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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 avoldd by t o m alkaline diuresis and administration of follnlc acid. Renal dysfunction secondary to semustlne (CHACNU) 18 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-associated renal 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 Insuff lc len~~ can be prevented by hydration and forced dlsuresis; in 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.

S 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 amy- loidosis as well as minimal-change nephritis. They

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. Cis- platin 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 may have direct infiltration of the kidney by tumdr Methotrexate (MTX), an inhibitor of folate syn- cells as well as an obstructive nephropathy caused thesis. is one of the earliest and one of the most by lower urinary tract invasion and compression. used agents in cancer chemotherapy. Used for Different radiologic investigations with iodine more than 30 years. MTX has shown activity in

From rhe Senice de Midedne lnrtrnr er Laboraroire d ' ln - great number of tumors. such as leukemia. !I -' \.esrigarion Clinique H. 7hgnon. Cenrre des Tumeurs de phoma. choriocarcinoma, osteosarcoma. and I'Universire Ljbre de Bturelles. lr~srirur Jules Border. B n u - mors of the breast, h e d and neck, and lung." elles.

Address reprinr rcquesrs ro F: Ries. MD. Imrirur Jules Bor- Since MTX is excreted primarily by the kidney.

der. I Rue Heger- order. IWO Bnuelles. Belgique. any changes in renal function will have an effect C 1986 bv rhe National Kidt~e; Fou&iion. Inc. on hfTX plasma levels arid MTX clearance, with 02 n-6386/86/08os-oo14soj. 0010 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

y elevated concentrations of the d r ~ g . ~ . ~ . ~ liferating or cycling cells. since those of the e marrow and gastrointestinal tract are most

usceptible to the toxic effects of MTX and intox- with MTX secondary to renal failure, pri- result in marrow hypoplaiia and severe mu-

cositis. Apart from causing important systemic toxicity, high plasma concentrations of MTX are also nephrotoxic per se, and renal failure has been implicated in 20% of the deaths associated with highdose MTX adminis t ra t i~n.~

I W'" qeveral mechanisms may contribute to MTX- :r~ated renal failure: precipitation of MTX in renal tubules, direct antimitotic effect on renal

tubular cells, and possibly, alteration of glomeru- Iar filtration rate (GFR). Among these mechanisms, tubular precipitation producing obstructive renal failure is the best known and the most widely accepted. MTX solubility has been shown to change with urinary pH, and the drug was shown to be two to ten times more soluble at pH 6.9 than at pH 5.7.9.'0 Precipitation of the drug may occur in concentrated and acid urine resulting in renal ~ b u l a r obstruction by an amorphous yellow material; this has been shown at autopsy examinations of MTX-treated patients dying from acute renal f a i l ~ r e . ~ The amorphous material was identified as MTX by immunofluorescent techniques. The risk of tubular MTX precipitation can be minimized by

< hydration as well as alkalinization. I - ' ) Since hy- : dration and alkalinization programs have been in-

>- troduced into clinical practice, the incidence of re- : nal toxicity has decreased dramatically.

3ther observations suggest that MTX might in- 2ce renal failure without tubular precipitation be-

1 cause oliguria or anuria are rarely found. and true obstructive nephropathy has only been reported in <. a few case repc~r ts .~ Since MTX reaches high con-

., centrations for prolonged periods in h e urine, renal tubular epithelialcells undergoing renewal or repair could be potentially susceptible to this con-

t - centration by time effect of the drug. l 4

A high-dose MTX-related decrease in GFR was observed in pediatric and adult patients,I5.l6 but the pathogenetic mechanism of this phenomenon is still unclear.

MTX nephrotoxicity may be predicted by , several tests: (1) ~ o w ' u r i n a r ~ pH during high-dose

I MTX infusion may be associated with impending toxicity. In high-dose MTX programs. urinary pH should be maintained above pH 7 by intravenous

(IV) or oral bicarbonate admin i~ t ra t ion .~ (2) A rise of serum creatinine value from baseline pretreatment value may identify patients at risk for additional renal damage. For these patients, administration of leucovorin rescue as well as vigorous hydration and alkalinization should be considered.9 (3) Monitoring of serum MTX levels is of primordial importance and identifies patients needing additional rescue measures. Leucovorin rescue should be provided until MTX serum levels - , fall below lo-' m o l / ~ . 17-19 i - ' i- i P '-/dl z 6 . 0 9 )

