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Nephrotoxicity From ChemotherapeuticAgents: Clinical Manifestations,

Pathobiology, and Prevention/Therapy

Mark A. Perazella, MD, FASN,* and Gilbert W. Moeckel, MD, PhD, FASN†

Summary: Nephrotoxicity remains a vexing complication of chemotherapeutic agents. Anumber of kidney lesions can result from these drugs, including primarily tubular-limiteddysfunction, glomerular injury with proteinuria, full-blown acute kidney injury, and long-termchronic kidney injury. In most cases, these kidney lesions develop from innate toxicity ofthese medications, but underlying host risk factors and the renal handling of these drugsclearly increase the likelihood of nephrotoxicity. This article reviews some of the classicnephrotoxic chemotherapeutic agents and focuses on examples of the clinical and his-topathologic kidney lesions they cause as well as measures that may prevent or treatdrug-induced nephrotoxicity.Semin Nephrol 30:570-581 © 2010 Published by Elsevier Inc.Keywords: Chemotherapy, cancer, drugs, nephrotoxicity, cisplatin, methotrexate,ifosfamide, pamidronate

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apid advances in cancer therapy havechanged the landscape of oncology forpatients and practitioners. Patients are

eriving significant benefit with increased sur-ival, decreased tumor progression, and inome cases with less severe overall adverserug effects. Unfortunately, nephrotoxic effectsf these agents remain a significant untowardomplication, and sometimes limit effectiveherapy.1-6 Clinicians ordering these drugs andephrologists consulting when an adverse renalvent develops should be familiar with the pa-ient factors that increase nephrotoxic risk,linical and histopathologic manifestations ofenal toxicity, and prevention and treatment ofhemotherapy-induced nephrotoxicity. This ar-icle reviews these areas, focusing on drugs thatepresent examples of the various types of kid-ey toxicity that develop from these agents.

Section of Nephrology, Department of Medicine, Yale University School ofMedicine, New Haven, CT.

Department of Pathology, Yale University School of Medicine, New Haven,CT.

ddress reprint requests to Mark A. Perazella, MD, FASN, Section of Ne-phrology, Boardman Building 114, 330 Cedar St, New Haven, CT 06520-8029. E-mail: [email protected]

270-9295/ - see front matter
a2010 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2010.09.005
Seminars in N70

ISK FACTORS FORNHANCED NEPHROTOXICITY

he nephrotoxicity of chemotherapeutic agentss enhanced by underlying host risk factors, gen-ral renal handling of these drugs, and innateoxicity of the individual agent (Table 1). Morehan one of these factors commonly conspireso increase risk for nephrotoxicity. Importantly,arious forms of malignancy are associated withisk for many of these factors. For example,oth true and effective decreases in circulatinglood volume, hepatic dysfunction and obstruc-ive jaundice, metabolic disturbances, and nu-erous forms of acute or chronic kidney injury

esult from either direct cancer effects or otherndirect effects of the malignant process. As

any as 60% of patients manifest some formf kidney disease.1 Examples include myeloma-ssociated kidney disease, renal infiltration byumor, secondary glomerulonephritides (ie,embranous glomerulonephritis), urinary ob-

truction from various cancers, tumor lysisyndrome, hypercalcemia, and other forms ofeoplastic injury. Host factors, kidney drugandling pathways, and drug toxicity factors
re briefly reviewed later.
ephrology, Vol 30, No 6, November 2010, pp 570-581

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Nephrotoxicity from chemotherapeutic agents 571

ost Factors

onmodifiable risk factors such as older agend female sex are associated with reductionsn total body water and unrecognized lowerlomerular filtration rate (GFR) despite normalerum creatinine levels, leading to drug over-osage. The elderly, often afflicted by cancer,ave increased propensity to vasoconstrictionrom excessive angiotensin-II and endothelinnd higher levels of oxidatively modified bi-markers.7

Vomiting, diarrhea, and diuretic use lead torue volume depletion, while congestive heartailure, ascites, and sepsis promote effective vol-me depletion in cancer patients receiving che-otherapy and increase renal vulnerability to var-

ous agents. In addition, malignancy-inducedephrotic syndrome and hepatic dysfunction in-rease risk through multiple mechanisms that in-lude altered renal perfusion from reduced effec-ive circulating blood volume, hypoalbuminemiaith increased free circulating drug, and unrec-gnized renal impairment.8-10 Cancer-associatedbstructive jaundice also enhances toxicity toertain drugs through decreased renal bloodow and direct effects of bile salts on tubularpithelia.11 Renal hypoperfusion and prerenalzotemia increase nephrotoxicity of drugs ex-reted primarily by the kidney, in those reab-orbed in the proximal tubule, and in those thatre insoluble in the urine, where crystal precip-tation occurs within distal tubular lumens withluggish flow.8-10,12

