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KidneyProblemsinAn0-CancerTreatment

RumeyzaTuranKazanciogluBezmialemVakifUniversityDivisionofNephrology

Istanbul,Turkey

DISCLOSURES

•  Ihavenodisclosuresrelatedtothistopic

FROM2005RenalfailureinthecancerpaGentisoHenmulGfactorial,butitissGllclinicallyusefultoconsidercausesasprerenal,intrinsic,andpostrenal

Notsurprising,prerenalfailureiscommonThespectrumofintrinsicrenaldiseaseinthispaGentpopulaGonisbroad:MulGplemyeloma-relatedrenalfailurePostrenalcausesincancerpaGentsaremorecommonthaninthegeneralpopulaGon:obstrucGonmayoccuratanyleveloftheurogenitaltractandcommonobstrucGngtumorsincludethoseoftheprostate,bladder,uterus,anduterinecervix

HumphreysBD,etal.JAmSocNephrol200516:151–161.

WELLKNOWN

Chemoradiotherapyinducestumorcelllysis

withreleaseofintracellularconsGtuents,

includingpotassium,phosphate,andnucleic

acids.

PurinedegradaGoncreatesxanthine,whichis

metabolizedtouricacidandnormally

excretedbythekidney.

Intumorlysissyndrome,veryhighlevelsof

uricacidmayaccumulate,leadingto

intratubularcrystallizaGonandrenalfailure.

LONGKNOWN

• Isradiotherapysafeforkidneys?(RTHinprostatecancerand

malignancyinpelvisandpossiblelong-termcomplica0ons)

• Renaltoxicityofnewtargetedtherapies

• Anyotherissues/aspectsimpac0ngCKDprogression

TheoccurrenceofrenaldysfuncGonasaconsequenceofionizing

radiaGonhasbeenknownformorethan100years

IniGalreportstermedthiscondiGon“radiaGonnephriGs,”but

thatisamisnomer,becauseitisnotaninflammatorycondiGon

https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter10.pdf

RenalradiaGoninjurymaybeavoidedbytheexclusionofan

adequatevolumeofkidneyexposureduringradiaGontherapy,

butthekidneys’centrallocaGoncanmakethisdifficultto

impossiblewhentumorsoftheabdomenorretroperitoneum

aretreated,orduringtotalbodyirradiaGon

• AteamatRoswellParkCancerInsGtuteinBuffalo,N.Y.,studied129

paGentswhounderwent3DconformalRTdirectedattheabdomenforGI

cancers.TheresearchersmeasuredBP,hemoglobin,serumcreaGnine,

andcreaGnineclearancepriortoRT,duringRT,andaHerRTinthree-to

six-monthintervals.CreaGnineclearancewascalculatedusingthe

CockcroH-Gaultformula. Yang G et al. Renal And Urology News 2008

• Ofthe129paGents,28hadatleast12monthsoffollow-upandthe

requiredlaboratorydatatocalculatecreaGnineclearance.ThepaGents

hadamedianageof60.5years(range37-78years);12subjectswere

female.TheprimaryRTsiteswerepancreas(17paGents),stomach(four),

hepatobilary(three),duodenum(two),ampulla(one),and

retroperitoneum(one).ThemedianradiaGondosewas45.9Gy(range

41.4-50.4)givendailyas1.8GyperfracGon.

Yang G et al. Renal And Urology News 2008

• AHeramedianfollow-upof16months,meancreaGnineclearance

decreasedby22.5%inpaGentswhoreceivedradiaGontotheabdominal

area.ThisreducGoninrenalfuncGonappearedtooccurbetween12and

18monthsaHercompleGonofRT.

• Post-RTmeancreaGnineclearancewas80.2mL/min,asignificant

decreasefrom103.5mL/minpriortotreatment.

•  InaddiGon,pre-RTbaselinecreaGnineclearancewassignificantlyassociatedwithdecreasingpost-RTcreaGnineclearance.Foreach1mL/

mindecreaseinbaselinecreaGnineclearance,themeanpost-RT

creaGnineclearancedecreasedby0.4mL/minaHercontrollingforother

factors.

•  TheresearchersfoundnocorrelaGonbetweenradiaGondoseanddeclineincreaGnineclearance.

•  InpelvisradiaGontherapy,thepronouncedradiosensiGvityofrenalGssue

limitsthetotalradiotherapeuGcdosethatcanbeappliedsafelyto

treatmentvolumesthatincludethekidneys.

Baradaran-Ghahfarokhi M. J Renal Inj Prev 2012;1(2):49-50

• RadiaGonnephropathyisrenalinjuryandlossoffuncGoncausedbyionizingradiaGonaHersufficientirradiaGonofbothkidneys.

