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KidneyProblemsinAn0-CancerTreatment
RumeyzaTuranKazanciogluBezmialemVakifUniversityDivisionofNephrology
Istanbul,Turkey
KDIGO
DISCLOSURES
• Ihavenodisclosuresrelatedtothistopic
KDIGO
FROM2005RenalfailureinthecancerpaGentisoHenmulGfactorial,butitissGllclinicallyusefultoconsidercausesasprerenal,intrinsic,andpostrenal
Notsurprising,prerenalfailureiscommonThespectrumofintrinsicrenaldiseaseinthispaGentpopulaGonisbroad:MulGplemyeloma-relatedrenalfailurePostrenalcausesincancerpaGentsaremorecommonthaninthegeneralpopulaGon:obstrucGonmayoccuratanyleveloftheurogenitaltractandcommonobstrucGngtumorsincludethoseoftheprostate,bladder,uterus,anduterinecervix
HumphreysBD,etal.JAmSocNephrol200516:151–161.
KDIGO
WELLKNOWN
Chemoradiotherapyinducestumorcelllysis
withreleaseofintracellularconsGtuents,
includingpotassium,phosphate,andnucleic
acids.
PurinedegradaGoncreatesxanthine,whichis
metabolizedtouricacidandnormally
excretedbythekidney.
Intumorlysissyndrome,veryhighlevelsof
uricacidmayaccumulate,leadingto
intratubularcrystallizaGonandrenalfailure.
HumphreysBD,etal.JAmSocNephrol200516:151–161.
KDIGO
LONGKNOWN
HumphreysBD,etal.JAmSocNephrol200516:151–161.
KDIGO
• Isradiotherapysafeforkidneys?(RTHinprostatecancerand
malignancyinpelvisandpossiblelong-termcomplica0ons)
• Renaltoxicityofnewtargetedtherapies
• Anyotherissues/aspectsimpac0ngCKDprogression
KDIGO
• Isradiotherapysafeforkidneys?(RTHinprostatecancerand
malignancyinpelvisandpossiblelong-termcomplica0ons)
• Renaltoxicityofnewtargetedtherapies
• Anyotherissues/aspectsimpac0ngCKDprogression
KDIGO
TheoccurrenceofrenaldysfuncGonasaconsequenceofionizing
radiaGonhasbeenknownformorethan100years
IniGalreportstermedthiscondiGon“radiaGonnephriGs,”but
thatisamisnomer,becauseitisnotaninflammatorycondiGon
https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter10.pdf
KDIGO
RenalradiaGoninjurymaybeavoidedbytheexclusionofan
adequatevolumeofkidneyexposureduringradiaGontherapy,
butthekidneys’centrallocaGoncanmakethisdifficultto
impossiblewhentumorsoftheabdomenorretroperitoneum
aretreated,orduringtotalbodyirradiaGon
https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter10.pdf
KDIGO
• 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
KDIGO
• 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
KDIGO
• AHeramedianfollow-upof16months,meancreaGnineclearance
decreasedby22.5%inpaGentswhoreceivedradiaGontotheabdominal
area.ThisreducGoninrenalfuncGonappearedtooccurbetween12and
18monthsaHercompleGonofRT.
• Post-RTmeancreaGnineclearancewas80.2mL/min,asignificant
decreasefrom103.5mL/minpriortotreatment.
Yang G et al. Renal And Urology News 2008
KDIGO
• InaddiGon,pre-RTbaselinecreaGnineclearancewassignificantlyassociatedwithdecreasingpost-RTcreaGnineclearance.Foreach1mL/
mindecreaseinbaselinecreaGnineclearance,themeanpost-RT
creaGnineclearancedecreasedby0.4mL/minaHercontrollingforother
factors.
• TheresearchersfoundnocorrelaGonbetweenradiaGondoseanddeclineincreaGnineclearance.
Yang G et al. Renal And Urology News 2008
KDIGO
• InpelvisradiaGontherapy,thepronouncedradiosensiGvityofrenalGssue
limitsthetotalradiotherapeuGcdosethatcanbeappliedsafelyto
treatmentvolumesthatincludethekidneys.
