is noma. Nephrotoxicity of this compound had been still unclear. described in early preclinical toxicology experiMTX nephrotoxicity may be predicted by m e n t ~ , ~ , 'but' evidence for possible nephrotoxic,~ ity in humans appeared only much later in 1978 several tests: (1) ~ o w ' u r i n a pH during high-dose r~ MTX infusion may be associated with impending and 1979.26.27 Since then. numerous other reports toxicity. In high-dose MTX programs. urinary pH on semustine nephrotoxiciry have been should be maintained above pH 7 by intravenous publisl~ed.~~-~~

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RlES AND KLASTERSKY

The most frequent clinical manifestation is a slowly rising serum creatinine level with progressive irreversible renal failure. Pathologic findings are generally consistent with the presence of small and atrophic kidneys, signs of tubular atrophy, hyalinization, glomerulosclerosis, and interstitial fibrosis. 32 Semustine nephrotoxicity is cumulative; renal dysfunction has been noted in 26%of patients who received total cumulative doses in excess of 1,400 m g / n ~ ~ . ~ I median cumulative dose at which nephrotoxicity is likely to occur has been estimated to be near 2,000 mg/m2.32It is, thus, not surprising that this problem generally appears only in patients being treated for more than 1 year, which requires a prolonged survival time. Compared to the other nitrosoureas, it can be noted that semustine nephrotoxicity totally differs from that of streptozotocin, the most nephrotoxic compound of the nitrosourea group. The other nitrosoureas. ie, chlorozotocin, lomustine, and carmustine. seem to be much less nephrotoxic, with only occasional cases reported. The specific mechanisms of semustine-related nephrotoxicity remain unclear and there are no established recommendations for toxicity protection. Prochlorperazine, a commonly used phenothiazine with antiemetic properties, has been reported in animal studies to reduce the frequency as well as the severity of semustine-related renal lesions33: the clinical impact of this observation has not yet been established.
STREPTOZOTOCIN

dosage schedule and frequent examinations for p r o t e i n ~ r i a . The. drug should be discontinued ~~ ~~ when proteinuria or other signs of renal dysfu;: tion develop; with resolving proteinuria, drug ..:. .-. ministration might be carefully continued.

Mithramycin, a naturally occurring cytotoxic antibiotic, has shown some activity against gohownadal cancer, as well as glioblastomas*~~; ever, its multiple toxic side effects have precluded its widespread use. Apart from causing important hematologic and cloning abnormalities, gastrointestinal, central nervous, and hepatic dysfunction, as well as hypocalcemia, it also induces renal toxicity, manifested by signs of renal failure and proteinuria. This renal toxic effect tends to be cumulat~: .. and may be irreversible; drug-related deaths due ti: renal failure have been reported in 6 of 32 patients treated with the drug.4s Histopathologic changes consist primarily of renal tubular swelling, degeneration. necrosis, and atrophy with sparing of the glomeruli. Mithramycin still has some applications in refractory cancer-related hypercalcemia, where lower doses are generally effecti~e.*~.~' Mitomycin C (MMC) is a naturally occurring alkylating agent, introduced for clinical use as early as 1958. It has been demonstrated to be active against carcinomas of the gastrointest~n.: tract; breast. prostate, and a few other carcinomas as we11.49.s0 Activation of mitomycin seems to require in vivo metabolism to form short-lived metabolites that are highly reactive. Its serum half-life varies from nine to 17 minutes, and inactivation of the drug occurs in various organs including the liver and the kidney. Renal excretion of mitomycin is negligible.49 Early reports on animal studies had shown various nephrotoxic effects in dogs, monkeys, and mice.s1-" Reports on possible renal toxicity in humans occurred only much later.s4 These studies generally showed microangiopathic changes in r h ~ renal circulation with hemolytic anemia. thrombocytopenia. proteinuria, hematuria, renal failure. systemic hypertension, pulmonary edema, and congestive heart failure. This clinical syndrome has been variously described as microangiopathic