•  IonizingradiaGonofsufficientenergydisruptschemicalbondsandknocks

electronsoutofatoms.

•  ItgeneratesoxygenradicalsthatcausepromptDNAinjurywithin

millisecondsofirradiaGon.

Glomerularinjuryischronologicallyfirst,andinvolvesatleastits

endotheliumandmesangium,withevoluGontoglomerularscarringdueto

thromboGcmicroangiopathy.

Expressionoftubularinjuryappearstooccursomewhatlater,evenifitis

setinmoGonatthesameGmeastheglomerularinjury.

Baradaran-Ghahfarokhi M. J Renal Inj Prev 2012;1(2):49-50

OxidaGveinjurytotheglomeruli,couldplayamechanisGcrole.

DenudedtubulescouldallowintersGGalentrytomediatorsthatescape

frominjuredglomeruli.

Localmediatorexpression,suchasTGFβ1oracGvaGonofrenin-

angiotensinsystemiskeyincreaGngtubulointersGGalscarring.

TherearesomeraresyndromesofradiaGonsensiGvitysuchasataxia

telangiectasia,butnotclinicallyfrequent.Baradaran-Ghahfarokhi M. J Renal Inj Prev 2012;1(2):49-50

•  23GyasthethresholddoseforradiaGonnephropathy,fromradiaGonof

bothkidneyswhengivenin20fracGonsover4weeks.

•  Ifthetotalirradiatedrenalvolumeis30%ofbothkidneys,CKDwillnot

occurfromirradiaGonalonealthoughtheremaybeinjurytothesmall,

irradiatedvolumeofkidneysthatleadstohypertension.

Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936

TARGETEDTHERAPIES

TheNa0onalCancerIns0tute(NCI)definestargetedtherapiesas

‘drugsorsubstancesthatblockthegrowthandspreadofcancerby

interferingwithspecificmoleculesinvolvedintumorgrowthand

progression’

Jhaiveretal.KidneyIntRep(2017)2108-123Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936

Jhaiveretal.KidneyIntRep(2017)2108-123

TARGETEDTHERAPY

•  Thetotalnumberofrenaladverseevents2943•  1390(47.3%)weremetabolicdisturbances,

•  1243(42.2%)wererenalimpairment

•  310(10.5%)werehypertension

Ipilumumabandcetuximabwith508and467events,respecGvelyTherateofadverseeventsweresimilarbetweenmen(n:1369)andwomen(n:1305)ThemostcommonelectrolyteabnormalitywasHypokalemia(n:539)

HypophosphatemiaHypomagnesemiaHyponatremia

PROTEASOMEINHIBITORS•  TheselecGveproteasomeinhibitorcarfilzomib

• AcceleratedapprovalintheUSAin2012forsingle-agentuseinpaGentswithrelapsedandrefractoryMM

• Carfilzomibassociatedwith•  TMA •  Podocytopathy •  Tumour lysis-like phenomenon •  Worsening of kidney function •  AKI

• AverylowincidenceofFDA-reportedadverserenaleventswithcarfilzomib(transientnatureoftheinjurynotbeingreported)

VEGF&VEGFRECEPTORBLOCKADE

•  VEGFisproducedbythepodocytesthatnormallyexpressVEGFreceptor

presentonglomerularandperitubularendotheliumandmesangialcells

•  LocalsynthesisofVEGFformaintenanceofnormalglomerularfuncGon

andintegrityoftheglomerularbasementmembrane

• Duringthetreatment,themostcommonkidneydamageisproteinuria,

evennephroGcsyndromewithhypertension

DosedependentIrreversible

TYROSINEKINASEINHIBITORS

2typesoftyrosinekinases:cellularandreceptortyrosinekinases

TYROSINEKINASEINHIBITORS•  SincetheTKIshaveananG-VEGFeffect,similarrenalTMA-likefindingscan

beseenwiththemaswell

• Apreeclampsia-likesyndromehasbeenobservedduringsuniGnibtherapy

•  SuniGnibandsorafenibalsocauseacuteandchronicintersGGalnephriGs,aswellasasee-saweffectofchronicintersGGalandendothelialdamage

leadingtoCKD

EPIDERMALGROWTHFACTORRECEPTOR1TARGETINHIBITORS

EPIDERMALGROWTHFACTORRECEPTOR1TARGETINHIBITORS• MagnesiumreabsorpGonindistalconvolutedtubuleispartlydependent

onEGFRacGvityonthebasolateralmembrane.