Metabolic disturbances resulting from cer-ain tumors also increase renal vulnerability toertain drugs and potential toxins. Severe hy-ercalcemia, which often complicates my-loma and lung cancer, induces afferent arterio-ar vasoconstriction and renal sodium/water

asting, leading to prerenal physiology, whichnhances nephrotoxic drug injury. Systemicetabolic acidosis may decrease urine pH and

ncrease intratubular crystal deposition withrugs such as methotrexate and its metabolites,hich are insoluble in a low pH environment.12

yperuricemia and acute tumor lysis exacer-ate renal injury further.

Underlying acute kidney injury (AKI) andhronic kidney disease (CKD) are important

Table 1. Risk Factors for Chemotherapy-Induced Renal Toxicity

Host factorsOlder age and female sexNephrotic syndrome, cirrhosis, obstructive

jaundiceAcute or chronic kidney diseaseTrue or effective circulating blood volume

depletionDiminished GFRIncreased proximal tubular toxinreabsorption

Sluggish distal tubular urine flow ratesMetabolic disturbances

Hypokalemia, hypomagnesemia,hypocalcemia

HypercalcemiaAlkaline or acid urine pH

Immune response genesIncreased allergic reactions to drugs

Pharmacogenetics favoring drug/toxintoxicity

Gene mutations in hepatic and renalcytochrome P450 enzyme systems

Gene mutations in transport proteinsand renal transporters

Renal drug handlingHigh blood (and drug) delivery rate to the

kidneysRelatively hypoxic renal environmentIncreased drug/toxin concentration in

renal medulla and interstitiumBiotransformation of substances to reactive

oxygen species, causing oxidative stressHigh metabolic rate of tubular cells in the

loop of HenleProximal tubular uptake of toxins

Apical tubular uptake via endocytosis orother pathway

Basolateral tubular transport via organicanion transporter and organic cationtransporter pathways

Innate drug toxicityHigh-dose drug/toxin exposure and

prolonged course of therapyInsoluble drug or metabolites form crystals

within the intratubular lumensPotent direct nephrotoxic effects of the

drug or toxinDrug combinations enhance nephrotoxicity

Nonsteroidal anti-inflammatory drugs,aminoglycosides, radiocontrast

isk factors for increasing vulnerability to neph-

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572 M.A. Perazella and G.W. Moeckel

otoxic injury.8-10 Excessive drug dosing, expo-ure of a reduced number of functioningephrons to toxins, development of ischemia-pre-onditioned tubular cells, and more robust renalxidative injury response to toxins are all contrib-tors in these 2 settings.

The underlying genetic makeup of the hostlso can enhance renal vulnerability to potentialephrotoxins.13-15 The drug or its metaboliteorm adducts that modify their physical struc-ure, making them more immunogenic. Aeightened allergic response owing to differ-nces in innate host immune response genesan predispose certain patients to developmentf drug-induced acute interstitial nephritis.harmacogenetics also may explain the hetero-eneous response of patients to drugs as itelates to efficacy and toxicity. Renal cyto-hrome P450 enzymes importantly participaten drug metabolism13-15 and gene polymor-hisms favoring reduced metabolism could in-rease nephrotoxic risk as well. Polymorphismsf genes encoding proteins involved in the me-abolism and subsequent renal elimination ofrugs have been described and are correlatedith various levels of drug sensitivity. Loss-of-

unction mutations in apical secretory trans-orters and mutations in kinases that regulaterug carrier proteins can impair drug elimina-ion and promote nephrotoxicity by increasingntracellular toxin concentrations.14

enal Drug Handling

he mechanism by which the kidney metabo-izes and excretes various drugs also may in-rease nephrotoxicity. Significant renal expo-ure occurs owing to the high rate of drugelivery to the kidney, a result of the high bloodow to the kidney, which approaches 25% ofardiac output. Many renal cells, particularlyhose in the loop of Henle and medullary col-ecting duct, exist in a relatively hypoxic envi-onment owing to the high metabolic rates re-uired by active transport processes andecreased blood flow to inner-medullary re-ions. This excess cellular workload and hy-oxic environment promotes increased sensi-ivity to injury when exposure to potentiallyephrotoxic substances occurs.16,17 High con-
entration of parent compounds and their me- a
abolites accumulate in the renal medullaryells and interstitium through the enormousoncentrating ability of the kidney.16,17 In-reased tissue concentration of these drugs pro-otes injury through both direct toxicity and

schemic damage.Biotransformation of drugs by multiple renal

nzyme systems, including cytochrome P450nd flavin-containing monooxygenases, favorshe formation of toxic metabolites and reactivexygen species.16-18 The presence of these by-roducts of metabolism tilts the balance in

avor of oxidative stress, which outstrips nat-ral antioxidants and increases renal injury viaucleic acid alkylation or oxidation, proteinamage, lipid peroxidation, and DNA strandreaks.16-18

