09 Nephrotoxicity Induced by Cancer Chemotherapy With Special Emphasis on Cisplatin Toxicity

8/2/2019 09 Nephrotoxicity Induced by Cancer Chemotherapy With Special Emphasis on Cisplatin Toxicity

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m r m c y A ~ N p C Z F - m c A t M C OZ i z - L ' p ~ ~c~10.cI $ i F - /su=Nephrotoxicity Induced b y Cancer Chemotherapy WithSpecial Emphasis on Cisplatin Toxicity

F. Ries. MD, and J. Klastersky, MDRena liailure in cancer patients Is a common problem in oncology; this complicatlon is frequently multlfactorial

In origih. Several antineoplastlc agents are potentially nephrotoxlc; previous renal mpairment as well aa comblnr.tlons with other nephrotoxic drugs may Increase he risk of nephrotoxiclty during administration of chemotherapy.Methotrexate-related renal damage most frequently occula with hlghdose therapy and can be av o ld d by t o malkaline diuresis and administration of fo llnlc acid. Renal dysfunction secondary to semustlne (CHACNU) 18clearly related o cumulative doses in excess to 1,200 mglma; the onset may be delayed and renal failure pro greudespite drug discontinuation. Streptozotocin is also nephrotoxic and may cause proteinuria and renal tubularacidosis; progressive renal failu-dicted by a close monitoring of protelnuria and preventd by drugdiscontinuance. Mltomycin-associated enal failure frequently presents with sign8 of microanglopathlc hemolyticanemia; 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 In su ff lc le n~ ~can be prevented by hydration and forced dlsuresis; i n addltlon, hyperhydratlon with mannltol-Induced 8allnedluresis may allow administration of high doses and thus circumvent the dose-limiting effect of clsplatln-Inducedrenal toxicity. Cisplatin-induced renal magnesium wasting occurs frequently and should be supplemented. C?!-;.rapproaches to reduce c~splatin ephrotoxicity 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 NCE THE KIDNEY is highly susceptible totoxic injury by a multitude of different drugs.it is not surprising that several antineoplasticagents may exert potent nephrotoxicity. In cancerpatients. however, one must always be aware ofadditive or synergistic efiects that may potentiatechemotherapy-induced nephrotoxicity. Cancer pa-tients are frequently treated with nephrotoxic anti-biotics (eg, aminoglycosides or amphotericin B).They may suffer from radiation-induced nephro-toxicity. or present with hypercalcemia. hyperuri-cemia. lysozymuria. cancer-related microan-giopathic hemolysis. or disseminated intravascularcoagulopathy. These patients also may presentwith immune complex-mediated glomerulopathyor paraprotein-'felated nephropathy, and with amy-loidosis as well as minimal-change nephritis. They

contrast media may be potentially harmful to thekidney; cancer patients frequently suffer fromurinary tract infections. It is. therefore, importantto take into account every potentially harmful ef-fect when looking for chemotherapy-relatednephrotoxicity.The agents whose potential for nephrotoxicityhas 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 greaterdetail. In addition. the reader is informed that theproblem of chemotherapy-related nephrotoxicityhas been analyzed in several review articles.'.'METHOTREXATEmay 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 mostby lower urinary tract invasion and compression. used agents in cancer chemotherapy. Used forDifferent radiologic investigations with iodine more than 30 years. MTX has shown activity in

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

Address reprinr rcquesrs ro F: Ries. MD. mrirur 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 effectC 198 6 bv rhe National Ki dt~ e; ou&iion. Inc. on hfTX plasma levels arid MTX clearance, with02 n-6386/86/08os-oo14soj. 0010 subsequent exposuro of the whole organism to per-

