MANAGEMENTOFAKIANDCKDINMALIGNANCY

ANITHAVIJAYANMDPROFESSOROFMEDICINEDIVISIONOFNEPHROLOGY

KDIGO

DISCLOSURES

 NxStage–Speaker,Scien@ficAdvisoryBoard Sanofi-Speaker

KDIGO

ACUTEKIDNEYINJURY

DEFINITIONCANCERRELATEDAKI

TLSCAST

NEPHROPATHYMANAGEMENT

KDIGO

Defini@onofAKI(KDIGOguidelines)

Anabrupt(within48hours)reduc@oninkidneyfunc@on–Ø riseinserumcrea@nine(SCr)by≥0.3mg/dLØ apercentageincreaseinSCrof≥50%frombaselineoverthepast7daysØ ordocumentedoliguriaoflessthan0.5ml/kg/hourformorethan6hours

Kidney Intl 2: 8-12, 2012

KDIGO

Classifica@on/StagingSystemforAKI

Stage SerumCrea<nineCriteria UrineOutputCriteria

1 RiseinSCr≥0.3mg/dLor≥150-200%frombaseline

<0.5ml/kg/hrfor>6hr

2 RiseinSCr>200-300%frombaseline <0.5ml/kg/hrfor>12hr

3

RiseinSCr>300%frombaseline,orSCr>4mg/dLwithanacuteincreaseofatleast0.5mg/dL

<0.3ml/kg/hrfor>24hroranuria>12hr

Kidney Intl 2: 8-12, 2012

KDIGO

ICUacquiredAKI

Rocha et al, NDT, Jan 2009

0%

10%

20%

30%

40%

50%

60%

Sepsis Ischemia Nephrotoxins Rhabdo Obstruc@on

CAUSESOFAKIAMONGALLPATIENTS Overallincidenceisabout20%

 Pa@entswithmalignancy: MostcommoncauseofAKIissepsis Incidence12–50% RequiringRRT–9-30% MortalityinthoseneedingRRT:70–85%

Bouchard et al, CJASN 2015; Campbell et al ACKD 2014

KDIGO

Zengetal,CJASN2014

AKIINSETTINGOFOTHERCO-MORBIDITIES

KDIGO

AKIIncreasesTheRiskOfProgressionToESRD

Hsuetal,CJASN2009

KDIGO

CostofAKIALLAKIPATIENTS AKI-DPATIENTS

Silveretal,JHospMed2017

KDIGO

DIRECTLYRELATEDBYMALIGNANCY

DIRECTEFFECTSOFCHEMOTHERAPY

COMPLICATIONSOFTREATMENTOFMALIGNANCY OTHERFACTORS

ACUTEKIDNEYINJURYKDIGO

Directlycausedbymalignancy

 Obstruc@on◦ Prostatecancer◦ Urothelialmalignancy◦ Ovarian/Uterinemalignancy◦ Extrinsiccompressionfrommetastases,lymphadenopathy Infiltra@on◦ Lymphoma/leukemia Intrinsicdamage◦ Mul@plemyelomawithcastnephropathy/lightchaindeposi@ondisease Hypercalcemia

KDIGO

Directtoxicityfromchemotherapyagents

Glomerularinjury/TMA◦ Checkpointinhibitors◦ VEGFinhibitors◦ Gemcitabine

 Inters@@alNephri@s◦ Checkpointinhibitors

 Tubularinjury◦ Pla@numcompounds◦ Methotrexate◦ Trabec@din(rhabdomyolysis)◦ Pemetrexed

KDIGO

Complica@onsoftreatment

Pre-renalAKI(especiallyifconcomitantlyonNSAIDs,RAASblockers)◦ severediarrheawithirinotecan◦ nausea/vomi@ngwithotherchemotherapyagentsIntrinsicrenalinjury◦ Tumorlysissyndrome

 Obstruc@on◦ Urothelialstrictures(previoussurgery/radia@on)

KDIGO

Otherfactors Sepsis ContrastinducedAKI Nephrotoxins◦ Bisphosphonates◦ NSAIDs◦ ACEI◦ ARB◦ Aminoglycosides◦ Vancomycin◦ Amphotericin◦ IVAcyclovir

 AKIposthematopoie@cstemcelltransplant

KDIGO

MANAGEMENTOFAKIKDIGO

KDIGORECOMMENDATIONSFORMANAGEMENTOFAKI

Discon<nuenephrotoxicagentsEnsureadequatevolumestatusandperfusionpressureConsiderfunc<onalhemodynamicmonitoringMonitorserumcrea<nineandurineoutputAvoidhyperglycemiaConsideralterna<vestoradiocontrastprocedures