Enhanced toxicity in proximal tubular cellsccurs as a result of the extensive cellular up-ake of drugs by basolateral transport systems.roximal tubular cell toxin exposure occurs viaasolateral delivery of exogenous organic ionsy peritubular capillaries.19,20 Drug delivery viaeritubular capillaries is followed by uptake

nto proximal tubular cells via a family of trans-orters, including human organic anion andation transporters.19,20 Loss-of-function muta-ions in and competition for apical secretoryransporters,21 which reduces toxin efflux fromell into urine, may promote accumulation ofoxic substances within the proximal tubularell and cause cellular injury via apoptosis orecrosis. This extensive trafficking of sub-tances increases renal tubular exposure andisk for increased concentration of toxin whenther risk factors supervene.

nnate Drug Toxicity

he underlying characteristics of the offendingrug also play an important role in the devel-pment of nephrotoxicity. Prolonged therapyt high doses with toxic drugs enhances renalnjury based on excessive renal exposure, evenn the absence of other risks. Methotrexate andts metabolites are insoluble in human urine and

ay cause renal injury through tubular obstruc-ion or direct toxicity. Drug combinations alsoncrease the risk of nephrotoxicity. Exposure torugs such as aminoglycosides, nonsteroidal
nti-inflammatory drugs, radiocontrast, and other

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ephrotoxins are examples of enhanced nephro-oxic risk when cancer chemotherapeutic agentsre administered concurrently.8-10

A unique and newly recognized form ofephrotoxicity has been described with anti-ngiogenesis therapy.22,23 Vascular endothelialrowth factor, produced by podocytes, is re-uired to maintain normal fenestrated endothe-

ial cell function and is particularly importantor normal functioning of the glomerular base-ent membrane.24 Reduction in vascular endo-

helial growth factor or its effects by the variousnti-angiogenic drugs leads to loss of theealthy fenestrated endothelial phenotype andromotes microvascular injury and thromboticicroangiopathy, causing proteinuria and kid-

ey disease. Reduced nephrin expression in thelit diaphragms from these drugs also may con-ribute further to proteinuria.23,25

OTENTIALONSEQUENCES OF NEPHROTOXICITY

nfortunately, several untoward consequencesay develop from kidney injury caused by

hese drugs. Acute effects include increasedorbidity such as infectious complications,rolonged length of hospital stays, increasedosts, and higher mortality rates. These acuteomplications are caused in part by the adverseffects of AKI itself as well as the extrarenaloxicities of high drug levels from underex-reted drugs in the setting of reduced GFR.hese include bone marrow suppression;reakdown of skin and other mucosal barriers;olume depletion with hypotension from vom-ting, diarrhea, and other insensible losses; andther end-organ dysfunction. Also, the occur-ence of AKI very often leads to loss of tumorherapy owing to withholding, discontinuing,r underdosing of chemotherapeutic agentshile renal function is abnormal. Removal withialysis or continuous renal replacement ther-py may reduce drug efficacy further. This ulti-ately may impair effective tumor therapy and

ltimate death from progressive cancer.A two-fold increase in mortality was noted in

ritically ill patients with cancer who devel-ped a 10% increase in serum creatinine level.26

ortality rates of hospitalized patients with a
alignancy and AKI in the setting of multi- t
rgan dysfunction range from 72% to 85%,igher than those without cancer.2 Many ofhese patients likely develop severe AKI thatequires acute dialysis or continuous renal re-lacement therapy.Patients who survive their malignancy may

ery well be left with some level of CKD orven end-stage renal disease requiring long-erm dialysis therapy or renal transplantation.oth CKD and end-stage renal disease are asso-iated with increased morbidity (anemia, renalsteodystrophy, cardiovascular disease, malnu-rition, and others) and mortality. Hypertensionften accompanies kidney disease, increasingisk for other cardiovascular complicationsbove and beyond that associated with CKDlone. Metabolic complications such as hypoka-emia, hypophosphatemia, metabolic acidosis,nd hypomagnesemia may complicate therapynd cause assorted chronic conditions such assteomalacia, osteoporosis, increased risk forardiac arrhythmias, muscle cramping, andhronic inflammation. Metabolic disturbancesan be permanent, depending on agent andose administered.