Streptozotocin is a nitrosourea that has been used successfully in. the treatment of islet cell t u m 0 r s . ~ ~ - 3 ~ toxicity is the major doseRenal limiting side"effect of this drug. Nephrotoxicity seems to be dcse-related and. to some extent, cumulative. occurring most frequently at doses in excess of 1.5 g / m 2 / ~ k . 3 7 ~ 3 a Toxicity generally presents initially as mild pr~teinuria.'~ with continued use, proximal rebut nal tubular damage may develop.38 Fanconi syndrome. renal tubular acidosis. hypokalemia, renal glycosuria. hypophosphatemia, and most significantly, life-threatening oliguria and anuria have been reported. Nephrogenic diabetes insipidus seems to be less frequent.*.41 The best prevention for potentially harmful nephrotoxicity should be afforded by an optimal

. .-

NEPHROTOXICITY OF CMOSTATICS

37 1

hemolytic anemia.55 MMC-related hemolyticuremic syndrome.56 and MMC nephrotoxicity. 57 Several clinical manifestations show similarities with cancer-related microangiopathy and coagu10pathy,~~-~ldifferent authors have suggested a and possible relation between both problem^.^^.^^ In one large series, 140 of 143 patients treated with mitornycin had renal impairments7; among these, 6 % died of renal failure. Three patients developed rapidly progressive renal disease with sharp elevations of BUN and'creatinine level. hypenension, proteinuria, hematuria, signs of microangiopathic hemolytic anemia. and death from renal failure. Several other patients in that series presented with some degree of red-cell fragmentation, thrombocytopenia. proteinuria. and hypertension, but the clinical course was generally less tulminant and renal failure frequently developed without signs of hemolysis. As in other studrelated to repeated doses of 10 to 20 mglm2, with a total dose-range between 40 and 115 mglm2. The time interval between the onset of MMC therapy and renal failure was 4 to 16 months. with an average of 10 to 11 months. Renal toxicity of MMC is apparently not doserelated and the precise pathogenetic mechanism autopsy material have shown microangiopathic lesions with fibrous thrombi in the glomeruli and small arteries.65 glomerular nuclear degeneration and thickened basement membrane.s4 intirnal hy-

tions without any effect on progressive renal f a i l ~ r e . Combinations of immunosuppressive ~~.~~ and antiplatelet drugs, with or without plasmapheresis, has been shown to be only of marginal benefit.63 Temporary progression of the disease activity has been attributed to blood transfusions, which should, therefore, be administered with ~ a u t i o n . ~ Hemodialysis may be necessary for ~.~' life-threatening renal failure, but it will not effect the underlying disease process. For patients treated with MMC, renal and hematologic function should be monitored regularly after initiation of chemotherapy. MMC should be discontinued if early toxic manifestations, especially azoternia or hematuria, are detected. To date, there are no data available to predict individual susceptibility to this complication. Further studies are needed to clarify the causes, prevention. and treatment of the renal complication. and use.
AZACYTIDINE

.,

5-Azacytidine, a pyrimidine analogue, is a useful agent in acute nonlymphocytic leukemia.70 This drug was shown to be associated with azoteAbnormalirnia and renal tubular dy~function.~' collecting ducts, have been described. Polyuria, salt wasting, defective reabsorption of phosphate. aminoaciduria, and renal glycosuria have also been do~umented.'~
CISPLATIN

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tients with MMC-associated hernolytic-uremic syndrome63; these immune complexes showed high platelet aggregation activity in vitro. The constituent antibody of each complex faded to react with MMC antigen preparations, whereas in vitro reactivity to endodermally derived neoplasms could be detected. These data suggest that MMC might not be the only etiologic factor of this syndrome, but that some tumor-specific relationship might exist as well. Mitomycin-associated nephrotoxic reactions must be c~nsideredrefractory to most treatments studied until now. In small studies. steroids, anticoagulants, and platelet inhibitors have been tried u n s u c c e ~ s f u l l y .Plasmapheresis has shown ~~~~~~ variable resolution of the hematologic manifesta-

