Hypertension and Cardiovascular Morbidity Following Surgery for Kidney Cancer

Hypertension

and

Cardiovascular

Morbidity

Following

Surgery

for

Kidney

Cancer

Umberto

Capitanio

*

,

Alessandro

Larcher

,

Francesco

Cianflone

,

Francesco

Trevisani

,

Alessandro

Nini

,

Alexandre

Mottrie

,

Andrea

Mari

,

Riccardo

Campi

,

Riccardo

Tellini

,

Alberto

Briganti

,

Alessandro

Veccia

,

Hendrik

Van

Poppel

,

Marco

Carini

,

Claudio

Simeone

,

Andrea

Salonia

,

Andrea

Minervini

,

Alessandro

Antonelli

,

Francesco

Montorsi

,

Roberto

Bertini

a_{UnitofUrology,DivisionofExperimentalOncology,UrologicalResearchInstitute(URI),IRCCSOspedaleSanRaffaele,Milan,Italy;}b_{ORSIAcademy,Melle,}

Belgium;c_{DepartmentofUrology,OnzeLieveVrouwHospital,Aalst,Belgium;}d_{ClinicaUrologicaI,AziendaOspedalieraUniversitariaCareggi,Università}

deglistudidiFirenze,Firenze,Italy;e_{DepartmentofUrology,Universitàdeglistudie SpedaliCivilidiBrescia,Brescia,Italy;}f_{DepartmentofUrology,}

UniversityHospitalGasthuisberg,KatholiekeUniversiteitLeuven,Leuven,Belgium

a v ai l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n al h o m e p a g e : e u o n c o l o g y . e u r o p e a n u r o l o g y. c o m Articleinfo Articlehistory: AcceptedFebruary28,2019 AssociateEditor: GianlucaGiannarini Keywords: Kidneycancer Renalcancer Cardiovascularevents Hypertension Partialnephrectomy Radicalnephrectomy Abstract

Background: Despitebetterrenalfunctionfollowingnephron-sparingsurgery(NSS) relativetoradicalnephrectomy(RN),thereisnoconsensuswithrespecttothelong-term sequelaeassociatedwithsurgery.

Objective: Toinvestigatetheeffectofsurgeryandthetemporalpatternoftwodifferent cardiovascularevent(CVe)categoriesafterNSSversusRN.

Design,setting,andparticipants: Wecollecteddataof898patientswithcT1–2N0M0 renal massand nohistory ofCVe treatedwithNSSversus RN.CVecategorieswere dichotomised in (1) de novo hypertension(HT) and (2) othermajorcardiovascular events(MCEs).

Outcomemeasurementsandstatisticalanalysis: Multivariablecompetingregression analyses(MVAs)testedtheadjustedeffectofsurgerytypeoneachCVecategory.

Resultsandlimitations: AmongpatientstreatedwithRN,38%ofHTeventsoccurred immediatelyaftersurgery.Conversely,inNSScounterparts,theonsetofHTwasdiluted overtheyearsaftersurgery(10%ofHTeventsinthefirst6mo).WhenanMCEwas considered,anincreasing long-termtime-dependent prevalenceof theoutcomewas observedinbothgroups,withnostatisticallysignificantlydifferencebetweenNSSandRN. AtMVA,RNwasassociatedwithahigherHTrisk(hazardratio[HR]2.89;p=0.006)than butasimilarMCErisk(HR0.85;p=0.6)toNSS.

Conclusions: RelativetoRN,NSSshowedanindependentprotectiveeffectonHTbut notonMCEs.InpatientswithnohistoryofpreoperativeHTorMCEs,theonsetofHTafter RNisaveryearlyevent,dueprobablytotheacutelossofrenalparenchyma.Thisisnot thecasefortheothercardiovascularmorbidity,whichdevelopsinthelong-termperiod, regardlessofthetypeofsurgeryperformed.

Patientsummary: Inrenalcancerpatientswithoutamedicalhistoryofcardiopathy, preserving healthy kidney tissue at surgery is associated with a decreased risk of developingpostoperativehypertension.

©2019EuropeanAssociationofUrology.PublishedbyElsevierB.V.Allrightsreserved.