LINICAL PRESENTATIONND PATHOLOGIC CORRELATION

t is critical for clinicians to recognize thearly symptoms and signs of nephrotoxicityn patients receiving culprit chemotherapeuticgents. Unfortunately, small changes in renalunction (0.3-mg/dL increase in serum creati-ine level) that meet the definition of AKI oftenre clinically asymptomatic. Thus, those provid-ng care to these patients must monitor serumhemistries and examine the urine with urinal-sis and microscopy to recognize renal dysfunc-ion as early as possible. Because it is not pos-ible to cover all of the clinical presentations,e will review those that are of most interest or

epresent newer nephrotoxins. Four major clin-cal presentations will be discussed: tubulopa-hies, AKI, nephritic/nephrotic syndrome, andhronic kidney disease (Table 2).

ubulopathies

everal agents are capable of causing isolated
ubular injury. Many cause both tubular injury

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nd a reduction in GFR (either AKI or CKD),specially with higher doses. Drugs that causenjury to one or more tubular segments includeisplatin, ifosfamide, azacitidine, and diazi-uone, all of which are associated with Fanconiyndrome (FS).1-5 Cetuximab causes isolated re-al magnesium wasting whereas imatinib andefitinib promote renal phosphate wasting and

Table 2. Categories of Chemotherapy-Induced Renal Toxicity

TubulopathiesFS

Cisplatin, ifosfamide, azacitadine,Diaziquone, imatinib, gefitinib

Salt wastingCisplatin, azacitidine

Magnesium wastingCisplatin, cetuximab, panitumumab

NDICisplatin, ifosfamide

Syndrome of inappropriate antidiuretichormone

Cyclophosphamide, vincristineAKI

Prerenal kidney injury (capillary leaksyndrome)

Interleukin-2, denileukin diftitoxAcute tubular necrosis

Platinums, zoledronate, ifosfamide,mithramycin

Pentostatin, imatinib, diaziquoneCrystal nephropathy

MTXThrombotic microangiopathy

Mitomycin C, gemcitabineNephritic/nephrotic syndromes

Thrombotic microangiopathyAnti-angiogenesis agents, mitomycin C,gemcitabine

Minimal change diseaseInterferon, pamidronate

FSGSInterferon, pamidronate

CKDChronic interstitial nephritis

Nitrosureas, cisplatin, MTXGlomerulosclerosis

Nitrosureas

ypophosphatemia as the result of a partial Fan- p

oni syndrome.1 Drugs such as vincristine andyclophosphamide enhance release of antidi-retic hormone, increasing risk of hyponatre-ia from inappropriate water retention. Only

fosfamide and cetuximab are discussed.Ifosfamide is well known to cause proximal

ubular injury and FS, as well as nephrogeniciabetes insipidus (NDI), and, less commonly,KI. The metabolite chloracetaldehyde is thought

o cause tubular injury. Risk factors for renalnjury include previous exposure to cisplatin,nderlying CKD, and cumulative dose exceed-

ng 90 g/m2.1,2 Moderate to high risk of toxicityccurs with doses in excess of 100 g/m2.1,2

hese various tubulopathies can be perma-ent in 25% (moderate to severe) to 44%mild) of patients.4,27 FS, which occurs in upo 25% of patients, is characterized by urinaryasting of potassium, phosphate, bicarbon-

te (type 2 renal tubular acidosis), uric acid,nd glucose. Symptoms reflecting these elec-rolyte, divalent, and acid-base disturbancesay develop, however, the syndrome most

ften comes to attention from abnormal se-um (hypokalemic metabolic acidosis, hy-ophosphatemia) and urine (glucosuria, phos-haturia) test results.1-3 Over time, chronicffects of these abnormalities include osteoma-acia, osteoporosis, hypokalemic nephropathy,nd enhanced cardiac arrhythmias in certainatients. NDI is manifested as polyuria unre-ponsive to vasopressin. Hypokalemia can ex-cerbate this problem further through directubular effects.

The histopathologic features of FS inducedy ifosfamide are similar to those found withther causes of this entity. By light microscopy,

oss of proximal tubule brush-border mem-rane and mild acute tubular injury is often thenly detectable lesion. Examination of ultra-tructural changes by transmission electron mi-roscopy reveals abnormal mitochondrial dila-ion with absent cristae (Fig. 1A). Abnormalitochondrial function leads to impairment of

odium-potassium adenosine triphosphataseump that maintains the sodium gradientcross the proximal tubular epithelium. Thefosfamide metabolite chloracetaldehyde haseen shown to impair proximal tubular trans-
ort through a similar mechanism.28