Baradaran-Ghahfarokhi M. J Renal Inj Prev 2012;1(2):49-50
KDIGO
• RadiaGonnephropathyisrenalinjuryandlossoffuncGoncausedbyionizingradiaGonaHersufficientirradiaGonofbothkidneys.
• IonizingradiaGonofsufficientenergydisruptschemicalbondsandknocks
electronsoutofatoms.
• ItgeneratesoxygenradicalsthatcausepromptDNAinjurywithin
millisecondsofirradiaGon.
https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter10.pdf
KDIGO
Glomerularinjuryischronologicallyfirst,andinvolvesatleastits
endotheliumandmesangium,withevoluGontoglomerularscarringdueto
thromboGcmicroangiopathy.
Expressionoftubularinjuryappearstooccursomewhatlater,evenifitis
setinmoGonatthesameGmeastheglomerularinjury.
Baradaran-Ghahfarokhi M. J Renal Inj Prev 2012;1(2):49-50
KDIGO
OxidaGveinjurytotheglomeruli,couldplayamechanisGcrole.
DenudedtubulescouldallowintersGGalentrytomediatorsthatescape
frominjuredglomeruli.
Localmediatorexpression,suchasTGFβ1oracGvaGonofrenin-
angiotensinsystemiskeyincreaGngtubulointersGGalscarring.
TherearesomeraresyndromesofradiaGonsensiGvitysuchasataxia
telangiectasia,butnotclinicallyfrequent.Baradaran-Ghahfarokhi M. J Renal Inj Prev 2012;1(2):49-50
KDIGO
• 23GyasthethresholddoseforradiaGonnephropathy,fromradiaGonof
bothkidneyswhengivenin20fracGonsover4weeks.
• Ifthetotalirradiatedrenalvolumeis30%ofbothkidneys,CKDwillnot
occurfromirradiaGonalonealthoughtheremaybeinjurytothesmall,
irradiatedvolumeofkidneysthatleadstohypertension.
https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter10.pdf
KDIGO
https://www.asn-online.org/education/distancelearning/curricula/onco/Chapter10.pdf
KDIGO
• Isradiotherapysafeforkidneys?(RTHinprostatecancerand
malignancyinpelvisandpossiblelong-termcomplica0ons)
• Renaltoxicityofnewtargetedtherapies
• Anyotherissues/aspectsimpac0ngCKDprogression
KDIGO
KDIGO
Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
KDIGO
KDIGO
TARGETEDTHERAPIES
TheNa0onalCancerIns0tute(NCI)definestargetedtherapiesas
‘drugsorsubstancesthatblockthegrowthandspreadofcancerby
interferingwithspecificmoleculesinvolvedintumorgrowthand
progression’
Jhaiveretal.KidneyIntRep(2017)2108-123Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
KDIGO
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
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
PROTEASOMEINHIBITORS• TheselecGveproteasomeinhibitorcarfilzomib
• AcceleratedapprovalintheUSAin2012forsingle-agentuseinpaGentswithrelapsedandrefractoryMM
• Carfilzomibassociatedwith• TMA • Podocytopathy • Tumour lysis-like phenomenon • Worsening of kidney function • AKI
• AverylowincidenceofFDA-reportedadverserenaleventswithcarfilzomib(transientnatureoftheinjurynotbeingreported)
Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
VEGF&VEGFRECEPTORBLOCKADE
• VEGFisproducedbythepodocytesthatnormallyexpressVEGFreceptor
presentonglomerularandperitubularendotheliumandmesangialcells
• LocalsynthesisofVEGFformaintenanceofnormalglomerularfuncGon
andintegrityoftheglomerularbasementmembrane
• Duringthetreatment,themostcommonkidneydamageisproteinuria,
evennephroGcsyndromewithhypertension
Jhaiveretal.KidneyIntRep(2017)2108-123Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
VEGF&VEGFRECEPTORBLOCKADE
Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
VEGF&VEGFRECEPTORBLOCKADE
Jhaiveretal.KidneyIntRep(2017)2108-123
DosedependentIrreversible
KDIGO
TYROSINEKINASEINHIBITORS
2typesoftyrosinekinases:cellularandreceptortyrosinekinases
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
TYROSINEKINASEINHIBITORS• SincetheTKIshaveananG-VEGFeffect,similarrenalTMA-likefindingscan
beseenwiththemaswell
• Apreeclampsia-likesyndromehasbeenobservedduringsuniGnibtherapy
• SuniGnibandsorafenibalsocauseacuteandchronicintersGGalnephriGs,aswellasasee-saweffectofchronicintersGGalandendothelialdamage
leadingtoCKD
Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
EPIDERMALGROWTHFACTORRECEPTOR1TARGETINHIBITORS
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
EPIDERMALGROWTHFACTORRECEPTOR1TARGETINHIBITORS• MagnesiumreabsorpGonindistalconvolutedtubuleispartlydependent
onEGFRacGvityonthebasolateralmembrane.