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


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EPHROTOXICITY OF CYTOSTATICSy elevated c on cen tr atio ns of t he d r ~ g . ~ . ~ . ~liferating or cycling cells. since those of the

e marrow and gastrointestinal tract are mostusceptible to the toxic effects of M TX and intox-with MTX secondary to renal failure, pri-

result in marrow hypop laiia and sev ere mu-cositis. Apart from causing important systemictoxicity, high plasma concentrations of MTX arealso nephrotoxic per se, and renal failur e has beenimplicated in 20% of the deaths associated withh ighdose MTX admin i s t ra t i~ n .~

qeveral mechanisms may contribute to MTX-:r~ ate d enal failure: p recipitation of M TX inrenal tubules, direct antimitotic effect on renaltubular cells, and possibly, alteration of glomeru-Iar filtration rate (GFR).Among these mecha-nisms, tubular precipitation pro ducing obstructiverenal failure is the best know n and the most widelyaccepted. MTX solubility has been shown tochange with urinary pH, and the drug was shownto be two to ten times more soluble at pH 6.9 thanat pH 5.7.9.'0 Precipitation o f the dr ug may occurin concentrated and acid urine resulting in renal~ b u l a rbstruction by an amorphous yellow mate-rial; this has been shown at autopsy examinationsof MTX-treated patients dying from acute renalf a i l ~ r e . ~he amorphous material was identified asMTX by immunofluorescent techniques. The riskof 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 prac tice, the incidence of re-nal toxicity has decreased dramatically.3th er observations suggest that MT X might in-

2ce renal failure without tubu lar precipitation be-cause oliguria or anuria are rarely found. and trueobstructive nephropathy has only been reported ina few case repc ~r ts . ~ince MTX reaches high con-centrations for prolonged periods in h e urine, re-nal tubular epi thelialc ells undergoing renewal orrepair could be potentially susceptible to this con-

- centration by time effect of the drug. 4A high-dose MTX-related decrease in GFR wasobserved in pediatric and adult pa tients,I5.l6 butthe pathogenetic mecha nism of this phenomeno n isstill unclear.MTX nephrotoxicity may be predicted by

, several tests: ( 1 ) ~ o w ' u r i n a r ~H during high-doseMTX infusion may be associated with impendingtoxicity. In high-dose MTX programs. urinary pHshould be maintained above pH 7 by intravenous

(IV) or o ra l b ica rbona te ad mi n i~ t ra t i o n .~2) A riseof serum creatinine value from baseline pretreat-ment value may identify patients at risk for addi-tional renal damage. For these patients, adminis-tration of leucovorin rescue as well as vigoroushydration and alkalinization should be consid-ered.9 (3) Monitoring of serum MTX levels is ofprimordial importance and identifies patientsneeding additional rescue measures. Leucovorinrescue should be provided until M TX s erum levels -,fal l below lo- ' m o l / ~ .7-19 i - ' i- i P '-/dl z 6 . 0 9 )

In patients with established nephrotoxicity,leucovorin rescue treatment may counteract thecytotoxic effects of MTX. Leucovorin (tetrahy-drofolate), inhibitins MTX activity by competi-tion. is administered in high-dose MTX programsat conventional dose s of 15 mg, r epeated at regularintervals12; since MTX concentrations are some-times extremely high in MTX-induced renalfailure, the doses of leucovorin rescue should beapprop r i a t e ly i nc rea~ ed .~owering of M TX levelsby means of peritoneal dialysis, hemodialysis. orhemoperfusion s eem s to be of marginal v a l ~ e . ~ ~ - ~ ~Since, in most cases. patients are not oliguric oranuric in MTX-related renal failure, high fluid in-take with alkalinization should always be main-tained. Apart from v igorous hyd ration, alkaliniza-tion. and administration of leucovorin duringhigh-dose MTX therapy, care should be taken toavoid the drug in patients who suffer from pre-liminary renal insufficiency or to postpone its usein patients who are dehydrated; urine acidifyingagents and salicglate derivatives should be avoidedbefore and during MTX treatment. Good knowl-edge and careful application of these efficientmeasures for prevention of MTX-related nephro-toxicity have been associated with the near disap-pearance of this potentially harmful complication.