*Correspondingauthor.DepartmentofUrology,SanRaffaeleScientificInstitute,viaOlgettina60, 20132Milan,Italy.Tel.+390226437286;Fax:+390226437298.

E-mailaddress:capitanio.umberto@hsr.it(U.Capitanio).

https://doi.org/10.1016/j.euo.2019.02.006

1. Introduction

Theequipoiseinoncologicaloutcomesbetween nephron-sparing surgery (NSS) and radical nephrectomy (RN) for patientswithclinicallylocalisedkidneycancer[1]iswell established. For this reason—according to all available international guidelines—if a healthy part of the kidney canbesafelyspared,thetreatmentofchoiceisNSS.Notably, better renal function following NSSrepresents the most widelyacceptedclinicalbenefitofNSScomparedwithRN

[2].Moreover,ithasbeensuggestedthatNSSmaydecrease the risk of end-stage renal disease and cardiovascular events(CVe)aftersurgery[1–5].

Tobetterunderstandthenaturalhistoryof cardiovascu-larmorbidityaftersurgery,wecreatedamulti-institutional collaborationtoinvestigatetheeffectofNSSontwospecific cardiovascular categories and to analyse the temporal patternofpresentationofalltheevents.

2. Patientsandmethods 2.1. Population

Amulti-institutionalcollaborationofthreetertiarycarecentresenabled thecollectionintoaprospectivelymaintaineddatabaseof2092 conse-cutivepatientsdiagnosedwithasingleclinicalT1_–2N0M0renalmass whounderwentelectivesurgicaltreatmentbetween1987and2016.To ruleoutanypotentialconfoundingeffectofapre-existingconditionof cardiovascularmorbidity,wehaveexcludedfromouranalysisallcases withaprevioushistoryofeitherhypertension(HT)orCVe(n=1173). Patientswithmissingfollow-upinformationwerealsoexcluded(n=21). Aftertheseexclusions,the_finalcohortconsistedof898patientswith cT1_–2N0M0renalmassandnobaselineCVe.

2.2. Clinicalandpathologicalevaluation

Clinicaltumoursizewascalculatedbasedonpreoperativeimagingand was defined as the greatest tumour diameter in centimetres. The estimatedglomerular filtrationrate (eGFR)was calculatedwith the ChronicKidneyDiseaseEpidemiologyCollaborationformulainpatients youngerthan70yrold,whiletheBerlinInitiativeStudy(BIS1)formula wasusedforolderpatients(_70yr).

2.3. Outcomes

TheoutcomesconsideredforthisstudyweredenovoHTandmajor cardiovascular events(MCEs). HT wasde_fined as adiagnosis ofHT requiringatleastonedrug,whilecoronaryheartdisease, cerebrovascu-larevent,thromboembolicevent,dysrhythmias,andperipheral arterio-pathywereconsideredasMCEs.Thetreatingphysicianorcardiologist definedtheneedfortherapyincaseofHTandcharacterisationofMCE type. Those endpoints were collected by scrutinizing subsequent hospital admission charts or during periodic follow-up visits or, alternatively,byphonecallifapatientwasreferredtoanotherhospital aftersurgery.InpatientswithmultipleMCE,onlythefirstoccurredafter surgerywastakenintoconsiderationforthepurposeofouranalysis,to accountforthecompetingnatureofthetwoconditions.

2.4. Covariates

Analyseswereadjusted forthe following covariates:age atsurgery, gender, preoperative eGFR, comorbidities (de_fined according to the

Charlsoncomorbidityindex[CCI])[6],diabetes,smokinghistory(active smokervsformersmokervsnosmokinghistory),clinicaltumoursize, andyearofsurgery.

2.5. Statisticalanalyses

Statisticalanalysesaswellasreportingandinterpretationoftheresults wereconductedaccordingtoestablishedguidelines[7]andconsistedof threesteps.First,mediansandinterquartilerangeswerereportedfor continuousvariables,orfrequenciesandproportionswerereportedfor categoricalvariables.Mann-Whitneyandchi-squaretestswereusedto comparethestatisticalsignificanceofdifferencesinthedistributionof continuousandcategoricalvariables,respectively,betweencasestreated withNSSversusRN.