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Cetuximab, a monoclonal antibody againsthe epidermal growth factor (EGF) receptor, is

new anticancer agent used for metastaticolorectal cancer and other malignancies.1 Uri-ary magnesium wasting is its major adverseenal effect. The EGF receptor is expressed inenal epithelia, where EGF binding activates theg�� channel TRPM6 (transient receptor po-

ential cation channel, subfamily M, member 6)n the apical membrane of the distal convolutedubule, ultimately promoting Mg�� reabsorp-ion. Not surprisingly, EGF-receptor blockadeith cetuximab causes magnesuria, potentially

eading to severe hypomagnesemia in approxi-ately 10% to 15% of patients. Diagnosis is

linched by showing an increased fractionalxcretion of magnesium (�15% in the setting ofypomagnesemia). Panitumumab, another EGF-eceptor antibody, also is associated with mag-esuria because 36% of treated patients in a

igure 1. (A) Ultrastructural findings of ifosfamide-inducrush-border membrane. The cytoplasm shows small vamagnification, 12,000�). (B) ATI seen in a case of cispilation with flattened epithelium and extensive nucleaenuded (periodic acid–Schiff, 200�). (C) Transmissio

ntraluminal large fibrin thrombus in a case of mitomycinwelling and numerous fibrin tactoids are present withinith collapsing glomerulopathy in a patient treated wit

ontracted, podocytes are enlarged, and there is early t

hase III trial developed hypomagnesemia, of d

hich 3% manifested severe symptomatic hy-omagnesemia.1 Oral and intravenous magne-ium supplementation often are required to re-uce cramping, arrhythmias, and other relatedlectrolyte disturbances (hypokalemia).

KI

nfortunately, chemotherapeutic agents are aommon cause of AKI (Table 2). The traditionallassification of AKI can be applied to these drugsecause they cause injury in all renal compart-ents—prerenal, intrinsic (parenchymal), andostrenal.1-6 Most commonly, AKI results fromcute tubular injury (ATI) that occurs in a dose-elated fashion from several drugs. Less com-only, prerenal AKI results from drugs such as

nterleukin-2 and denileukin, which cause a cap-llary leak syndrome. Other forms of parenchymalenal injury associated with AKI occur with these

oximal tubule injury. There is mild apical blebbing of theand the mitochondria are dilated with distorted cristae

toxicity. The proximal tubule shows significant luminal-out. Short stretches of the basement membrane aretron micrograph of a glomerular capillary loop withuced thrombotic microangiopathy. There is endothelialpillary lumen (magnification, 8,000�). (D) Glomerulusidronate. The glomerular capillary lumen are markedlyatrophy adjacent to glomeruli (Jones, 200�).

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rystal nephropathy. We focus on 3 examplerugs in this section—cisplatin, methotrexate,nd mitomycin C.

cute Tubular Injury

isplatin is the classic nephrotoxin of the che-otherapeutic drug class. Its efficacy as an an-

icancer agent, especially for solid tumors, islmost matched by its nephrotoxicity.1-5,29 Asoted, cisplatin can cause several forms of tu-ular injury with FS, sodium, and magnesiumasting, and NDI causing polyuria. However,KI complicates therapy as the drug exposure

ncreases; one third of patients develop thisomplication after one dose and the risk of AKIncreases with a higher cumulative dose. Prox-mal tubular injury is in part caused by theathway of renal excretion of cisplatin. Entry ofrug from the peritubular capillaries into theell occurs via the basolateral organic cationransporter. With escalating drug dose, highellular drug concentrations may induce cellu-ar injury via multiple mechanisms that are dis-ussed later. The clinician should be aware ofhese toxicities when administering cisplatin toatients, especially in those with risk factors for

ncreased nephrotoxicity (kidney disease, vol-me depletion, hypomagnesemia). In addition toonitoring serum creatinine levels within 3 to 7ays after therapy, serum magnesium concen-rations as well as urine studies to examine forubular injury (FS, sodium wasting, NDI) shoulde undertaken.1-4,29 Examination of the urineediment reveals renal tubular epithelial cells/asts and/or granular casts. In those developingTI, the drug should be discontinued at least

emporarily. Other platinum agents such as car-oplatin, oxaliplatin, and nedaplatin are lessephrotoxic than cisplatin, but are not riskree, particularly in patients with risk factorsnd a high cumulative dose.

Cisplatin causes predominantly proximal tu-ular injury, the glomerulus usually is spared.istologic changes are seen mostly in the parsonvoluta and pars recta of the proximal tubulend consist of ATI with desquamation of tubu-ar epithelial cells (Fig. 1B). Mitochondrialwelling and nuclear pallor also have been de-cribed in the distal nephron. Interstitial nephri-
is is absent in most cases.30 a
Conversion of cisplatin to toxic molecules isn important step in the induction of nephro-oxicity.31 Cellular accumulation of cisplatin isssociated with the formation of reactive thiolompounds and monohydroxyl complexes thatre highly toxic to the proximal tubule cell.oxic injury is mediated through a variety ofechanisms including oxidative stress, reactive

itrogen species, and induction of pro-apop-otic and inflammatory pathways.