SEMUSTINE (METHYL-CCNU)Semustine. l ike the other nitrosourea com-

pounds. is a highly lipid-soluble drug that hassome clinical activity in neoplasms of the brain.gastrointestinal tract. as well as malignant mela-noma. Nephrotoxicity of this compound had beendescribed in early preclinical toxicology experi-m e n t ~ , ~ , ' , ~ 'ut evidence for possible nephrotoxic-ity in humans appeared only much later in 1978and 1979.26.27 ince then. numerou s othe r reportso n s e m u s t i n e n e p h r o t o x i c i r y h a v e b e e np u b l i s l ~ e d . ~ ~ - ~ ~


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The most frequent clinical manifestation is aslowly rising serum creatinine level with progres-sive irreversible renal failure. Pathologic findingsare generally consistent with the presence of sm alland atrophic kidneys, signs of tubular atroph y, hy-alinization, glomerulosclerosis, and interstitialfibrosis.32Semustine nephrotoxicity is cumulative; renaldysfunction has been noted in 26%of patients whoreceived total cumulative do ses in excess of 1,400m g / n ~ ~ . ~ I median cumulative dose at whichnephrotoxicity is likely to occur has been esti-mated to be near 2,000 mg/m2.32It is, thus, notsurprising that this problem generally appears onlyin patients being treated fo r m ore than 1 year,which requires a prolonged survival time.Compared to the other nitrosoureas, it can benoted that sem ustine nephrotoxicity totally differsfrom that of streptozotocin, the most nephrotoxiccompound of the nitrosourea group. The other ni-trosoureas. ie, chlorozotocin, lomustine, and car-mustine. seem to be much less nephrotoxic, withonly occasional cases re porte d.The specific mechanisms of semustine-relatednephrotoxicity remain unclear and there are noestablished recommendations for toxicity protec-t i on . P roch lo rpe raz ine , a commonly usedphenothiazine with antiemetic properties, has beenreported in animal studies to reduce the frequencyas well as the severity of semustine-related renallesions33: the clinical im pact of this observationhas not yet been established.

STREPTOZOTOCINStreptozotocin is a nitrosourea that has beenused successfully in. the treatment of islet cellt u m 0 r s . ~ ~ - 3 ~enal toxicity is the major dose-limiting side"effect of this drug. Nephrotoxicity

seems to be dcse-related and. to some extent, cu-mulative. occurring most frequently at doses in ex-cess of 1.5 g / m 2 / ~k .3 7~ 3aToxicity generally presents initially as mildpr~te inur ia . '~ut with continued u se, proximal re-nal tubular damage may dev elop.3 8 Fanconi syn-drome. renal tubular acidosis. hypokalemia, renalglycosuria. hypophosphatemia, and most signifi-cantly, life-threatening oliguria and anuria havebeen reported. Nephrogenic diabetes insipidusseems to be less frequent.*.41The best prevention for potentially harmfulnephrotoxicity should be afforded by an optimal

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

Mithramycin, a naturally occurring cytotoxicantibiotic, has shown some activity against go-nadal cancer, as well as g l i o b l a s t o m a s * ~ ~ ;ow-ever, its multiple toxic side effects have precludedits widespread use. Apart from causing importanthematologic and cloning abnormalities, gastroin-testinal, central nervous, and hepatic dysfunction,as well as hypoca lcemia, it also induces renal tox-icity, manifested by signs of renal failure and pro-teinuria.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 patientstreated with the drug.4s Histopathologic changesconsist primarily of renal tubular swelling, de-generation. necrosis, and atrophy with sparing ofthe glom eruli. M ithramycin still has some applica-tions in refractory cancer-related hypercalcemia,where lower doses are general ly eff ec t i~ e.* ~. ~ '

Mitomycin C (MMC) is a naturally occurringalkylating agent, introduced for clinical use asearly as 1958. It has been demonstrated to be ac-tive against carcinomas of the gastrointest~n.:tract; breast. prostate, and a few other carcinomasas we11.49.s0Activation of mitomycin seems to require i nvivo metabolism to form short-lived metabolitesthat are highly reactive. Its serum half-life variesfrom nine to 17 minutes, and inactivation of thedrug occurs in various organs including the liverand the kidney. Renal excretion of mitomycin isnegligible.49Early reports on anima l studies had show n vari-ous nephrotoxic effects in dogs, monkeys, andmic e.s1-" Re ports on possible renal toxicity in hu-mans occurred only much later.s4 These studiesgenerally show ed m icroangiopathic changes in r h ~renal circulation with hem olytic anem ia. thrombo -cytopenia. proteinuria, hematuria, renal failure.systemic hypertension, pulmonary edema, andcongestive heart failure. This clinical syndromehas been variously described as microangiopathic