Non-invasivediagnos<cworkupConsiderinvasivediagnos<cwork-up

CheckforchangesindrugdosingConsiderRRT

AssessforRRT

HighRisk AKIStage1 AKIStage2 AKIStage3

ICUadmission

Avoidsubclaviancatheters

KidneyInterna@onalSupplements(2012)

KDIGO

TumorlysissyndromeKDIGO

HyperphosphatemiaHyperkalemiaElevatedUricacid

Spontaneous

Ajerchemotherapy

Triggerinflammatorymediators Renalvasoconstric@on

Inflamma@on

Uricacidcrystalliza@onCa-Pnephropathy

AKI

TUMORCELLS CELLLYSIS

KDIGO

Purine catabolism

Hypoxanthine

Xanthine

Uric acid

Excretion

Xanthine oxidase

Xanthine oxidase

ALLANTOIN

EXCRETION

Urateoxidase KDIGO

CAIRO-BISHOPCLASSIFICATIONFORTLS

LABORATORYCRITERIA

Ø SerumK>6.0mEq/Lorincreaseby25%frombaseline

Ø SerumCa<7mg/dLordecreaseby25%frombaseline

Ø SerumP>4.5mg/dLorincreaseby25%frombaseline

Ø SerumUA>8.0mg/dLorincreaseby25%frombaseline

CLINICALCRITERIA

Ø AKI:increaseinSCr1.5xULNØ CardiacarrhythmiaØ Seizures

CAVEATS:3daysbeforeorwithin7daysajerchemotherapyInsameInsame24hourperiodMaybedelayedforsolidtumors

KDIGO

RISKFACTORSFORTLS

Tumorcharacteris@cs

• Hematologicalmalignancieswithhightumorburden• WBC>50,000• ElevatedLDH• Burkips’slymphoma• DLBCL• Lymphoblas@cleukemia

• Solidtumorswithverylargetumorburden*

Pa@entcharacteris@cs

•  UnderlyingCKD•  Concomitantnephrotoxins

•  ConcomitantCHF/Liverdisease

•  Volumedeple@on•  Lympha@c/leukemicinfiltra@onofthekidney

•  Hyperuricemiaatbaseline

Chemotherapyfactors

•  Specifictargetedtreatments•  Venetoclax(BCL-2inhibitor)

•  Obinutuzumab(CD-20monoclonalAb)

•  Ibru@nib(BTKinhibitor)

•  Dinaciclib(CDKinhibitor)

KDIGO

TLSAFTERTREATMENTOFCLLWITHVENETOCLAX

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

18.0%

20.0%

%PAT

IENTSW

ITHTLS

TotalTLS LabTLS ClinicalTLS

RobertsetalNEJM2016

KDIGO

RISKSTRATIFICATION

IVFLUIDS–NSorIsotonicfluidAVOIDNEPHROTOXINS

IVFLUIDS–NSorIsotonicfluidAVOIDNEPHROTOXINS

ALLOPURINOLORFEBUXOSTATCONSIDERPROPHYLACTIC

RASBURICASEIFVERYHIGHRISK

LOWRISK MODERATE/HIGHRISK

INITIATIONOFCHEMOTHERAPY

MONITORFORTLS–RenalPanel,UricAcidevery12-24hours

TUMORCHARACTERISTICSPATIENTCHARACTERISTICSTYPEOFCHEMOTHERAPY

IFTLSOCCURS

Rasburicase/Ini@a@onofRRT

URINARYALKALINATIONNOTRECOMMENDED

KDIGO

WilsonandBernsCJASN2012

Randomizedtrialsofrasburicase

KDIGO

CASTNEPHROPATHYKDIGO

CASTNEPHROPATHY

 Mul@plemyeloma◦ representsapproximately1%ofallmalignancies◦ Approximately15%ofallhematologicalmalignancies

 Approximately20-30%ofMMpa@entshavecastnephropathy MostcommoncauseofAKIinMMIscastnephropathy AKIassociatedwithreducedsurvivalKDIGO

KBasnayakeetal,KidneyInterna@onal(2011)79,1289–1301;