Second, given the competing natureof the outcomesexamined, smoothedPoissoncumulativecurveswereusedtoassesstheratesofHT andMCEs.

Third,theimpactoftreatmentmodality,namely,NSSversusRN,on the studyoutcomes wasestimatedusingamultivariable competing regressionanalysis(MVA)afteradjustmentforallthestudycovariates. AllstatisticaltestswereperformedusingtheRStudiographicalinterface v.0.98forRsoftwareenvironmentv.3.0.2withthefollowinglibraries, packages,andscripts:Hmisc,plyr,stats,rms,andcmprsk.Alltestswere twosided,withasignificancelevelsetatp<0.05.

3. Results

RNandNSSwereperformed,respectively,in36%(n=326) and64%(n=572)ofthepatients(Table1).Patientstreated withNSSwerediagnosedwithasmallertumour(median clinicalsize3vs6cm;p<0.0001)andhadhighereGFRat baseline (median eGFR 93 vs 87; p<0.0005) relative to theirRNcounterparts.

Median follow-upwas58 mo(interquartile range22– 115).Figs.1and2depictthesmoothedPoissoncumulative prevalence of HT and MCEs in NSS and RN patients, respectively.The5-yrHTandMCErateswere,respectively, 3.3%and6.3%inNSScasesversus5.1%and4.2%inRNcases. In NSS, theonset of HT was diluted overthe years after surgery(10%ofallHTeventsinthefirst6mo;Fig.1,red curve),while38%ofallHTeventsinRNoccurredinthefirst 6moaftersurgery(Fig.2,redcurve).Conversely,thevast majorityofMCEsaccumulateregularlyovertime,regardless ofthetypeofsurgery(Figs.1and2,greycurves).AtMVA, afteraccountingforallthepotentialconfounders,RNwas associatedwithahigherriskofHT(hazardratio2.89;95% confidenceinterval1.35–6.17;p=0.006)butasimilarMCE risk (hazard ratio0.85; 95%confidence interval 0.4–1.17; p=0.66)relativetoNSS(Table2).

4. Discussion

NSSiscurrentlythestandardofcareforpatientswhoare candidates for surgeryfor aclinical T1renalmass, when technicallyfeasible[1,8,9].NSSisequivalenttoRNinterms ofcancercontrol[10–14]butisassociatedwithbetterrenal function [15,16]. Recent data have suggested a potential benefitintermsofdecreasingtheriskofsubsequentCVein patients treated with NSS in comparison with RN [16– 19].Manymechanismshavebeensuggestedtoexplainwhy

renal function deterioration may be associated with increased cardiovascular morbidity (eg, endothelial dys-function, increased arterial calcification and stiffness

[20,21],increasedlevelsofinflammatoryfactors[22],high

apolipoprotein levels, anaemia [23], and left ventricular hypertrophy [24,25]). Nonetheless, all available data are invariablybased on nephropathicpatients, living donors, andtransplantrecipients,andthereisapaucityofdatain thecontextofkidneycancerpatients.Remarkably,thelatter should be regarded as a significant different clinical scenario, due to the differences observed in age and comorbidityprofile (eg,diabetes, chronic kidney disease, etc.)thatpreventanyclinicallyvalidgeneralisationofthe sameresearchfindings.

Many previous reports revealed a greater number of cardiovasculareventsinpatients treatedwith RNthanin thosetreatedwithNSS[26–28],althoughcontroversiesare still there. Huang et al. [27] analysed the Surveillance, Epidemiology, and End Results (SEER)-Medicare cancer registry,andcollecteddatafor2991patientstreatedwith NSS(19%)orRN(81%)between1995and2002.Afteramean follow-upperiodof 43mo,theyreporteda20%CVerate aftersurgery,witha1.4-foldgreaternumberofeventsafter RN(p<0.05).However,theresultscouldnotbeadjustedfor potentialconfoundersinpatientselection.Inthissetting,a recentEuropeancollaboration conducteda multi-institu-tional retrospective study, which included 1331 patients