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NEPHROTOXICITY OF CMOSTATICS 371

hemolytic anemia.55 MM C-related hemo lytic- tions without any effect on progressive renaluremic syndrom e.56 and MM C n ephrotox icity.57 f a i l ~ r e . ~ ~ . ~ ~ombinations of immunosuppressiveSeveral 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 marginal1 0 p a t h y , ~ ~ - ~ lnd different authors have suggested a benefit.63 Temporary progress ion of the diseasepossible relation between both problem^.^^.^^ activity has been attributed to blood transfusions,In one large series, 140 of 143 patients treated which should, the refo re, be administered withwith mitornycin had renal impairments7; among ~ a u t i o n . ~ ~ . ~ 'emodialysis may be necessary forthese, 6 % died of renal failure. Three patients de- life-threatening renal failure, but it will not effectveloped rapidly progressive renal disease with the underlying disease process.sharp elevations of BUN and'creatinine level. hy- For patients treated with MM C, 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 berenal 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. Totion, 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. Furthertulminant 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. andrelated to repeated doses of 10 to 20 mg lm2 , with a use.

., total dose-range between 40 and 115 mglm 2. Thetime 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.70Renal toxicity of MMC is apparen tly not dose- This drug was show n to be associated with azote-related and the precise pathogenetic mechanism rnia and renal tubular d y ~ fu n c ti o n .~ ' bnormali-

.: 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 glycosu ria have also:. and thickened basement membrane.s4 intirnal hy- been d o ~ u m en te d .' ~

CISPLATINIn 1969, platinum comp ounds were reported by

. tients with MMC-associated hernolytic-uremic Rosenberg et al to exen potent antitumor activitysyndrom e63; these immune complexes showed in mice73; cisdiamm inedichloroplatinum I1 (cis-high platelet aggregation activity in vitro. T he platin) was the most active dru g amon g these com -constituent antibody of each complex faded to p o u n d ~ . ~ ~isplatin, therefore, entered toxicologicreact with MM C antigen preparations , whereas in evaluation in before introduction intovitro reactivity to endodermally derived neo- phase I clinical trial^.^^-^' Since then, cisplatin hasplasms could be detected. These data suggest that been studied in numerous phase 111111 trials (aloneMM C might not be the only etiologic factor of this or with other agents) , and it has proven t o be onesyndrome, but that some tumor-specific relation- of the most potent chemotherap eutic ag ents, beingship might exist as well. active in cancer of the ov ary ,8 4 t e ~ t i s , ~ . ~ ~lad-M itomycin -a ssoc ia ted nephrotoxic r eactions de r, 87 -89 ead and neck ,90 l ~ n g , ~ ' . ~ ~ndome-must be c~ns idered efrac tory to most trea tments t r i ~ m . ~ ~terine c ervix ,94 and many o thers.studied until now. In small studies. steroids, anti- Several excellent reviews deal with problem s suchf 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 . ~ ~ ~ ~ ~ ~lasmapheresis 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