In 1969, platinum compounds were reported by Rosenberg et al to exen potent antitumor activity in mice73; cisdiamminedichloroplatinum I1 (cisplatin) was the most active drug among these comp o u n d ~Cisplatin, therefore, entered toxicologic .~~ evaluation in before introduction into phase I clinical trial^.^^-^' Since then, cisplatin has been studied in numerous phase 111111 trials (alone or with other agents), and it has proven to be one of the most potent chemotherapeutic agents, being active in cancer of the ovary,84 t e ~ t i s , blad- ~ ~.~ der,87-89head and neck,90 l ~ n g , ~endome'.~~ t r i ~ m .uterine cervix,94 and many others. ~~ Several excellent reviews deal with problems such as mechanism of action, activity on diverse tumors. as well as toxicity of isp plat in.^^.^^^ Since 1971, animal studies have shown a major

RlES AND KLASTERSKY

cisplatin-induced nephrot~xicity'~ proved to that be dose related.76 These and other reports with studies performed on various animal models showed a strong relationship between the administered dose and uremia, as well as dose-related structural alterations detected on microscopic kidney examination. These alterations consisted predominantly in tubular necrosis. As could be expected from animal studies, early clinical reports showed similar toxicity in humans.78-m.82.a3 paIn tients with n&mal kidney function, rising BUN levels were noted during the second week after a bolus cisplatin administration in excess of 50 mg/ m2 of body surface area (BSA); reversible nephrotoxicity was generally noted between 50 and 75 mglm2ld, while doses 2 100 mglm21d were frequently followed by acute renal failure with pronounced tubular cell necrosis. Renal failure progressing from reversible to irreversible stages was described with repeated treatment courses. These early studies were performed without particular hydration or drug-induced diuresis programs. Several authors have reviewed the problem of the - ~ ~ ~ cisplatin-related n e p h r o t o x i ~ i t y ~ ~ ~conclu-; sions of their articles. as well as more recent information, will be analyzed in the following discussion. In fact, cisplatin nephrotoxicity remains of particular interest since renal damage is one of its most critical side effects and frequently constitutes a dose-limiting factor.
Mechanism of Acrion and Implications for Renal T o x i c i ~

chloride concentration environment: cisplatin passage from a chloride-rich plasmatic milieu ( !03 mEq/L) to a low-chloride invacytoplasmic mii;.. I (4 mEqIL) constitutes a passage from electr:.s.,l neutrality (with a stable bis-chloro molecule [I]) t o aqueous activation (II, III, V), chloride ligands in the cis position being replaced by water molecules (Fig 1). These aquated forms are highly reactive with nucleophiles and can loose hydrogen ions to form cytotoxic hydroxyl radicals (IV, V); these latter compounds can also form cytotoxic oxygenbridged dimers and trimers. At equilibrium, the proportion between these diversely cytotoxic cornplexes depends on chloride concentration and, to a lesser extent, on pH and total platinum concentration. 107.108 Since platinum tissue concentrations are panl; larly high in the kidneys after drug admini~tratit~;~ in dogs and h u r n a n ~ , ~ 5 . ' ~ data suggesting an and ~ active tubular secretion of cisplatin or metabolites,'10-112 can be hypothesized that renal toxicit ity might be similar to its general cytotoxic effects. This implies that intratubular reduction of cisplatin concentration by abundant hydration, as well as activation of tubular chloride reuptake by forced chlouresis, might favorably influence the equilibrium between stable nontoxic cisplatin 0 ) and aquated forms (11, III, V), as well as cytotoxic hydroxyl species (IV,VI), thereby reducing renal tubular damage without affecting general cytotoxicity.
Cisplarin Tissue Disrriburion, Pharmacokinetics. and Renal Handling After IV administration. cisplatin undergoes rapid distribution to nearly all organs. Tissue platinum concentration studies at various points after cisplatin administration in dogs show a very rapid accumulation of the metal in the kidney (three to four times the plasma concentration ten minutes after administration) with persistently elevated values fbr more than 1 week. lop A very high postmortem renal concentration of platinum has also been reported in humans two days after administration of a single dose of 2 mg/kg of cii platin.95 Platinum concentrates in various other tissues (gonadal tissue, lung, liver, fat)lo9;studies in humans have shown that 90% of the drug is protein-bound in plasma and that 27 % to 45% of the drug is excreted in the urine within five days of administration. 1 1 3 Data on free platinum renal clearance in humans indicate that platinum clear-

Several studies suggest that cisplatin exerts its activity in a manner similar to aklylating agents by drug interaction with \the nucleophilic sites of These infrastrand pyrimidines in DNA.97.98.'06 DNA cross-link will occur after physiologic activation of the dnlg, which will take place in a low

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Fig 1. Chloridedependent aquation reactions of cisplatin.