In patients with established nephrotoxicity, leucovorin rescue treatment may counteract the cytotoxic effects of MTX. Leucovorin (tetrahy- drofolate), inhibitins MTX activity by competition. is administered in high-dose MTX programs at conventional doses of 15 mg, repeated at regular intervals12; since MTX concentrations are some- times extremely high in MTX-induced renal failure, the doses of leucovorin rescue should be appropriately i n c r e a ~ e d . ~ Lowering of MTX levels by means of peritoneal dialysis, hemodialysis. or hemoperfusion seems to be of marginal v a l ~ e . ~ ~ - ~ ~ Since, in most cases. patients are not oliguric or anuric in MTX-related renal failure, high fluid in- take with alkalinization should always be maintained. Apart from vigorous hydration, alkalinization. and administration of leucovorin during high-dose MTX therapy, care should be taken to avoid the drug in patients who suffer from preliminary renal insufficiency or to postpone its use in patients who are dehydrated; urine acidifying agents and salicglate derivatives should be avoided before and during MTX treatment. Good knowledge and careful application of these efficient measures for prevention of MTX-related nephrotoxicity have been associated with the near disap- pearance of this potentially harmful complication.

SEMUSTINE (METHYL-CCNU)

Semustine. like the other nitrosourea compounds. is a highly lipid-soluble drug that has some clinical activity in neoplasms of the brain. gastrointestinal tract. as well as malignant melanoma. Nephrotoxicity of this compound had been described in early preclinical toxicology experi- m e n t ~ , ~ , ' , ~ ' but evidence for possible nephrotoxicity in humans appeared only much later in 1978 and 1979.26.27 Since then. numerous other reports on semustine nephrotoxiciry have been p u b l i s l ~ e d . ~ ~ - ~ ~

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, hy- alinization, 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 esti- mated to be near 2,000 mg/m2.32 It 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 car- mustine. 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

Streptozotocin is a nitrosourea that has been used successfully in. the treatment of islet cell tum0rs .~~-3~ Renal toxicity is the major dose- 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 /m2/~k.37~3a

Toxicity generally presents initially as mild pr~teinuria.'~ but with continued use, proximal renal 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

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 gonadal cancer, as well as glioblastomas*~~; however, 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

. . .-

NEPHROTOXICITY OF CMOSTATICS 37 1

hemolytic anemia.55 MMC-related hemolytic- tions without any effect on progressive renal uremic syndrome.56 and MMC nephrotoxicity. 57 f a i l ~ r e . ~ ~ . ~ ~ Combinations of immunosuppressive Several clinical manifestations show similarities and antiplatelet drugs, with or without plas- with cancer-related microangiopathy and coagu- mapheresis, has been shown to be only of marginal 10pathy,~~-~l and different authors have suggested a benefit.63 Temporary progression of the disease possible relation between both problem^.^^.^^ activity has been attributed to blood transfusions,

In one large series, 140 of 143 patients treated which should, therefore, be administered with with mitornycin had renal impairments7; among ~ a u t i o n . ~ ~ . ~ ' Hemodialysis may be necessary for these, 6% died of renal failure. Three patients de- life-threatening renal failure, but it will not effect veloped rapidly progressive renal disease with the underlying disease process. sharp elevations of BUN and'creatinine level. hy- For patients treated with MMC, renal and hema- penension, proteinuria, hematuria, signs of mi- tologic function should be monitored regularly af- croangiopathic hemolytic anemia. and death from ter initiation of chemotherapy. MMC should be renal failure. Several other patients in that series discontinued if early toxic manifestations, espe- presented with some degree of red-cell fragmenta- cially azoternia or hematuria, are detected. To tion, thrombocytopenia. proteinuria. and hyper- date, there are no data available to predict individ- tension, but the clinical course was generally less ual susceptibility to this complication. Further tulminant and renal failure frequently developed studies are needed to clarify the causes, preven- without signs of hemolysis. As in other stud- tion. and treatment of the renal complication. and

related to repeated doses of 10 to 20 mglm2, with a use. ., total dose-range between 40 and 115 mglm2. The

time interval between the onset of MMC therapy AZACYTIDINE

: and renal failure was 4 to 16 months. with an 5-Azacytidine, a pyrimidine analogue, is a use- average of 10 to 11 months. ful agent in acute nonlymphocytic leukemia.70

Renal toxicity of MMC is apparently not dose- This drug was shown to be associated with azote- related and the precise pathogenetic mechanism rnia and renal tubular dy~function.~' Abnormali-

.: autopsy material have shown microangiopathic le- collecting ducts, have been described. Polyuria, sions with fibrous thrombi in the glomeruli and salt wasting, defective reabsorption of phosphate.