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cisplatin-induced nephrot~xici ty'~hat proved tobe dose related.76 These and other reports withstudies performed on various animal modelsshowed a strong relationship between the adminis-tered dose and uremia, as well as dose-relatedstructural alterations detected on microscopic kid-ney examination. These alterations consisted pre-dominantly in tubular necrosis. As could be ex-pected from animal studies, early clinical reportsshowed similar toxicity in humans.78-m.82.a3n pa-tients with n&mal kidney function, rising BUNlevels were noted during the second week after abolus cisplatin administration in excess of 50 mg/m2 of body surface area (BSA); reversible nephro-toxicity was generally noted between 50 and 75mglm2ld, while doses 2 100 mglm21d were fre-quently followed by acute renal failure with pro-nounced tubular cell necrosis. Renal failure pro-gressing from reversible to irreversible stages wasdescribed with repeated treatment courses. Theseearly studies were performed without particularhydration or drug-induced diuresis programs.Several authors have reviewed the problem ofcisplatin-related nephrotoxi~ity~~~-~~~;he conclu-sions of their articles. as well as more recent infor-mation, will be analyzed in the following discus-sion. In fact, cisplatin nephrotoxicity remains ofparticular interest since renal damage is one of itsmost critical side effects and frequently constitutesa dose-limiting factor.Mechanism of Acrion and Implicationsfor Renal Toxici~

Several studies suggest that cisplatin exerts itsactivity in a manner similar to aklylating agents bydrug interaction with \the nucleophilic sites ofpyrimidines in DNA.97.98.'06 hese infrastrandDNA cross-link will occur after physiologic ac-tivation of the dnlg, which will take place in a low

u 1"UiCl , 103 .MIL1Fig 1. Chloridedependent aquation reactions ofcisplatin.

chloride concentration environment: cisplatin pas-sage from a chloride-rich plasmatic milieu ( !03mEq/L) to a low-chloride invacytoplasmic mii;.. I(4 mEqIL) constitutes a passage from electr:.s.,lneutrality (with a stable bis-chloro molecule [I]) toaqueous activation (II, III, V), chloride ligands inthe cis position being replaced by water molecules(Fig 1). These aquated forms are highly reactivewith nucleophiles and can loose hydrogen ions toform cytotoxic hydroxyl radicals (IV, V); these lat-ter compounds can also form cytotoxic oxygen-bridged dimers and trimers. At equilibrium, theproportion between these diversely cytotoxic corn-plexes depends on chloride concentration and, to alesser extent, on pH and total platinum concentra-tion. 107.108

Since platinum tissue concentrations are panl;larly high in the kidneys after drug admini~tratit~;~in dogs and hurnan~,~5.'~~nd data suggesting anactive tubular secretion of cisplatin or metabo-lites,'10-112t can be hypothesized that renal toxic-ity might be similar to its general cytotoxic effects.This implies that intratubular reduction of cisplatinconcentration by abundant hydration, as well asactivation of tubular chloride reuptake by forcedchlouresis, might favorably influence the equilib-rium between stable nontoxic cisplatin 0) andaquated forms (11, III, V), as well as cytotoxic hy-droxyl species (IV,VI), thereby reducing renal t u -bular damage without affecting general cytotoxic-ity.Cisplarin Tissue Disrriburion, Pharmacokinetics.and Renal Handling

After IV administration. cisplatin undergoesrapid distribution to nearly all organs. Tissueplatinum concentration studies at various points af-ter cisplatin administration in dogs show a veryrapid accumulation of the metal in the kidney(three to four times the plasma concentration tenminutes after administration) with persistently ele-vated values fbr more than 1 week. op A very highpostmortem renal concentration of platinum hasalso been reported in humans two days after ad-ministration of a single dose of 2 mg/kg of ciiplatin.95 Platinum concentrates in various othertissues (gonadal tissue, lung, liver, fat)lo9;studiesin humans have shown that 90% of the drug isprotein-bound in plasma and that 27 % to 45% ofth e drug is excreted in the urine within five days ofadministration.11 3 Data on free platinum renalclearance in humans indicate that platinum clear-