NEPHROTOXICITY OF CYTOSTATICS

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ance exceeds the GFR, suggesting active secretion [of the drug or a metab01ite.I~~ might be exAs -petted, cisplatin pharmacokinetics are altered in ipatients with renal insufficiency, and normal or i near normal values of creatinine clearance are \generally considered necessary in order to avoid jcxcessive nephrotoxici@ This general rule seems , to be of questionable importance in cases of agerelated decrease in renal function and especially in cases of a unique functional kidney. In fact, both conditions generally result in a lower 24-hour creatinine clearance, but as has been shown in a recent clinical study, they are not associated with greater renal toxicity if standard hydration is performed and if cisplatin dosage does not exceed 60 mg/m2/d.' I 4 This study even suggests a protective mechanism in patients with unique kidneys (14 of 43 patients studied) compared with those with two normally functioning kidneys. In fact, the reduced number of nephrons will produce a higher flow of ultrafiltrate per tubule with lower tubular cisplatin concentration and probably less tubular "contact" between the toxin and tubular epithelium. This is illustrated by a higher than normal 24-hour diuresis, wit!! lower cisplatin urinary concentrations for an identical cisplatin dose and hydration program in these patients, compared with those with two normally functioning kidneys. A similar mechanism is thought to contnbute to the relative lack of excessive age-associated cisplatin-induced nephrotoxicity. Other studies (in animals and humans), based on rhythmic changes in kidney function, according to circadian rhythms, have shown that optimal renal tolerance of cisplatin occurs very near to the time of day associated with the normal circadian maximum in urinary volume. This beneficial effect is potentiated by concurrent hydration and is correlated by lower urinary cisplatin concentrations. 15-I l 7 These studies, along with those on hydration and forced diuresis suggest the primordial role of reducing cisplatin urinary concentrations by high urinary output; in fact. direct tubular exposure for a few hours to a concentration of 200 pg/mL of cisplatin seems to be necessary for tubular damage to occur.96 Parhologic Kidney Changes As documented by animal and human studies. cisplatin induces several microscopic kidney changes that are dose-related and, to a lesser degree. cumu!ative. 96,102,'03.118 These changes in-

clude epithelial cell degeneration, proximal tubular necrosis, dilatation and necrosis of distal tubules, interstitial edema. and lymphocytic infiltration. Glomerular changes are generally not observed and most alterations are considered to be nonspecific. Tbbular damage is also suggested by sensitive assays for tubular enzymes, thought to be liberated by renal injury: alanine-aminopeptidase, N-acetyl-0-glucosaminidase (NAG) I l 9 . I z 0 ; these studies support the concept that all areas of the tubule may be injured to some extent. Studies on urinary activity of NAG, a lysosomal enzyme released into the urine from the brush border of proximal tubular cells, have shown a positive correlation between cisplatin nephrotoxicity and NAG urinary activity. Potentiation of cisplatin tissue uptake by NAG tissue activity has been reas well as a circadian rhythm of urinary NAG activity, suggesting that rhythmic changes in NAG activity may cause variations in cisplatin nephrotoxicity along with circadian rhythms. PZmicroglobulin, possibly another mediator of tubular injury, was shown to be significantly elevated in the urine 12 hours after treatment with cisplatinI2l: since no patient in that report developed laboratory evidence of renal toxicity, this increased /32-microglobulinuriahas been interpreted as reflecting subclinical renal damage. Hypomagnesemia and renal magnesium wasting are the most prominent electrolytic disorders secondary' to cisplatin administration. 122-124 Hypomagnesemia d e v e l o e 2 % of 44 patieh e seriesLz2 with a treatment schedule of 70 mg/ m2 cisplatin (on day l ) , repeated every 21 days. Among patients with hypomagnesemia. the nadir Mg concentration (median) was 0.92 mEq/L. usually occumng more than 2 weeks after drug administration and generally after one or two courses of cisplatin had been given. Similar hypomagnesemia was also observed in other studies1Z3.125 is frequently complicated by hypoand calcemia that is probably secondary to diminished PTH release and/or end-organ resistance to parathyroid hormone induced by hypomagnesemia.126z 7 Clinical manifestations of hypomagneI semia. including abnormalities in neuromuscular. central nervous system. and cardiac function that may appear for serum levels of less than 1 mEq/L. should be treated by parented replacement of magilesium sulfate. Associated hypocalcemia is responsive to .magnesium repletion and is unresponsive to calcium replacement alone. The more

