Mini percutaneous nephrolithotomy is a noninferior modality to standard percutaneous nephrolithotomy for the management of 20-40 mm renal calculi: A Multicenter randomized controlled trial

Platinum

Priority

–

Stone

Disease

EditorialbyPanagiotisKallidonis,DespoinaLiourdi,EvangelosLiatsikosandArmanTsaturyanonpp. 122–123ofthisissue

Mini

Percutaneous

Nephrolithotomy

Is

a

Noninferior

Modality

to

Standard

Percutaneous

Nephrolithotomy

for

the

Management

of

20

–40

mm

Renal

Calculi:

A

Multicenter

Randomized

Controlled

Trial

Guohua

Zeng

a,y,

*

,

Chao

Cai

a,y

,

Xianzhong

Duan

b,y

,

Xu

Xun

c,y

,

Houping

Mao

d

,

Xuedong

Li

e

,

Yong

Nie

f

,

Jianjun

Xie

g

,

Jiongming

Li

h

,

Jun

Lu

i

,

Xiaofeng

Zou

j

,

Jianfeng

Mo

k

,

Chengyang

Li

l

,

Jianzhong

Li

m

,

Weiguo

Wang

n

,

Yonggang

Yu

o

,

Xiang

Fei

p

,

Xianen

Gu

q

,

Jianhui

Chen

r

,

Xiangbo

Kong

s

,

Jian

Pan

t

,

Wei

Zhu

a

,

Zhijian

Zhao

a

,

Wenqi

Wu

a

,

Hongling

Sun

a

,

Yongda

Liu

a

,

Jean

de

la

Rosette

a,u,v

a_{DepartmentofUrology,MinimallyInvasiveSurgeryCenter,GuangdongKeyLaboratoryofUrology,TheFirstAffiliatedHospitalofGuangzhouMedicalUniversity,}

Guangzhou,China;b_{DepartmentofUrology,BaoshanNo.2People’sHospital,Baoshan,China;}c_{DepartmentofUrology,People’sHospitalofNanhaiDistrict,Foshan,China;}

d_{DepartmentofUrology,TheFirstAffiliatedHospitalofFujianMedicalUniversity,Fuzhou,China;}e_{DepartmentofUrology,TheSecondAffiliatedHospitalofHarbin}

MedicalUniversity,Harbin,China;f_{DepartmentofUrology,YichangYilingHospital,Yichang,China;}g_{DepartmentofUrology,SuzhouMunicipalHospital,Suzhou,China;}

h_{DepartmentofUrology,TheSecondAffiliatedHospitalofKunmingMedicalUniversity,Kunming,China;}i_{DepartmentofUrology,ShanghaiGeneralHospital,Shanghai,}

China;j_{DepartmentofUrology,TheFirstAffiliatedHospitalofGannanMedicalUniversity,Ganzhou,China;}k_{DepartmentofUrology,TheSixthAffiliatedHospitalof}

GuangzhouMedicalUniversity,Qingyuan,China;l_{DepartmentofUrology,TheFirstAffiliatedHospitalofGuangxiMedicalUniversity,Nanning,China;}m_Departmentof

Urology,TheGeneralHospitalofShenyangMilitary,Shenyang,China;n_{DepartmentofUrology,JiningNo.1People’sHospital,Jining,China;}o_{DepartmentofUrology, 181st}

HospitalofChinesePeople’sLiberationArmy,Guilin,China;p_{DepartmentofUrology,ShengJingHospitalofChinaMedicalUniversity,Shenyang,China;}q_Departmentof

Urology,ChuiYangLiuHospitalaffiliatedtoTsinghuaUniversity,Beijing,China;r_{DepartmentofUrology,FujianMedicalUniversityUnionHospital,Fuzhou,China;}

s_{DepartmentofUrology,China–JapanUnionHospital,JilinUniversity,Changchun,China;}t_{DepartmentofUrology,JiangmenCentralHospital,Jiangmen,China;}

u_{AmsterdamUMC,UniversityofAmsterdam,Amsterdam,TheNetherlands;}v_{DepartmentofUrology,IstanbulMedipolUniversity,Istanbul,Turkey}

a v a i l ab 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 a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Articleinfo Articlehistory: AcceptedSeptember10,2020 AssociateEditor: J.-N.Cornu StatisticalEditor: EmilyZambor Keywords: Mini Percutaneousnephrolithotomy Abstract

Background: Highqualityofevidencecomparingminipercutaneousnephrolithotomy (mPNL)withstandardpercutaneousnephrolithotomy(sPNL)forthetreatmentof larger-sizedrenalstonesislacking.

Objective: TocomparetheefficacyandsafetyofmPNLandsPNLforthetreatmentof 20–40mmrenalstones.