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ance exceeds the GFR, suggesting active secretion[of the drug or a metab01ite.I~~ s might be ex--petted, cisplatin pharmacokinetics are altered ini atients with renal insufficiency, and normal ori near normal values of creatinine clearance are\generally considered necessary in order to avoidjcxcessive nephrotoxici@ This general rule seems, to be of questionable importance in cases of age-related decrease in renal function and especially incases of a unique functional kidney. In fact, bothconditions generally result in a lower 24-hourcreatinine clearance, but as has been shown in arecent clinical study, they are not associated withgreater renal toxicity if standard hydration is per-formed and if cisplatin dosage does not exceed 60mg/m2/d. I 4 This study even suggests a protectivemechanism in patients with unique kidneys (14 of43 patients studied) compared with those with twonormally functioning kidneys. In fact, the reducednumber of nephrons will produce a higher flow ofultrafiltrate per tubule with lower tubular cisplatinconcentration and probably less tubular "contact"between the toxin and tubular epithelium. This isillustrated by a higher than normal 24-hour diure-sis, wit!! lower cisplatin urinary concentrations foran identical cisplatin dose and hydration programin these patients, compared with those with two' ormally functioning kidneys. A similar mecha-nism is thought to contnbute to the relative lack ofexcessive age-associated cisplatin-induced nephro-toxicity.

. Other studies (in animals and humans), based onrhythmic changes in kidney function, according tocircadian rhythms, have shown that optimal renaltolerance of cisplatin occurs very near to the timeof day associated with the normal circadian max-imum in urinary volume. This beneficial effect ispotentiated by concurrent hydration and is corre-lated by lower urinary cisplatin concentra-tions. 15- I l 7 These studies, along with those on hy-dration and forced diuresis suggest the primordialrole of reducing cisplatin urinary concentrationsby high urinary output; in fact. direct tubular ex-posure for a few hours to a concentration of 200pg/mL of cisplatin seems to be necessary for tubu-lar damage to occur.96Parhologic Kidney Changes

As documented by animal and human studies.cisplatin induces several microscopic kidneychanges that are dose-related and, to a lesser de-gree. cumu!ative. 96,102, '03.118 These changes in-

clude epithelial cell degeneration, proximal tubu-lar necrosis, dilatation and necrosis of distaltubules, interstitial edema. and lymphocytic in-filtration. Glomerular changes are generally notobserved and most alterations are considered to benonspecific. Tbbular damage is also suggested bysensitive assays for tubular enzymes, thought to beliberated by renal injury: alanine-aminopeptidase,N-acetyl-0-glucosaminidase (NAG) l 9 . I z 0 ;these studies support the concept that all areas ofthe tubule may be injured to some extent.

Studies on urinary activity of NAG, a lysosomalenzyme released into the urine from the brush bor-der of proximal tubular cells, have shown a posi-tive correlation between cisplatin nephrotoxicityand NAG urinary activity. Potentiation of cisplatintissue uptake by NAG tissue activity has been re-

as well as a circadian rhythm of urinaryNAG activity, suggesting that rhythmic changes inNAG activity may cause variations in cisplatinnephrotoxicity along with circadian rhythms. PZ -microglobulin, possibly another mediator of tubu-lar injury, was shown to be significantly elevatedin the urine 12 hours after treatment with cis-platinI2l: since no patient in that report developedlaboratory evidence of renal toxicity, this in-creased /32-microglobulinuriahas been interpretedas reflecting subclinical renal damage.Hypomagnesemia and renal magnesium wastingare the most prominent electrolytic disorders sec-ondary' to cisplatin administration. 1 2 2 - 1 2 4 Hypo-magnesemia d e v e l o e 2 % of 44 patie-h e eriesLz2 ith a treatment schedule of 70 mg/m2 cisplatin (on day l ) , repeated every 21 days.Among patients with hypomagnesemia. the nadirMg concentration (median) was 0.92 mEq/L.usually occumng more than 2 weeks after drugadministration and generally after one or twocourses of cisplatin had been given. Similar hypo-magnesemia was also observed in other stud-ies1Z3.125nd is frequently complicated by hypo-calcemia that is probably secondary to diminishedPTH release and/or end-organ resistance toparathyroid hormone induced by hypomagnese-mia.126z 7 Clinical manifestations of hypomagne-semia. including abnormalities in neuromuscular.central nervous system. and cardiac function thatmay appear for serum levels of less than 1 mEq/L.should be treated by parented replacement ofmagilesium sulfate. Associated hypocalcemia isresponsive to .magnesium repletion and is unre-sponsive to calcium replacement alone. The more