RlES AND KLASTERSKY

creased nephrotoxicity in chloridedeprived rats and significantly reduced renal damage with pharmacologically induced chloriuresis; this favorabi: Prevention of' Cisplatin-Induced Nephrotoxiciry effect could be explained by the reduction ni Preexistent renal insufficiency should always be highly toxic aqueous-cisplatin complexes in excluded before starting cisplatin therapy; dehychloride-rich urine. lo' dration, arterial hypeitension and hyperuricemia Continuous infusion of cisplatin results in reshouid be corrected; concomitant administration duced gastrointestinal and renal of nephrotoxic drugs, especially aminoglycoside when compared with earlier studies with equal antibiotics, should be avoided.Iz8 daily doses. Continuous infusion should, however, Numerous clinical trials proposing various hyalways be associated with adequate hydration pro~~ dration programs have been d e ~ c r i b e d . ~ ~ .All . l ~ 9 grams, the influence on renal toxicity of vigorous of these schedules are valuable, provided that hyurinary output being more important than the dration status is closely monitored. Most hydration duration of infusion. programs are performed with normal saline soluPharmacologic Interaction With tion or glucose 5 % in saline and are given for variCisplatin Nephrotoxici~ ous durations, before, during, and after cisplatin administration. Hydration alone can be considered Unlike mannitol and furosemide, which exert sufficiently effective if cisplatin is administered as their activity by inducing a potent diuresis, various 20 mglm2ld by one- to two-hour infusion for five other compounds have been proposed on the basis consecutive days. of a potential for detoxification. Among these. Forceddiuresis programs, combining hydration probenecid has been studied in animals (F344 rat with furosemide or mannitol administration, have model) and was shown to decrease the peak values proved clinically beneficial in numerous studof BUN and creatinine if administered one hour ies,84.130.132 superiority of hydration-diuretic and prior to cisplatin; this protection has been ascribed programs compared to hydration alone has been to probenecid inhibition of active secretion of cissuggested.'33 Most of the more recent programs platin by the p-aminohippurate system.14' permit administration of cisplatin at doses of 100 WR-2721[S-2-(3-aminopropy1amino)ro 120 mg/m2 as short daily infusions or adminisethylphosphorothioic acid], a radioprotective tration of 20 to 40 mglm21d for five consecutive agent, has been shown to exert protective activity days. Intensive parenteral hydration with on renal function in the same F344 rat model.IJ2 mannitol-induced diuresis even permits prevention Diethyldithiocarbamate (DDTC). a potent SHof dose-limiting nephrotoxicity. In these patients. group chelator administered to F344 rats after a myelotoxicity might become a major problem134; known nephrotoxic dose of cisplatin. may prevent combined with cisplatin administration in hyperrenal pathologic as well as functional changes.14' tonic saline, doses as high as 200 mglm2 have been This protective activity is ascribed to competition administered, with thrombocytopenia being the with cisplatin for protein-bound sulfhydril groups most promineht toxic effect."' In a recent study, within proximal tubular cells. Protein binding of three "highdosf" regimens, with doses between cisplatin in tubular cells, with resultant inhibition 180 and 220 mglm2/d, were compared: cisplatin of transport enzymes, is one postulated mechawas dissolved in 5% saline and was administered nism of cisplatin nephrotoxicity in rats and, along with a well-defined prehydration-mannitolperhaps, in humans. The closely related disulfiram induced diuresis and posthydration program. In (Antabuse: Ayerst Laboratories. New York). being that study it was concluded that cisplatin, given at metabolized to diethylthiocarbarnate. might exen a a dose of 200 mg/m2 in five daily fractions, comsimilar protective effect. bined with an appropriate hydration and diuresis Sodium thiosulfate has also been studied for its program. was devoid of significant nephrotoxicity nephrotoxicity preventive effects. L 4 4 This sulhrand was probably much less ototoxic than singlecontaining compound is thought to reacr CObolus high-dose admini~trati0n.l~~ chloride High valently with cisplatin, resulting in complexes that diuresis may improve the therapeutic index of cis.~~~ are neither toxic nor t ~ m o r i c i d a l Apart from platin by reduced nephrotoxicity without loss of markedly reducing general cisplatin toxicity by its antitumor activity. Animal studies have shown insystemic activity, sodium thiosulfate might exert rarely seen hypokalemia should be treated by replacement of both potassium and magnesium.