'. small arteries.65 glomerular nuclear degeneration aminoaciduria, and renal glycosuria have also :. and thickened basement membrane.s4 intirnal hy- been do~umented.'~

CISPLATIN

In 1969, platinum compounds were reported by . tients with MMC-associated hernolytic-uremic Rosenberg et al to exen potent antitumor activity

syndrome63; these immune complexes showed in mice73; cisdiamminedichloroplatinum I1 (cis- high platelet aggregation activity in vitro. The platin) was the most active drug among these com- constituent antibody of each complex faded to p o u n d ~ . ~ ~ Cisplatin, therefore, entered toxicologic react with MMC antigen preparations, whereas in evaluation in before introduction into vitro reactivity to endodermally derived neo- phase I clinical trial^.^^-^' Since then, cisplatin has plasms could be detected. These data suggest that been studied in numerous phase 111111 trials (alone MMC might not be the only etiologic factor of this or with other agents), and it has proven to be one syndrome, but that some tumor-specific relation- of the most potent chemotherapeutic agents, being ship might exist as well. active in cancer of the ovary,84 t e ~ t i s , ~ . ~ ~ blad-

Mitomycin-associated nephrotoxic reactions der,87-89 head and neck,90 l ~ n g , ~ ' . ~ ~ endome- must be c~nsidered refractory to most treatments t r i ~ m . ~ ~ uterine cervix,94 and many others. studied until now. In small studies. steroids, anti- Several excellent reviews deal with problems such

f coagulants, and platelet inhibitors have been tried as mechanism of action, activity on diverse tu-

( u n s u c c e ~ s f u l l y . ~ ~ ~ ~ ~ ~ Plasmapheresis has shown mors. as well as toxicity of isp plat in.^^.^^^

I variable resolution of the hematologic manifesta- Since 1971, animal studies have shown a major

RlES AND KLASTERSKY

cisplatin-induced nephrot~xicity'~ that proved to 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 pre- dominantly in tubular necrosis. As could be ex- pected from animal studies, early clinical reports showed similar toxicity in humans.78-m.82.a3 In patients 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 pro- nounced tubular cell necrosis. Renal failure pro- gressing 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 cisplatin-related n e p h r o t o x i ~ i t y ~ ~ ~ - ~ ~ ~ ; the conclusions of their articles. as well as more recent infor- mation, will be analyzed in the following discus- sion. 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 Tox ic i~

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

u I1"Ui Cl , 103 .MIL1

Fig 1. Chloridedependent aquation reactions of cisplatin.

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]) to 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 lat- ter compounds can also form cytotoxic oxygen- bridged dimers and trimers. At equilibrium, the proportion between these diversely cytotoxic corn- plexes 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 . ' ~ ~ and data suggesting an active tubular secretion of cisplatin or metabolites,'10-112 it can be hypothesized that renal toxicity 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. 113 Data on free platinum renal clearance in humans indicate that platinum clear-

NEPHROTOXICITY OF CYTOSTATICS

ance exceeds the GFR, suggesting active secretion [of the drug or a metab01ite.I~~ As might be ex- -petted, cisplatin pharmacokinetics are altered in i patients 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 age- related 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 max- imum in urinary volume. This beneficial effect is potentiated by concurrent hydration and is corre- lated 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 posi- tive correlation between cisplatin nephrotoxicity and NAG urinary activity. Potentiation of cisplatin tissue uptake by NAG tissue activity has been re-

as 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. PZ- microglobulin, possibly another mediator of tubular injury, was shown to be significantly elevated in the urine 12 hours after treatment with cis- platinI2l: since no patient in that report developed laboratory evidence of renal toxicity, this increased /32-microglobulinuria has been interpreted as reflecting subclinical renal damage.

Hypomagnesemia and renal magnesium wasting are the most prominent electrolytic disorders secondary' to cisplatin administration. 122-124 Hypo- magnesemia d e v e l o e 2 % of 44 patie- h 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 stud- ies1Z3.125 and is frequently complicated by hypocalcemia that is probably secondary to diminished PTH release and/or end-organ resistance to parathyroid hormone induced by hypomagnesemia.126 I z 7 Clinical manifestations of hypomagnesemia. 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 unre- sponsive to calcium replacement alone. The more

RlES AND KLAST ERSKY

rarely seen hypokalemia should be treated by replacement of both potassium and magnesium.

Prevention of' Cisplatin-Induced Nephrotoxiciry

Preexistent renal insufficiency should always be excluded before starting cisplatin therapy; dehy- dration, arterial hypeitension and hyperuricemia shouid be corrected; concomitant administration of nephrotoxic drugs, especially aminoglycoside antibiotics, should be avoided.Iz8

Numerous clinical trials proposing various hydration programs have been d e ~ c r i b e d . ~ ~ . ~ ~ . l ~ 9 All of these schedules are valuable, provided that hydration status is closely monitored. Most hydration programs are performed with normal saline solu- tion or glucose 5 % in saline and are given for various durations, before, during, and after cisplatin administration. Hydration alone can be considered sufficiently effective if cisplatin is administered as 20 mglm2ld by one- to two-hour infusion for five consecutive days.