Reactive oxygen species directly affect pro-ein synthesis and structure, DNA synthesis,nd cell repair mechanisms.32 They also causeirect mitochondrial dysfunction.33 Kidneysreated with cisplatin have higher concentra-ions of peroxynitrite and nitric oxide.34 Perox-nitrite causes changes in protein structure andunction, lipid peroxidation, and reduction inell defense mechanisms.

Cisplatin activates the initiator caspase 1,hich leads to activation of the effector caspaseand subsequently to the induction of apopto-

is. Cisplatin-induced ATI is reduced in caspase–deficient mice.35 Cisplatin further initiates

ncreases in cytokines such as tumor necrosisactor-� (TNF-�), transcribing growth factor-�,nd monocyte chemoattractant protein-1. TNF-�as a central role in inducing cisplatin-mediatedell injury by inducing apoptosis, reactive oxy-en species, and activation of multiple cyto-ines in the kidney. TNF-� inhibitors ameliorateisplatin-induced nephrotoxicity by 50% andeduce cisplatin-induced structural damage.36

NF-� null mice are protected against cisplatin-nduced renal injury.37

rystal Nephropathy

ethotrexate (MTX), an antifolate drug, is anffective antineoplastic agent when adminis-ered in a high dose (�1 g/m2).1-4 Nephrotox-city occurs primarily owing to precipitation ofarent drug and metabolites within tubular lu-ens, a phenomenon known as crystal ne-

hropathy.1-4,38 True or effective volume deple-ion and acidic urine are 2 major risk factors forKI. Direct tubular toxicity also may contribute

o kidney injury. The overall incidence rate of AKIs approximately 1.8% (range, 0%-12%), and, ineneral, renal injury is reversible. Initially, an
symptomatic serum creatinine increase develops

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ith nonoliguria followed by more severe AKI.arly on, urine microscopy often shows renalubular epithelial cells and/or casts. Rarely, drugrystals are visible in the urine (if acidic), but mayot be present in an alkaline pH. Excessive MTX

evels and systemic end organ toxicity often fol-ows prolonged AKI.

In addition to crystal precipitation, MTX haseen shown to induce formation of oxygenadicals with subsequent cellular injury, associ-ted with decreased adenosine deaminase activ-ty.39 Moreover, a recent study showed thatrug–drug interactions may play an importantole in high-dose MTX–induced AKI.40 The in-estigators concluded that interaction betweenigh-dose MTX and piperacillin-tazobactam re-uced renal clearance of MTX, leading to AKI.nother mechanism of methotrexate-mediatedephrotoxicity is through hyperhomocysteinemia,een in patients with deficient folate metabo-ism. A recent study using methylenetetrahydro-olate reductase null mice with hyperhomocystei-emia showed significant impairment of renalunction after MTX treatment.41 These results sug-est that pharmacogenetic analysis of polymor-hisms in folate-dependent enzymes may be use-

ul in optimizing MTX therapy.

hrombotic Microangiopathy

et another form of AKI, thrombotic microan-iopathy (TMA), occurs with the antitumor an-ibiotic mitomycin C.1-6 As with other drugs, aigher cumulative dose (�60 mg) appears to

ncrease the risk for TMA. In general, approxi-ately 10% of patients develop adverse renal

ffects after 5 to 12 months of mitomycin Cherapy. Although TMA may be renal-limited, hy-ertension and a microangiopathic hemolyticnemia with thrombocytopenia also occurs. He-aturia and proteinuria along with AKI are com-on and neurologic abnormalities, skin rash, and

oncardiogenic pulmonary edema may occur.Thrombotic microangiopathy (Fig. 1C) is

haracterized by vascular thrombi located inhe preglomerular arterioles or associated withlomerular lesions such as intracapillary fibrinhrombi, mesangiolysis, and double contour oflomerular basement membranes enclosingubendothelial electron-lucent flocculent mate-
ial. Vascular thrombi may be associated with u
ndothelial swelling and denudation of the vas-ular basement membrane. Besides the typicalndings of TMA, nuclear atypia in glomerulind tubular cells have been reported in mito-ycin toxicity.42,43 In a rat model of unilateralerfusion with mitomycin, cortical necrosis,nd nuclear atypia, manifested by bizarre largeuclei was noted in tubuli. These observationsupport a direct toxic effect of mitomycin, orne of its metabolites, on kidney cells.44

ephritic/Nephrotic Syndrome

resentation with hematuria and proteinuria orsolated proteinuria without AKI can occur

ith certain chemotherapeutic agents (Table). In some cases, these renal manifestationsay precede the development of AKI. The anti-

ngiogenesis drug class has brought excitemento the cancer therapeutics, but interesting re-al-related complications such as hypertension,lomerular endotheliosis, TMA, and a variety ofther renal lesions have been described. Theserugs are covered in other articles in this onco-ephrology issue of Seminars in Nephrologysee article by Eremina and Quaggin, p. 582).