• EGFRTIpreventsEGFbindingtoitsreceptorcausingmagnesiumwasGng
• HypomagnesaemiaresolvesaHertreatmentisdisconGnued
Jhaiveretal.KidneyIntRep(2017)2108-123Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
HUMANEPIDERMALGROWTHFACTOR2(HER-2)TARGETINHIBITORS
• Trastuzumab
• Pertuzumab
• LapaGnib
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
HUMANEPIDERMALGROWTHFACTOR2(HER-2)TARGETINHIBITORS
• Noreportedrenaltoxicity
• WhentrastuzumabisgivenincombinaGonwithanthracyclines,cardiorenal
syndromewasobserved
• ThecardiotoxicityoftrastuzumabmightbeincreasedinpaGentswithCKD
Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
BRAFTARGETINHIBITORS
BRAFisahumangenethatmakesB-rafprotein(fibrosarcomakinaseB),
whichisinvolvedintransmipngsignalswithincellsinvolvedincell
growth
MalignantMelanoma
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
BRAFTARGETINHIBITORS
Jhaiveretal.KidneyIntRep(2017)2108-123
Vemurafenib most pronounced withDabrafenib within2months
KDIGO
IMMUNECHECKPOINTINHIBITORS
KDIGO
IMMUNECHECKPOINTINHIBITORS
Postow A, et al. N Engl J Med 2018;378:158-68.
KDIGO
CYTOTOXICTLYMPHOCYTEANTIGEN4(CTLA-4)ASATARGET
Jhaiveretal.KidneyIntRep(2017)2108-123 Perazella MA, et al. J Am Soc Nephrol 29: 2039–2052, 2018
KDIGO
CYTOTOXICTLYMPHOCYTEANTIGEN4(CTLA-4)ASATARGET
KDIGO
KDIGO
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
KDIGO
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
KDIGO
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.
KDIGO
SCREENINGFORRENALTOXICITY
Jhaiveretal.KidneyIntRep(2017)2108-123
KDIGO
Jhaiver et al. Kidney Int Rep (2017) 2 108-123
KDIGO
• Isradiotherapysafeforkidneys?(RTHinprostatecancerand
malignancyinpelvisandpossiblelong-termcomplica0ons)
• Renaltoxicityofnewtargetedtherapies
• Anyotherissues/aspectsimpac0ngCKDprogression
KDIGO
TheinterfacebetweenCKDandcancerismulGfaceted.
CKDisfrequentlyobservedinpaGentswithcancer,andcancertreatment
contributestoCKDdevelopmentandprogression.
KDIGO
Izzeddine H, et al. Nephrol Dial Transplant (2015) 30: 1979–1988
KDIGO
IMPACTONCKDPROGRESSION
• Theextenttowhichchronicnephrotoxicityisdirectlyrelatedto
chemotherapy-inducedchronickidneycelldamage,versusaresultof
chronicinjurysGmulatedbyacutekidneycelldamageduringtreatment,
remainsunclear.
Pediatric Nephrology https://doi.org/10.1007/s00467-018-3976-5
KDIGO
• 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
KDIGO
IMPACTONCKDPROGRESSION
AnumberofanGneoplasGcagentsareclearedbythekidney,andmay
affecttheirfuncGon,includingchemotherapeuGcdrugs,molecular
targetedtherapies,analgesics,anGbioGcs,radiopharmaceuGcals,and
radiaGonandbone-targetedtherapies.