withaclinicalT1a–T1bN0M0renalmassandnormalrenal functionbeforesurgery,confirmingahigherCVeriskinRN patients (n=462, 35%) than in their NSS counterparts (n=869, 65%)[26]. Manycriticismswereraisedafterthe publicationofthereport.Specifically,itwassuggestedthat potentialselectionbiasesmighthaveflawedtheresultsdue tofactthatthecurvesdepictingtherateofCVebetweenNSS andRNshowedanearlyseparationimmediatelyafterthe surgery. Recently, Yap et al. [29] conducted a large retrospective study in 11 937 patients (who underwent either NSSorRN between1995and2010)selectedusing linkedadministrativedatabasesintheprovinceofOntario, Canada.Afteramedianfollow-upof57mo,theyestablished a benefit of NSS after controlling for competing risks of deathformyocardialinfarction(p<0.05).However,neither HT nor any other type of CVe, other than myocardial infarction,wasconsideredasanoutcome.

Toaddresstheneedofclarificationinthistopic,Wang etal.[30]conductedameta-analysisofrenalfunctionand cardiovascular outcomes in patients submitted to either NSSorRNforrenaltumour.Overall,26studieswerepooled fornew-onsetchronickidneydisease,andsixstudieswere pooled for cardiovascular outcomes; NSS was shown to correlate witha73% riskreductionof new-onsetchronic kidney diseasein allincludedpatients(hazard ratio[HR] 0.27;p<0.0001)anda65%riskreductioninpatientswith tumours>4cm(HR0.35;p<0.0001)comparedwithRN.It wasalsoshownthattherewerenosignificantdifferences between groups regarding postoperative CVe (HR 0.86; p=0.2)andcardiovasculardeath(HR0.79;p=0.2).

Afteraccountingforbothclinicalandtumour character-istics,wewereabletodemonstratethatNSSindependently decreases HT risk relative to RN (RN HR 2.89; 95% confidence interval [CI] 1.35–6.17; p=0.006), while no differencewasfoundinMCEriskbetweenthetwogroups (HR 0.85; 95% CI 0.4–1.17; p=0.6). In addition, we demonstrated thatwhile manyHTeventsin RNoccurin thefirst6moaftersurgery(38%ofallHTevents;Fig.2),in NSStheonsetofHThasbeendilutedovertheyearsafter surgery(Fig.1,redcurve).ThiswasnotthecaseforMCEs, wheretheeventsoccurredlaterduringthefollow-up,with an increasing time-dependent prevalence in both the groups (Fig. 1 and 2, grey curves). These findings were further confirmed atMVA, afteraccounting for potential confounders, where patients who underwent RN were showntohaveahigherHTrisk(HR2.89;95%CI1.35–6.17; p=0.006)thanbutasimilarMCErisk(HR0.85;95%CI0.4– 1.17; p=0.66) to their NSS counterparts (Table 2). Since someeventswererecordedimmediatelyaftersurgery,we could not include in the adjusted model the variable depictingpostoperativeeGFRtolimitthecollinearityandto avoidtheinclusionofavariablethatmighthaveaffectedthe outcomesonlyinthosepatientswithnoeventsinthefirst monthsaftersurgery.

One of the possible pathophysiological mechanisms beyondsuchafinding mayberelatedtotheacutelossof halfofnephrons,whichhappensinRNpatients.Inorderto compensate for the parenchymal loss and maintain the preoperative filtration function, the remaining kidney

Table1–Descriptivecharacteristicsof898T1–T2N0M0RCC patientstreatedwithNSS(n=572)orRN(n=326)atthreetertiary careinstitutions Variable NSS (n=572,64%) RN (n=326,36%) pvalue Age 0.6 Median 57 56 IQR 46–66 47–65 Gender 0.2 Male 361(63) 221(68) Female 211(37) 105(32) CCI 0.6 Median 0 0 IQR 0–2 0–1 PreoperativeeGFR <0.0005 Median 93 87 IQR 77–103 71–99 Diabetes 0.31 No 531(93) 309(95) Yes 41(7) 17(5) Smokingstatus 0.78 Nosmokinghistory 344(60) 198(61) Activesmoker 100(17) 61(19) Formersmoker 128(22) 67(21) Clinicalsize <0.0001 Median 3 6 IQR 2.4–4 4.6–7.5 Yearofsurgery <0.0001 Median 2009 2005 IQR 2007–2011 1999–2010