e focus on 2 drugs that cause glomerularathology: interferon and pamidronate.Immune modulators such as interferon-alfa,

nterferon-beta, and interferon-� are associatedith proteinuria that often is mild and revers-

ble (up to 15%), but can be more severe withephrotic-range proteinuria.1-4 Rarely, AKI mayomplicate therapy with these drugs within therst few weeks of administration. In general,he renal lesion is reversible, but persists inome patients even after drug discontinuation.enal injury by interferon is detected most ofteny observing dipstick proteinuria. An increase oferum creatinine level also signals kidney disease.n addition to a number of glomerular diseases,MA, ATI, and interstitial nephritis also have beenescribed with interferon therapy.

Interferon-alfa treatment for hematopoieticalignancies such as chronic myeloid leukemiaas been associated with a variety of lesions

ncluding membranoproliferative glomerulone-hritis, membranous glomerulopathy, and focalegmental glomerulosclerosis (FSGS). The un-erlying mechanisms that lead to renal injury are
ncertain but may include autoantibody-mediated

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mmune complex deposition or cytokine-medi-ted podocyte and endothelial cell injury. In aecent case report describing a proliferative glo-erulonephritis after interferon-alfa treatment,

he investigators showed immune sensitization bypositive indirect Coombs test. They took this as

ndirect proof that an idiosyncratic type of sensi-ivity reaction may have initiated the immuneomplex formation and subsequent deposition inhe glomeruli.45

The bisphosphonate pamidronate is used toorrect hypercalcemia and for antitumor effectsn various forms of metastatic bone cancer.igh-grade proteinuria and AKI in patients re-eiving high intravenous drug doses (90-180g) at frequent intervals (biweekly to monthly)as noted.1,5,46 The most frequent pathologic

esion is collapsing FSGS (Fig. 1D), althoughess aggressive patterns of podocyte injury, in-luding minimal change disease and noncol-apsing FSGS, may be seen. In many cases, ne-hrotic syndrome associated with pamidronate

s at least partially reversible after discontinua-ion of the offending agent. Pamidronate alsoas been associated rarely with diseases of theubules and interstitium, as noted with agentshat cause toxic nephropathy.

One mechanism associated with pamidr-nate-induced FSGS is podocyte apoptosis.47 Thisssumption is supported by the observations ofncreased mitochondrial number and variation in

itochondrial size and shape that have been de-cribed in podocytes and in tubular epithelium ofamidronate-treated patients.48 Concomitant tu-ulointerstitial lesions show variable preva-

ence in pamidronate-induced FSGS. Even in thebsence of glomerular lesions by light micros-opy significant tubular epithelial changes maye present in patients with pamidronate-associ-ted AKI.49 Experimental animal studies havehown a higher total rate of renal clearance ofamidronate, exceeding the GFR, indicating ac-ive tubular secretion.50 In an animal model pam-dronate increased urinary marker levels of tubu-ar injury.51 These findings indicate a tubulotoxicomponent of pamidronate-induced injury.

KD

t recently has been recognized that AKI may be
ssociated with irreversible renal injury and m
KD. This paradigm also applies to some of theommonly used chemotherapeutic agents.oth cisplatin and ifosfamide are described toause CKD after chronic exposure. Not surpris-ngly, higher cumulative drug dose, combinedreatment with other nephrotoxins, and hostisk factors (diabetes mellitus, hypertension,re-existing kidney disease) are associated withnhanced CKD. It is likely that AKI from ATI,MA, or other glomerular lesions lead to inter-titial fibrosis and glomerulosclerosis, whichollows a course of CKD.

The nitrosureas are alkylating agents thatause slow, progressive CKD over a period of 3o 5 years.1,2 Streptozotocin and semustine arehe most nephrotoxic, with more than threeuarters of exposed patients developing kidney

njury, particularly with high cumulative doses�1.4 g/m2). Carmustine and lomustine are lessephrotoxic, causing kidney disease in approx-

mately 10% of exposed patients. Although allf the nitrosureas cause slowly progressive lossf kidney function, streptozotocin also causesKI. In addition to kidney injury characterizedy an asymptomatic increase in serum creati-ine level, tubular insufficiency can accompanyitrosurea therapy resulting in clinically evidentS. Chronic tubulointerstitial nephritis, tubulartrophy, and glomerulosclerosis underlie theKD, which often continues despite discontin-ation of the drug.