KDIGO

KDIGO

DIFFERENCEINSIEVINGCOEFFICIENTBETWEENHIGH-FLUXandHCODIALYZERS

GondouinBandHutchisonCA,AdvCKD2011

KDIGO

HutchisonCAetal,CJASN2009

KDIGO

P<0.001

HutchisonCAetal,CJASN2009

KDIGO

MYRESTUDY

Highfluxdialyzer 33.3% 35.4%

Highcutoffdialyzer 41.3% 56.5%

98pa@ents

Dialysisindependenceat3mo

Dialysisindependenceat6mo

P=0.04P=0.42

Bridouxetal,JAMA2017

KDIGO

FinkelandFabbrini_JOncoNeph2017

KDIGO

RRTINAKI KDIGO

CONSIDERATIONSREGARDINGRRTINPATIENTSWITHMALIGNANCYANDAKI

 SHOULDRRTBEINITIATED?◦ Ethicalconcernsinterminalmalignancy◦ Ifcurrentillnessfelttobereversible,thenRRTshouldbeconsidered TIMINGOFRRT

 MODALITY

 DOSEOFRRT

KDIGO

Darmonetal,NDT2015

Mortalityincri@callyillpa@entswithhematologicalmalignanciesandAKI

KDIGO

DifferencesbetweenCRRTandIHDCRRT IHD

Hemodynamicstability + - Fluidbalanceachievement + - Superiormetaboliccontrol + - Con<nuousremovaloftoxins + - Stableintracranialpressure + - Unlimitednutri<on + - Needforintensivecarenursingsupport + - Simpletoperform ± - Rapidremovalofpoisons - + Limitedan<coagula<on - + Needforhemodialysisnursingsupport ± + Pa<entmobility - +

KDIGO

OUTCOMES:HDVSCRRT

 Nodifferenceinmortalitybetweenpa@entsini@atedonCRRTvsIHD Nodifferenceinrenalrecovery NodifferenceinICU/hospitalLOS

KDIGO

KDIGORecommenda@onsforRRTinAKI

 Usecon@nuousandintermipentRRTascomplementarytherapiesinAKIpa@ents(Notgraded)

 WesuggestusingCRRT,ratherthanstandardintermipentRRT,forhemodynamicallyunstablepa@ents(Grade2b)

 WesuggestusingCRRT,ratherthanintermipentRRT,forAKIpa@entswithacutebraininjuryorothercausesofincreasedintracranialpressureorgeneralizedbrainedema(Grade2b)

KidneyInterna@onal2:(1)2012

KDIGO

Edrees,Li,Vijayan,ACKD2016

COMPARISONOFDIFFERENTMODALITIES

KDIGO

DOSINGOFRRTINIHDANDCRRT

IHD◦ GoalisspKt/Vureaof1.3/treatment,3@mes/week

CRRT◦ Effluentvolumeof20-25ml/kg/hour

KDIGO

MANAGEMENTOFCKDINMALIGNANCYKDIGO

Toxicityfromotherdrugs Chemotherapytoxicity

Lossofnephronmass Mechanicalissues

ChronicKidneyDisease

KDIGO

CAUSESOFCKDINCANCERPATIENTS

Chemotherapytoxicity

VEGFinhibitors

Tyrosinekinaseinhibitors

Pla@numbaseddrugs

Gemcitabine

Checkpointinhibitors

Pemetrexed

Othernephrotoxins

Bisphosphonates

NSAIDs

IVcontrast

Nephronloss

Par@alnephrectomy

Unilateralnephrectomy

Mechanicalissues

Intrinsicobstruc@onof

ureter

Extrinsiccompressionof

ureter

Infiltra@onofthekidney

OTHER

DM

HTN

GN

KDIGO

ManagementofCKDinpa@entswithmalignancy

 BPcontrol Managementofproteinuria

 UseofACEI/ARB ManagementofanemiaofCKD

 OtherCKDrelatedissues◦ Boneandmineralmetabolism◦ Metabolicacidosis

 Chemotherapyassociatedcomplica@ons

 Glomerulonephri@sassociatedwithmalignancy

KDIGO

PerazellaandIzzedine,KidneyInterna@onal(2015)87,909–917

KDIGO

HypertensionandProteinuriawithVEGFinhibi@on

 Hypertension◦ Dosedependent◦ Rangefrom20–40%◦ Treatment–standardan@HTNmedica@ons◦ Chemotherapyshouldnotbeinterruptedforhypertension

 Proteinuria◦ Endotheliosis,focalfootprocesseffacement,GBMdamage–doublecontouring,mesangiolysis.◦  Inseverecases–TMAnoted(fibrindeposi@onandredbloodcellentrapment)◦ Dosedependent◦ *Incidencerangefrom5-10%withbevacizumab,dependingondose,typeoftumorandconcomitanttx◦ Treatment:JudicioususeofRAASblockers.◦ Con@nuechemotherapyunlessrapidworseningofrenalfunc@onorheavyproteinuria◦ Proteinuriacorrelateswithregressionofmalignancy