CCI=Charlsoncomorbidityindex;eGFR=estimatedglomerularfiltration

rate;IQR=interquartilerange;NSS=nephron-sparingsurgery;RCC=renal

cellcarcinoma;RN=radicalnephrectomy.

increases the arterial blood inflow, which induces a compensatory function of the remaining glomeruli

[31]. We suppose that thismight beachieved through a rapidincreaseintherenin-angiotensin-aldosteronesystem (RAAS)activation,withanincreasedreninproductioninthe kidney. Clearly increased RAAS activation could be the direct culprit of the increased HT risk in these patients, causing the hypertensive state in those already more susceptible to a cardiovascular homeostasis alteration

[32].Thishypothesisisfurthersupportedbythefactthat HT is an early event after surgery: the RAAS activation wouldbeanimmediateeventafterthenephrectomy,andit stands to reason thatthe HTonset would followshortly thereafter.Althoughfurtherresearchisneededtoconfirm such a hypothesis, the use of an angiotensin-converting enzyme inhibitor in patients who undergo nephrectomy might represent a potentially useful tool for clinical practice.

Moreover,itwaslongbelievedthatlivingkidneydonors (LKDs),whoaresubjectedtothesameparenchymallossas patientssubmittedtoRNforkidneycancer,werenotexposed to an increased CVe rate [33,34], but there is mounting evidencethatthesepatientsaresubjectedtoanincreasedCVe

risk too. Moody et al. [35] demonstrated that unilateral nephrectomy in healthy individuals is associated with structuralandfunctionalcardiovascularabnormalities (myo-cardialdeformation,increasedaorticstiffness,andincreasein leftventriclemass)within1yr.Inaddition,Mjøenetal.[36]

compared LKDs with healthy controls and observed a significant increase in cardiovascular mortality (HR 1.40; 95% CI 1.03–1.91; p=0.03). We suppose that in LKDs, cardiovascularalteration, andfollowingincreased CVerisk, might recognise the same causes as those in individuals submittedtoRN,duetothefactthatbothpopulationsundergo a sudden nephron loss[37].In case of surgeryfor kidney tumour,suchmechanismsarefurtheraugmentedbythefact thatkidneycancerpatientsareolderandmorecomorbidthan their LKD counterparts, and theseaspectsare well-known detrimentalfactorsforthedevelopmentofHTandMCEs.

Forthefirsttime,ourstudyprovidesanadjustedanalysis ofthetimingandriskofdevelopmentofHTandMCEsafter NSSorRN.Wedemonstratedadifferenttemporalpatternof presentation between NSS and RN for HT development, which suggests novel pathophysiological mechanisms beyondthefunctionaloutcomesofkidneytumourpatients treated with surgery. Besides these merits, the major

Fig.1–SmoothedPoissoncumulativecurvesdepictinghypertension(HT)andmajorcardiovascularevent(MCE)ratesin572patientsdiagnosedwitha

singleclinicalT1–2renalmasswhounderwentNSSbetween1987and2016.The5-yrHTandMCEratesare3.3%and6.3%,respectively.NSS=

limitation is related to thenonrandomised nature of the comparison.Sinceitispossiblethatthecharacteristicsofthe patients(CCI,presenceofHTordiabetes,etc.)treatedwith NSSandRNhavebeenchangingovertheyears,andthatthe accuracyofthetreatingphysiciantodetectdenovoHTor other MCEs hasbeen improving overthelast decade, we decidedtoadjustalltheanalysesfortheyearofsurgeryto correctthemforthesepossibleaspects.Moreover,withinthis datasource,wecouldnottestthemutualcausalrelationship betweenthepostoperativerenalfunctiondetrimentandthe riskofCVe.Finally,aswasthecaseformostdataavailableon the topic, the results could not be adjusted for other important risk factors for cardiovascular disease such as hyperlipidaemia,exerciseactivity,andalcoholuse.