further reduction in nephrotoxicity through particularly high intratubular thiosulfate to cisplatin concentration ratios. Intravenous sodium thiosulfate seems to be a most intiresting agent when administered in combination with intraperitoneal cisplatin. eg, for ovarian cancer. In this indication. parenteral thiosulfate adniinistration allowed escalation of intraperitoneal cisplatin up to a dose of 270 mg/m2 without significant nephrotoxicity, thus permitting an increased activity.i4s Other sulfur compounds, eg, thiourea, L-methionine. and penicillarnine, might also inhibit the biologic activity of cisplatin and might, therefore, interfere with its therapeutic as well as toxic effects.14C148 The carbonic anhydrase inhibitor acetazolarnide has also been considered potentially useful for prevention of cisplatin nephrotoxicity.i49.1s0 APa* from its activity as a diuretic, this organic acid could act by competition with cisplatin for tubular reabsorption, thus promoting cisplatin excretion: however, the presence of two sulfur atoms in this molecule could also permit chemical interaction and detoxification. In an animal study (male F344 rat model), pretreatment with acetazolarnide decreased cisplatin nephrotoxicity and diminished renal platinum content, as well as urinary platinum e ~ c r e t i 0 n . lComparison of acetazolamide and ~~ mannitol in the same animal model (performed by the same authors) shows acetazolamide to be more effective than mannitol in preventing cisplatininduced nephrotoxicity in male F344 rats. l S 0 The enzyme copper-zinc superoxide dismutase (orgotein) has also been associated with reduction of nephrotoxicity in rats, thus suggesting that superoxide radicals may participate in the nephrotoxic effects of c i ~ p l a t i n . ~ ~ ~ Selenium. known for its ability to combine to metals such as cadmium and mercury, as well as for its resemblance to sulfur by its chemical properties, shows theoretical promise as a cisplatinprecipitating agent. As shown in studies on mice. selenium is able to decrease cisplatin nephrotoxicity without influencing in vivo and in vitro tumor growth. This could suggest either detoxification by ligation to sites not involved in cisplatin antitumor activity or, perhaps, prevention of tubular reabsorption of the mo1esu:ar complex. 1 5 2
PERSPECTIVES AND CONCLUSIONS

induced diuresis, have considerably changed the spectrum of cisplatin's potential for renal toxicity. Introduction of some of the new detoxification agents will probably prove useful as well. Dosing plasma cisplatin levels at various times after drug infusion could be helpful to predict nephrotoxicity early in the course of cisplatin infusion. I s 3 Finally, several second-generation platinum complexes are being evaluated in preclinical and clinical studies for toxicity and antitumor activity. Among these, i p r o p l a t i ~ u m (CHIP) and carboplatinurn (CBDCA) show little or no n e p h r o t o x i ~ i t y . ~ ~ ~ - ~ ~ ~ These and other platinum compounds are possibly candidates as future alternatives to cisplatin in several conditions. Until then. however, cisplatin remains one of the most potent antineoplastic agents ever developed. Further work should be performed to reduce its potential for renal toxicity.
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NEPHROTOXICITY O F CYTOSTATICS

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