Thesedrugscancauseavarietyofrenaldiseaseandelectrolyte
disorders.
Małyszko J, et al. Nephrol Dial Transplant (2017) 32: 924–936
KDIGO
IMPACTONCKDPROGRESSION
KDIGO
HumphreysBD,etal.JAmSocNephrol200516:151–161.
KDIGO
RenalimpairmentincancerpaGentscandevelopfrommulGplefactors• dehydraGon• hypercalcemia
• theuseofnephrotoxicagents,suchasNSAIDs,forpainrelief
MaybeaggravatedincombinaGonwithotherindirectlyprecipitaGngfactors• aging• inadequatelymanagedhypertension
• unrecognizedmedicaldisease
KawaiK,etal.JpnJClinOncol2013;43(11)1055–1063
KDIGO
AccurateevaluaGonofGFRduringoncologictreatmentispivotalandis
usedtodefinesurgerystrategies,programprophylacGcmanagementof
contrastedexaminaGons,makedecisionsoncisplaGneligibility,and
adjustdrugprescripGons,parGcularlychemotherapyagents.
KDIGO
• ThereisevidencethatpaGentswithcancerexhibitasignificantlossofkidneyfuncGonduringanGcancertreatment.
• Launay-Vacheretal.retrospecGvelyassessedkidneyfuncGonin4945
paGentswithsolidtumorsandfoundareducGonineGFRfrom91to84
mL/min/1.73m2aHer2years,and17.7%ofpaGentschangedfromCKD
Stage2to3or4attheendofthefollowup.
TorresdaCostaeSilvaetal.AdvChronicKidneyDis.2018;25(1):49-56
KDIGO
• ChrisGansenandassociatesprospecGvelyfollowed37,267paGentswithcancerandfoundthattheriskofacutekidneyinjury(50%increaseinthe
baselineesGmatedGFR)was17.5%inthefirstyearaHercancerdiagnosis
and27%over5years.
• Consideringthatcancertreatmentfrequentlyextendsthroughmonthsor
evenyears,repeatedacutekidneyinjuryepisodesarelikelytocontribute
significantlytothedevelopmentandprogressionofCKDinpaGentswith
cancer.TorresdaCostaeSilvaetal.AdvChronicKidneyDis.2018;25(1):49-56
KDIGO
TorresdaCostaeSilvaetal.AdvChronicKidneyDis.2018;25(1):49-56
KDIGO
TorresdaCostaeSilvaetal.AdvChronicKidneyDis.2018;25(1):49-56
Inonestudy,approximately16%ofpaGentswithcancerhad
sarcopeniabeforetreatmentiniGaGonandreducGonsinmusclemassfrequently
developsoverthecourseofthetreatment,affecGngupto70%ofpaGents,
parGcularlyinpaGentswithlatestagecancerundergoingchemotherapy.
SuchpaGentswouldhavedecreasedtheesGmatedGFRduetolossofmuscle
massratherthanchangeintheirtrueGFR.
Assuch,usingasingleequaGoninthesamepersonmightgivethefalse
impressionofstableorimprovedGFR,wheninfacttherehasbeensubstanGal
loss.
KDIGO
Launay-VacherV,etal.ESMOOpen2016;1:e000091
Chenetalincluded143paGentswithmetastaGccolorectalcancerAllpaGentshadnormalserumcreaGnineatinclusionandwerealltreatedthesame,attheusualdosageofchemotherapy.AHertreatment,therenalfuncGonwasesGmated;paGentsweregroupeddependingonwhethertheyhadatinclusionarenalfuncGonloweror>60,andsafetyandsurvival(Gmetoprogression)werecomparedbetweengroups.35%ofthepaGentsinthisstudyhadarenalfuncGonbelow60inspiteofanormalScr.PaGentswithCKDexperiencedstaGsGcallysignificantlyhigherratesofdose-relatedadverseevents,whichleadtosignificantlyratesoftreatmentdisconGnuaGonorinterrupGon,andsignificantlyreducedGmetoprogression.
TheimportanceofadjusGnganGcancerdrugdosagestorenalfuncGonwhenpaGentshaveCKD
KDIGO
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
KDIGO
THANK YOU KDIGO