•  EGFRTIpreventsEGFbindingtoitsreceptorcausingmagnesiumwasGng

• HypomagnesaemiaresolvesaHertreatmentisdisconGnued

HUMANEPIDERMALGROWTHFACTOR2(HER-2)TARGETINHIBITORS

•  Trastuzumab

• Pertuzumab

•  LapaGnib

HUMANEPIDERMALGROWTHFACTOR2(HER-2)TARGETINHIBITORS

•  Noreportedrenaltoxicity

• WhentrastuzumabisgivenincombinaGonwithanthracyclines,cardiorenal

syndromewasobserved

•  ThecardiotoxicityoftrastuzumabmightbeincreasedinpaGentswithCKD

BRAFTARGETINHIBITORS

BRAFisahumangenethatmakesB-rafprotein(fibrosarcomakinaseB),

whichisinvolvedintransmipngsignalswithincellsinvolvedincell

growth

MalignantMelanoma

BRAFTARGETINHIBITORS

Vemurafenib most pronounced withDabrafenib within2months

IMMUNECHECKPOINTINHIBITORS

Postow A, et al. N Engl J Med 2018;378:158-68.

CYTOTOXICTLYMPHOCYTEANTIGEN4(CTLA-4)ASATARGET

Jhaiveretal.KidneyIntRep(2017)2108-123 Perazella MA, et al. J Am Soc Nephrol 29: 2039–2052, 2018

CYTOTOXICTLYMPHOCYTEANTIGEN4(CTLA-4)ASATARGET

ANTICYTOTOXICTLYMPHOCYTEANTIGEN4(CTLA-4)

•  Fromatotalof3695paGents,overallincidenceofAKIwas2.2%

•  Theincidenceofgrade3/4AKIwas0.6%

• AKIwasmorecommonwithipilimumab/nivolumabcombinaGontherapy

(4.9%)thanwithmonotherapywithipilimumab(2%),nivolumab(1.9%),

orpembrolizumab(1.4%)Perazella MA, et al. J Am Soc Nephrol 29: 2039–2052, 2018

ANTIPD-1THERAPY

• Ameta-analysisof48clinicaltrialsofPD-1inhibitortherapyshowedan

overallAKIincidencerateof2.1%

• Abnormalelectrolyteincidenceratesof0.6%–1.3%

•  Hypocalcemia incidence 1%

•  13% severe hypocalcemia

Perazella MA, et al. J Am Soc Nephrol 29: 2039–2052, 2018

CARTCELLS

Perazella MA, et al. J Am Soc Nephrol 29: 2039–2052, 2018

ChimericanGgenreceptor(CAR)Tcellinfusion–mediatedtoxicity.CARTcellsareinfusedandtheninteractwithcancercells,wheretheyexpandfurtherandreleaseIFN-gandTNF-a.CARTcellsalsocauselysisofcancercells,whichleadstoreleaseofcytokinesandacGvaGonofmacrophagesanddendriGccells.IL-1,IL-6,andIL-8arereleasedaswellasTNF-aandmonocytechemoasractant1(MCP1).IL-6isthemostsignificantcytokineinthecytokinereleasesyndrome.AKIandelectrolyteabnormaliGesmayoccurinthissepng.TocilizumabblocksIL-6frombindingtoitsreceptor,reducingtheeffectsofcytokinereleasesyndrome.

SCREENINGFORRENALTOXICITY

Jhaiver et al. Kidney Int Rep (2017) 2 108-123

TheinterfacebetweenCKDandcancerismulGfaceted.

CKDisfrequentlyobservedinpaGentswithcancer,andcancertreatment

contributestoCKDdevelopmentandprogression.

Izzeddine H, et al. Nephrol Dial Transplant (2015) 30: 1979–1988

IMPACTONCKDPROGRESSION

•  Theextenttowhichchronicnephrotoxicityisdirectlyrelatedto

chemotherapy-inducedchronickidneycelldamage,versusaresultof

chronicinjurysGmulatedbyacutekidneycelldamageduringtreatment,

remainsunclear.

Pediatric Nephrology https://doi.org/10.1007/s00467-018-3976-5

•  TheprevalenceofCKDishighamongcancerpaGents

•  Launay-Vacheretal.performedaretrospecGveassessmentof4684

paGentswithsolidtumorsfrom15centersinFrance(InsuffisanceR

enaleetMedicamentsAnGcancereuxstudies)

•  The prevalence of CKD Stage 3 or higher on the basis of MDRD Study

equation was 12% in the overall population and increased to 23% among

patients older than 75 years

TorresdaCostaeSilvaetal.AdvChronicKidneyDis.2018;25(1):49-56

AnumberofanGneoplasGcagentsareclearedbythekidney,andmay

affecttheirfuncGon,includingchemotherapeuGcdrugs,molecular

targetedtherapies,analgesics,anGbioGcs,radiopharmaceuGcals,and

radiaGonandbone-targetedtherapies.