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RlES AND KLASTERSKYrarely seen hypokalemia should be treated by re-placement of both potassium and magnesium.Prevention of'Cisplatin-Induced Nephrotoxiciry

Preexistent renal insufficiency should always beexcluded before starting cisplatin therapy; dehy-dration, arterial hypeitension and hyperuricemiashouid be corrected; concomitant administrationof nephrotoxic drugs, especially aminoglycosideantibiotics, should be avoided.Iz8Numerous clinical trials proposing various hy-d ra tio n p ro gr am s h av e been d e ~ c r i b e d . ~ ~ . ~ ~ . l ~ 9llof these schedules are valuable, provided that hy-dration status is closely mon itored. Most hydrationprograms are performed with normal saline solu-tion or glucose 5% in saline and are given for vari-ous durations, before, during, and after cisplatinadministration. Hydration alone can be consideredsufficiently effective if cisplatin is administered as20mglm2ld by one- to two-hour infusion for fiveconsecutive day s.

Forceddiuresis programs, combining hydrationwith furosemide or m annitol administration, haveproved clinically beneficial in numerous stud-ies,84.130.132nd superiority of hydration-diureticprograms compared to hydration alone has beensuggested.'33 Most of the more recent programspermit administration of cisplatin at doses of 100ro 120mg /m2 as short daily infusions or adminis-tration of 20 o 40 mglm21d for five consecutived a y s . I n t e n s iv e p a r e n t e r a l h y d r a t i o n w i thmannitol-induced diuresis even permits preventionof dose-limiting nephrotoxicity. In these patients.myelotoxicity might become a major problem134;combined with cisplatin administration in hyper-tonic saline, doses as high as 200mgl m2 have beenadministered, with thrombocytopenia being themos t promineht toxic effect."' In a recent study,three "hig hdo sf" regimens, with doses between180 and 220 mg lm2 /d, were compared: cisplatinwas dissolved in 5% saline and was administeredalong with a well-defined prehydration-mannitol-induced diuresis and posthydration program. Inthat study it was concluded that cisplatin, given ata dose of 200mg /m2 in five daily fractions, com-bined with an appropriate hydration and diuresisprogram. was devoid of significant nephrotoxicityand was probably much less ototoxic than single-bo lus h igh-dose admin i~ t ra t i0n . l~~igh chloridediure sis may improve the therapeutic index of cis-platin by reduced nephrotoxicity without loss ofantitumor activity. Animal studies have shown in-

creased nephrotoxicity in chloridedeprived ratsand significantly reduced renal damage with phar-macologically induced chloriuresis; this favorabi:effect could be explained by the reduction nihighly toxic aqueous-cisplat in complexes inchloride-rich urine. lo 'Continuous infusion of cisplatin results in re-duced gastrointestinal and renalwhen compared with earlier studies with equaldaily doses. C ontinuous infusion should, however,always be asso ciated with adequate hydration pro-grams, the influence on renal toxicity of vigorousurinary output being more important than theduration of infusion.Pharmacologic Interaction WithCisp la t in Nephro tox ic i~

Unlike mannitol and furosemide, which exerttheir activity by inducing a potent diuresis, variousother compounds have been proposed on the basisof a potential for detoxification. Among these.probenecid has been studied in animals (F344 atmodel) and w as shown to decrease the peak valuesof BUN and creatinine if administered one hourprior to cisplatin; this protection has been ascribedto probenec id inhibition of activ e secretion of cis-platin by the p-aminohippu rate system.14'WR-2721 S-2-(3-aminopropy1amino)-ethylphosphorothioic acid] , a radioprotect iveagent, has been shown to exert protective activityon renal function in the same F344 rat model.IJ2Diethyldithiocarbamate (DDTC). a potent SH-group chelator administered to F344 rats after aknown nep hrotoxic dose of cisplatin. may preventrenal pathologic a s well as functional changes.14'This protective activity is ascribed t o comp etitionwith cisplatin for protein-bound sulfhydril groupswithin proximal tubular cells. Protein binding ofcisplatin in tubular cells, with resultant inhibitionof transport enzymes, is one postulated mecha-nism of cisplatin nephrotoxicity in rats and,perhaps, in humans. The closely related disulfiram(An tabus e: Ayerst Laboratories. N ew York). beingmetabolized to diethylthiocarbarnate. might exen asimilar protective effect.