In the majority of patients receiving at least 6ourses of nitrosourea, irreversible and chroni-ally progressive renal damage occur. Kidneyiopsies from 7 of 18 patients who received ainimum of six courses or more showed tubu-

ar atrophy, interstitial fibrosis, and glomerulo-clerosis (see Fig. 2A and B).52 1-3-1-nitrosoureand chlorozotocin are structurally related anti-ancer agents with variable severity in regard toenal injury. In an animal study, a single highose of chlorozotocin resulted in acute injury ofhe proximal tubule, followed by severe papil-ary necrosis at a later time point. Similarly,-3-1-nitrosourea caused mild tubular injury ini-ially, whereas extensive papillary collectinguct necrosis was noticed 2 to 3 weeks after aingle high-dose application.53 The result is alowly progressive nephropathy with karyo-
egaly in collecting duct cells after 4 weeks.

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REVENTION/REATMENT OF NEPHROTOXICITY

n obvious preventive approach is to doserugs correctly for the underlying level of kid-ey function. Most dosing data are based onreatinine clearance (24-hour collection andockcroft-Gault), but the Modified Diet in Re-al Disease estimating equation provides similar

nformation.1-6 However, it is critical to recognizehat these formulas have several limitations thatake them inaccurate. Examples include AKI,

on–steady-state kidney function, extremes ofuscle mass, and other factors. Another pre-

entive strategy is to avoid or limit exposure tother known nephrotoxins such as nonsteroi-al anti-inflammatory drugs, radiocontrast, andminoglycosides. Correction of urinary obstruc-ion before drug exposure is logical.

Correction of hypovolemia with intravenousuids is important, and induction of high uri-ary flow rates with various fluids will reduceephrotoxicity. Specific examples include uri-ary alkalinization with isotonic sodium bicar-onate for MTX (reduces intratubular crystalormation) and either intravenous isotonic orypertonic saline for cisplatin, which stabilizeshe molecule and reduces evolution of the re-ctive aquated platinum species.1-6,29,38

Specific antidotes garner some benefit in re-ucing nephrotoxicity. Sodium thiosulfate andmifostine may reduce adverse kidney effectsrom cisplatin, sodium thiosulfate by acting as aompetitive analog for aquated platinum mole-

igure 2. (A and B) Extensive interstitial fibrosis andrichrome stain accentuates the increased interstitial matr segmental sclerosis in the same patient. The glomeellularity in the areas of scarring (hematoxylin-eosin, 1

ules and amifostine through its effects as a c

lutathione analog.1,29 Both are limited by nau-ea/vomiting and hypotension. Leucovorin res-ue and glucarbidase (not yet approved by theood and Drug Administration) are useful forTX nephrotoxicity. Leucovorin is used within

4 to 36 hours of high-dose MTX therapy torevent normal cells from suffering injury.54

lucarbidase, which cleaves MTX to noncyto-oxic metabolites, is used (compassionate basis)hen MTX levels are toxic and the risk for

ystemic toxicity is significant.54 Several antioxi-ants (n-acetylcysteine, glutathione, glutamine,itamin C or E) show utility in various animalodels of chemotherapy-induced kidney injury

nd may have a role in human beings, but def-nite efficacy is lacking. A number of agentsargeting cisplatin metabolism, intracellular sig-aling pathways, and inflammation are underctive investigation in animals.1,29

Removal of drug in the setting of toxicity andverdosage from associated AKI is somewhat

imited with current technology. Hemodialysisith high-flux membranes clears the plasma ofTX (76%), but is associated with immediateostdialysis plasma rebound.1 Plasmapheresis issed with varied (and somewhat limited) suc-ess for drug-induced TMA.

ONCLUSIONS

idney disease after chemotherapeutic drugegimens remains a significant problem in theanagement of cancer patients. Although re-

lar atrophy in a patient treated with nitrosurea. Theation (Trichrome, 40�). Several glomeruli show global

capillary lumens are solidified and there is decreased

tuburix formrular

ent advances have been made to reduce the

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ncidence of drug toxicity, many enigmatic dif-culties still remain. With improved under-tanding of the molecular mechanisms that leado toxic injury by chemotherapeutics, a numberf toxic reactions will be avoided in the future.olecular profiling that indicates a patient’sredisposition to toxic injury will allow prese-

ecting patients to a personalized drug regimenor treatment. Finally, the development of drugsargeting selective steps in tumor progressionill decrease the degree and incidence of toxic

njury to the kidney.

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