Thesedrugscancauseavarietyofrenaldiseaseandelectrolyte

disorders.

RenalimpairmentincancerpaGentscandevelopfrommulGplefactors•  dehydraGon•  hypercalcemia

•  theuseofnephrotoxicagents,suchasNSAIDs,forpainrelief

MaybeaggravatedincombinaGonwithotherindirectlyprecipitaGngfactors•  aging•  inadequatelymanagedhypertension

•  unrecognizedmedicaldisease

KawaiK,etal.JpnJClinOncol2013;43(11)1055–1063

AccurateevaluaGonofGFRduringoncologictreatmentispivotalandis

usedtodefinesurgerystrategies,programprophylacGcmanagementof

contrastedexaminaGons,makedecisionsoncisplaGneligibility,and

adjustdrugprescripGons,parGcularlychemotherapyagents.

•  ThereisevidencethatpaGentswithcancerexhibitasignificantlossofkidneyfuncGonduringanGcancertreatment.

•  Launay-Vacheretal.retrospecGvelyassessedkidneyfuncGonin4945

paGentswithsolidtumorsandfoundareducGonineGFRfrom91to84

mL/min/1.73m2aHer2years,and17.7%ofpaGentschangedfromCKD

Stage2to3or4attheendofthefollowup.

•  ChrisGansenandassociatesprospecGvelyfollowed37,267paGentswithcancerandfoundthattheriskofacutekidneyinjury(50%increaseinthe

baselineesGmatedGFR)was17.5%inthefirstyearaHercancerdiagnosis

and27%over5years.

• Consideringthatcancertreatmentfrequentlyextendsthroughmonthsor

evenyears,repeatedacutekidneyinjuryepisodesarelikelytocontribute

significantlytothedevelopmentandprogressionofCKDinpaGentswith

cancer.TorresdaCostaeSilvaetal.AdvChronicKidneyDis.2018;25(1):49-56

Inonestudy,approximately16%ofpaGentswithcancerhad

sarcopeniabeforetreatmentiniGaGonandreducGonsinmusclemassfrequently

developsoverthecourseofthetreatment,affecGngupto70%ofpaGents,

parGcularlyinpaGentswithlatestagecancerundergoingchemotherapy.

SuchpaGentswouldhavedecreasedtheesGmatedGFRduetolossofmuscle

massratherthanchangeintheirtrueGFR.

Assuch,usingasingleequaGoninthesamepersonmightgivethefalse

impressionofstableorimprovedGFR,wheninfacttherehasbeensubstanGal

Launay-VacherV,etal.ESMOOpen2016;1:e000091

Chenetalincluded143paGentswithmetastaGccolorectalcancerAllpaGentshadnormalserumcreaGnineatinclusionandwerealltreatedthesame,attheusualdosageofchemotherapy.AHertreatment,therenalfuncGonwasesGmated;paGentsweregroupeddependingonwhethertheyhadatinclusionarenalfuncGonloweror>60,andsafetyandsurvival(Gmetoprogression)werecomparedbetweengroups.35%ofthepaGentsinthisstudyhadarenalfuncGonbelow60inspiteofanormalScr.PaGentswithCKDexperiencedstaGsGcallysignificantlyhigherratesofdose-relatedadverseevents,whichleadtosignificantlyratesoftreatmentdisconGnuaGonorinterrupGon,andsignificantlyreducedGmetoprogression.

TheimportanceofadjusGnganGcancerdrugdosagestorenalfuncGonwhenpaGentshaveCKD

Is reduction of bisphosphonates and anti-RANKL antibodies recommended for patients with decreased renal function?

RecommendaGon

•  ReducGonofbisphosphonatesisrecommendedforpaGentswithdecreasedrenalfuncGon.

•  ReducGonofanG-RANKLanGbodiesisnotrecommendedforpaGentswithdecreasedrenalfuncGon.

•  ReducGonofbisphosphonatesisrecommendedforpaGentswithdecreasedrenalfuncGon.However,reducGonofanG-RANKLanGbodiesisnotrecommendedfor

paGentswithdecreasedrenalfuncGon.

Clin Exp Nephrol DOI 10.1007/s10157-017-1448-z

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Treatment - kdigo.org · • In pelvis radiaon therapy, the pronounced radiosensivity of renal ssue...

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