Sodium thiosulfate has also been studied for itsnephrotoxicity preventive effects. L44 T h i s s u lh r -containing compound is thought to reacr CO -valently with cisplatin, resulting in com plexe s thata re n eith er toxic n or t ~ m o r i c i d a l . ~ ~ ~part frommarkedly reducing general cisplatin toxicity by itssystemic activity, sodium thiosulfate might exert


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PERSPECTIVES AND CONCLUSIONSA better knowledge of various factors contribut-

ing to cisplatin nephrotoxicity, as well as optimaladministration programs with hydration and dmg-

further reduction in nep hrotoxicity through partic-ularly high intratubular thiosulfate to cisplatin c on-centration ratios. Intravenous sodium thiosulfateseems to be a most intiresting agent when ad-ministered in combination with intraperitoneal cis-platin. eg, for ovarian cancer. In this indication.parenteral thiosulfate adniinistration allowed e sca-lation of intraperitoneal cisplatin up to a dose of270 mg /m2 without significant nephrotoxicity, thuspermitting an increased activity.i4s Other sulfurcompounds, 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 itstherapeutic a s well as toxic effects.1 4C 148The carbonic anhydrase inhibitor acetazolarnidehas also been considered potentially useful for p re-vention of cisplatin nephrotoxicity. 49.1s0 APa*from its activity as a diuretic, this organic acidcould act by com petition with cisplatin for tubularreabsorption, thus promoting cisplatin excretion:however, the presence of two sulfur atoms in thismolecule could also permit chemical interactionand detoxification. In an animal study (male F 344rat model), pretreatment with acetazolarnide de-creased cisplatin nephrotoxicity and diminishedrenal platinum content, as well as urinary platinume ~ c r e t i 0 n . l ~ ~omparison of acetazolamide andmannitol i n the same animal model (perform ed bythe same authors) shows acetazolamide to be mo reeffective than mannitol in preventing cisplatin-induced nephrotoxicity in male F344 rats. l S 0 Theenzyme copper-zinc superoxide dismutase (orgo-tein) has also been associated with reduction ofnephrotoxicity in rats, thus suggesting that su-peroxide radicals may participate i n the nephro-to xic effe cts of c i ~ p l a t i n . ~ ~ ~Selenium. known for its ability to combine tometals such as cadmium and mercury, as well asfor its resem blance to sulfur by its chem ical prop -erties, shows theoretical promise as a cisplatin-precipitating agent. As shown in studies on mice.selenium is able to decrease cisplatin neph rotoxic-ity without influencing in vivo and in vitro tumorgrowth. This could suggest either detoxificationby ligation to sites not involved in cisplatin antitu-mor activity or, perhaps, prevention of tubularreabsorption of the mo1esu:ar complex. 1 5 2

spectrum of cisplatin's potential for renal toxicity.Introduction of some of the new detoxificationagents will probably prove useful as well. Dosingplasma cisplatin levels at various times after druginfusion could be helpful to predict nephrotoxicityearly in the course of cisplatin infusion . I s3 Finally,several second-generation platinum com plexes arebeing evaluated in preclinical and clinical studiesfor toxicity and antitumor activity. Among these,i p r o p l a t i ~ u m ( C H I P ) a n d c a r b op l a ti n u rn(C BD CA ) show l ittle or no n e p h r o t o x i ~ i t y . ~ ~ ~ - ~ ~ ~These and other platinum com poun ds are possiblycandidates as future alternatives to cisplatin inseveral conditions. Until then. however, cisplatinremains one of the most potent antineoplasticagents ever developed. Further work should beperformed to reduce its potential for renal toxicity.

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09 Nephrotoxicity Induced by Cancer Chemotherapy With Special Emphasis on Cisplatin Toxicity

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