Forceddiuresis programs, combining hydration with furosemide or mannitol administration, have proved clinically beneficial in numerous studies,84.130.132 and superiority of hydration-diuretic programs compared to hydration alone has been suggested.'33 Most of the more recent programs permit administration of cisplatin at doses of 100 ro 120 mg/m2 as short daily infusions or administration of 20 to 40 mglm21d for five consecutive days. Intensive parenteral hydration with mannitol-induced diuresis even permits prevention of dose-limiting nephrotoxicity. In these patients. myelotoxicity might become a major problem134; combined with cisplatin administration in hyper- tonic saline, doses as high as 200 mglm2 have been administered, with thrombocytopenia being the most promineht toxic effect."' In a recent study, three "highdosf" regimens, with doses between 180 and 220 mglm2/d, were compared: cisplatin was dissolved in 5% saline and was administered along with a well-defined prehydration-mannitol- induced diuresis and posthydration program. In that study it was concluded that cisplatin, given at a dose of 200 mg/m2 in five daily fractions, combined with an appropriate hydration and diuresis program. was devoid of significant nephrotoxicity and was probably much less ototoxic than single- bolus high-dose admini~tra t i0n. l~~ High chloride diuresis may improve the therapeutic index of cisplatin by reduced nephrotoxicity without loss of antitumor activity. Animal studies have shown in-

creased nephrotoxicity in chloridedeprived rats and significantly reduced renal damage with pharmacologically induced chloriuresis; this favorabi: effect could be explained by the reduction ni highly toxic aqueous-cisplatin complexes in chloride-rich urine. lo'

Continuous infusion of cisplatin results in reduced gastrointestinal and renal when compared with earlier studies with equal daily doses. Continuous infusion should, however, always be associated with adequate hydration programs, the influence on renal toxicity of vigorous urinary output being more important than the duration of infusion.

Pharmacologic Interaction With Cisplatin Nephrotoxici~

Unlike mannitol and furosemide, which exert their activity by inducing a potent diuresis, various other compounds have been proposed on the basis of a potential for detoxification. Among these. probenecid has been studied in animals (F344 rat model) and was shown to decrease the peak values of BUN and creatinine if administered one hour prior to cisplatin; this protection has been ascribed to probenecid inhibition of active secretion of cisplatin by the p-aminohippurate system.14' WR-2721 [S-2-(3-aminopropy1amino)-

ethylphosphorothioic acid], a radioprotective agent, has been shown to exert protective activity on renal function in the same F344 rat model.IJ2 Diethyldithiocarbamate (DDTC). a potent SH- group chelator administered to F344 rats after a known nephrotoxic dose of cisplatin. may prevent renal pathologic as well as functional changes.14' This protective activity is ascribed to competition with cisplatin for protein-bound sulfhydril groups within proximal tubular cells. Protein binding of cisplatin in tubular cells, with resultant inhibition of transport enzymes, is one postulated mechanism of cisplatin nephrotoxicity in rats and, perhaps, in humans. The closely related disulfiram (Antabuse: Ayerst Laboratories. New York). being metabolized to diethylthiocarbarnate. might exen a similar protective effect.

Sodium thiosulfate has also been studied for its nephrotoxicity preventive effects. L 4 4 This sulhr- containing compound is thought to reacr CO-

valently with cisplatin, resulting in complexes that are neither toxic nor t ~ m o r i c i d a l . ~ ~ ~ Apart from markedly reducing general cisplatin toxicity by its systemic activity, sodium thiosulfate might exert

PERSPECTIVES AND CONCLUSIONS

;

A better knowledge of various factors contribut- ing to cisplatin nephrotoxicity, as well as optimal administration programs with hydration and dmg-

further reduction in nephrotoxicity through partic- ularly 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 esca- lation 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 peni- cillarnine, might also inhibit the biologic activity

induced diuresis, have considerably changed the

of cisplatin and might, therefore, interfere with its 1 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 A Pa* 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 . l ~ ~ Comparison of acetazolamide and mannitol in the same animal model (performed by the same authors) shows acetazolamide to be more effective than mannitol in preventing cisplatin- induced nephrotoxicity in male F344 rats. lS0 The enzyme copper-zinc superoxide dismutase (orgotein) has also been associated with reduction of

I 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 cisplatin- precipitating 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. 152

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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