*Wuetal,JAmSocNephrol.2010Aug;21(8):1381–1389

KDIGO

MembranousGN Malignancymaybeseenin5–20%ofpa@entswithmembranousGN

 Mostcommon–Solidtumors(lung,prostate,breast,GI)Lesslikelyhematological

 MembranousGNmaybeseenwithGVHDaswell

DeVrieseetalJASN2017

KDIGO

ManagementofCKDinpa@entswithmalignancy

 BPcontrol Managementofproteinuria

 UseofACEI/ARB ManagementofanemiaofCKD

 OtherCKDrelatedissues◦ Boneandmineralmetabolism◦ Metabolicacidosis

 Chemotherapyassociatedcomplica@ons

 Glomerulonephri@sassociatedwithmalignancy

KDIGO

USEOFESAFORANEMIAOFCKDINCANCERPATIENTS CONCERNS◦ Increasedriskformortalityandprogressionofmalignancy

◦ Increasedriskforthromboembolicevents TREATSTUDY◦ RCTofpatentswithDM,CKDandanemia◦ RandomizedtoDarbepoe@ntogetHbto13g/dL

◦ orPlacebowithrescueDarbepoe@nifHb<9.0g/dL

 RESULTS◦ PrimaryEP–DeathorCVeventsnodifference

◦ Stroke–higherincidenceinDarbepoe@ngroup.(HR1.92,P<0.001)

6.9% 6.4%1.9% 1.2%7.4% 0.6%0%

1%

2%

3%

4%

5%

6%

7%

8%

Darbepoei@n Placebo

CANCEROUTCOMESINTREATTRIAL

CancerrelatedAE

Deathsapributedtocancer

Deathsapributedtocancerinthosewithmalignancyatbaseline

P=0.002

P=0.08

P=0.53

KDIGO

TreatmentofanemiawithESAinCKD

Nohistoryofmalignancy

StartESAperguidelinesifHb<9Primarygoal–preven@onoftransfusion

KeepHb9-11AvoidexcessivedosesofESAEnsureironreplete

Ac@vemalignancyormalignancyinremission(notconsideredcured)

BloodtransfusionforsevereanemiaIronsupplementa@on

AvoidESAifpossibleIfunabletoavoidESA-discusswithoncologistbenefits/risksUselowestdosepossibletokeepHb>9

Historyofmalignancy(“cured”)

Ifs@llfollowingoncology,d/woncologistbeforeini@a@ngESAStartatlowestpossibledoseEnsureironreplete

MaintainatlowestpossibleESAdosetokeepHb>9andreduceriskfortransfusion

KDIGO

ManagementofBPandMetabolicAcidosis

 BLOODPRESSURE GoalBP<130/80mmHg

 (JNCVIIIof<120/80mightbetoostringentandhigherriskforAKI)

 Pa@entswithmalignancyathighriskforvolumedeple@onandAKI

 Judicioususeofdiure@csandACEI/ARB,unlessthereisclearbenefit

 METABOLICACIDOSIS

 MaintainHCO3>22todelayprogressionofCKD

 UseNaHCO3tabletsastolerated–upto1300mg@d

KDIGO

SUMMARY MalignancyiscomplicatedbyAKIandCKDfromvariouscauses

 E@ologycanbedirectlyrelatedtomalignancyorchemotherapy

 AKI◦ ConcomitantfactorssuchasothernephrotoxinsandsepsisalsocontributetoAKI◦ TLS–recogni@onofriskfactors,intravenoushydra@onandappropriateuseofrasburicaseiskey◦ Castnephropathy–HCOdialyzershaveshownsomepromiseinmanagement,butnotapprovedforuseinUS◦ RenalreplacementtherapyinAKI–ethicalissuesshouldbeconsidered◦ Dose,@ming,andmodalityrecommenda@onsaresimilartopa@entswithoutmalignancy

 Concomitantdiseases–DMandHTN–contributetoCKD◦ VEGFinhibitorsleadtoproteinuriaandHTNfromFSGS,TMAorotherpodocyteinjury.◦ Chemotherapyshouldnotbeinterruptedformostpa@entswithproteinuriaandHTN◦ MembranousGNisassociatedwithmalignancy.Pa@entswithMembGNwithnega@vePLA2Rtes@ngshouldbescreenedformalignancy

◦ ESAshouldbeusedcau@ouslyinpa@entswithahistoryofmalignancyandavoidedifpossibleinthosewithmalignancy◦ BPgoalis<130/80.Cau@onwithRAASblockersifpa@enthasrecurrentepisodesofvolumedeple@onandAKI

KDIGO