5. Conclusions

In renal cell carcinoma patients without preoperative cardiovascular morbidity, theeffect of surgical approach varies according to the type of CVe that is considered. Relative to RN, NSS showed an independent protective effectonHTbutnotonMCEs.Inpatientswithnohistoryof preoperative HTor MCEs,the onsetofHTafterRN isan early event, due probably to the acute loss of renal parenchyma.

Fig.2–SmoothedPoissoncumulativecurvesdepictinghypertension(HT)andmajorcardiovascularevent(MCE)ratesin326patientsdiagnosedwitha

singleclinicalT1–2renalmasswhounderwentRNbetween1987and2016.The5-yrHTandMCEratesare5.1%and4.2%,respectively.RN=radical

nephrectomy.

Table2–Multivariablecompetingriskregressionanalysis addressingtheeffectofNSSversusRNontheriskofdevelopingHT orMCEsinpatientswithnocardiovascularhistoryafter

adjustmentforclinicalandpathologicalconfounders

Predictors MVApredictingHT MVApredictingMCE HR(95%CI) pvalue HR(95%CI) pvalue

Approach

NSS Ref. Ref.

RN 2.89(1.35–6.17) 0.006 0.85(0.4–1.78) 0.7

Age(yr) 1.02(0.99–1.05) 0.2 1.04(0.99–1.08) 0.09

Gender

Male Ref. Ref.

Female 1.16(0.63–2.16) 0.6 0.71(0.35–1.42) 0.3 CCI 1.02(0.73–1.44) 0.9 1.07(0.78–1.48) 0.7 PreoperativeeGFR 0.98(0.96–1) 0.1 0.99(0.97–1) 0.09 Diabetes No Ref. Ref. Yes 0.84(0.23–3.14) 0.8 2.16(0.86–5.43) 0.1 Smokingstatus

NosmokinghistoryRef. Ref.

Activesmoker 0.7(0.3–1.64) 0.4 1(0.47–2.12) 0.9

Formersmoker 0.72(0.31–1.67) 0.4 0.92(0.45–1.9) 0.8

Clinicalsize 0.94(0.82–1.07) 0.3 0.98(0.84–1.15) 0.8

Yearofsurgery 1.16(1.08–1.25) 0.0006 1.09(1.02–1.18) 0.01

CCI=Charlsoncomorbidityindex;CI=confidenceinterval;eGFR=estimated

glomerularfiltrationrate;HR=hazardratio;HT=hypertension;MCE=major

cardiovascularevent;MVA=multivariableanalyses;NSS=nephron-sparing

Authorcontributions:UmbertoCapitaniohadfullaccesstoallthedatain thestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Capitanio,Larcher.

Acquisitionofdata:Capitanio,Larcher,Cianflone,Trevisani,Nini,Mottrie, Mari, Campi, Tellini, Briganti, Veccia, Van Poppel, Carini, Simeone, Salonia,Minervini,Antonelli,Montorsi,Bertini.

Analysis and interpretation of data: Capitanio, Larcher, Cian_flone, Trevisani.

Draftingofthemanuscript:Capitanio,Larcher,Cianflone,Trevisani. Critical revision of the manuscript for important intellectual content: Capitanio, Larcher, Cianflone, Trevisani, Nini, Mottrie, Mari, Campi, Tellini,Veccia,VanPoppel,Carini,Simeone,Salonia,Minervini,Antonelli, Montorsi,Bertini.

Statisticalanalysis:Capitanio,Larcher,Cian_flone. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:None.

Supervision:Capitanio,Larcher,Cianflone,Trevisani,Nini,Mottrie,Mari, Campi,Tellini,Veccia,VanPoppel,Carini,Simeone,Salonia,Minervini, Antonelli,Montorsi,Bertini.

Other:None.

Financialdisclosures:Umberto Capitaniocertifiesthatallconflictsof interest, including speci_{fic financial} interests and relationships and af_filiationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/affiliation,grantsorfunding, consultan-cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatentsfiled,received,orpending),arethefollowing:None. Funding/Supportandroleofthesponsor:Researchactivityinthe_fieldof kidney cancer at Urological ResearchInstitute, IRCCSOspedale San Raffaele,issupportedbyanunrestrictedgrantfromRecordati.

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