Design,setting,andparticipants: Aparallel,open-label,andnoninferiorrandomized controlledtrialwasperformedat20Chinesecenters(2016–2019).Theinclusioncriteria werepatients18–70yrold,withnormalrenalfunction,and20–40mmrenalstones. Intervention: Percutaneousnephrolithotomy(NPL)wasperformedusingeither18For 24Fpercutaneousnephrostomytracts.

Outcomemeasurementsandstatisticalanalysis: Theprimaryoutcomewasthe one-sessionstone-freerate(SFR).Thesecondaryoutcomesincludedoperatingtime,visual analogpainscale(VAS)score,bloodloss,complicationsaspertheClavien-Dindograding system,andlengthofhospitalization.

y _{Theseauthorscontributetothisstudyequally.}

*Correspondingauthor.1KangdaRoad,HaizhuDistrict,Guangzhou,Guangdong510230,China.

Tel.+8613802916676;Fax:+8602034294165.

E-mailaddress:gzgyzgh@vip.sina.com(G.Zeng).

https://doi.org/10.1016/j.eururo.2020.09.026

1. Introduction

Percutaneous nephrolithotomy (PNL) is the preferred surgical procedure for the treatment of 20–40mm renal stones, as it has an excellent stone-free rate (SFR)

[1].However,PNLcanresultinseriousmorbidities:blood transfusion(7%),sepsis(0.5%),organinjury(0.4%), emboli-zation(0.4%), anddeath (0.05%) [2]. It hasbeen demon-strated that the large nephrostomy tract (24–30F), the so-calledstandardPNL(sPNL),partlycontributestothese morbidities [3]. Mini PNL (mPNL; 12–20F) was initially introducedforpediatricpatients.Later,itwasappliedtothe generalpopulationtoreducethemorbidities[4,5]. Current-ly,the generallyaccepted optionsfor treating 20–40mm renal stones included flexible ureteroscope lithotripsy (fURL) and PNL. Compared with mini percutaneous or micropercutaneous surgery, fURL has a lower SFR and requires staged procedures, but has lower complication rates and shorter hospitalization times [6–8]. With the improvements in nephroscope, lithotripter, nephrostomy sheath,andimagingtechniqueinthepast2decades,sPNL hasbeenchallengedbymPNL.Arecentsystematicreview and meta-analysis reported that mPNL could achieve a comparableSFR,butwithalongeroperativetime.However, mPNL hadthe advantages of lessblood loss and shorter hospitalization.Othercomplicationsweresimilar[1]. How-ever, thequality of evidence in this analysis had certain limitations:therewassignificantheterogeneityamongthe includedstudies,mostofthestudiesweresingle-armtrials, andthisanalysiscomprisedonlytwosmall-sized random-izedcontrolledtrials(RCTs).Hence,higher-qualityevidence isnecessarytoreachsoundconclusionsandmakesuitable recommendations.WeconductedalargemulticenterRCTto comparetheefficacyandsafetybetweensPNLandmPNL. 2. Patientsandmethods

2.1. Trialdesignandparticipants

This is a multicenter, parallel, open-label RCT. Patients were recruited from20 Chinesetertiary medical centers from January 2016 to August 2019 (ClinicalTrials. gov, NCT02635048). Each participating center performed >500 PNLs per year. Ethics committee approval was

obtained ateach site,andwritteninformed consentwas obtained from each patient. We presented the study following the Consolidated Standards of Reporting Trials (CONSORT)guidelines.

Theprimaryoutcomewasthe one-sessionSFR,and the secondaryoutcomesincludedoperatingtime,visual analog painscale(VAS)score,bloodloss,complications asperthe Clavien-Dindogradingsystem,andlengthofhospitalization. Patientsagedbetween18and70yrandwithnormalserum creatinine (133

m

mol/l), 20–40mm renal stones, and American Society of Anesthesiology scores of 1–2 were included.Morbidlyobesepatients(bodymassindex40kg/ m2_{), patients with congenital abnormalities, patients with} historiesofrenaltransplantorurinarydiversion,andpatients with solitary kidneys, uncorrected coagulopathy, or active urinarytractinfectionswereexcluded.

2.2. Randomizationandmasking

Centralrandomizedallocationwasusedwithout stratifica-tion. Arandomization listwasgeneratedbya statistician andsecurely storedatapassword-protectedcomputerof thesponsor’scenter.Onlyoneprotocol-blindedcoordinator knew the password and revealed the assignments in sequence to each center. Since the participating centers needed to prepare the appropriate instruments for the allocatedprocedures,theallocationwasrevealed1dbefore surgery.Consentformsweresigned.

2.3. Proceduresandqualitycontrol

A uniform operating methodology was established and approved by the principal investigator in each center. Protocol monitoringvisitswere conductedmonthlyatall centers.

Intravenousurographyand2mmnoncontrastcomputed tomography(CT)wereperformedinallpatients.Allcenters used the same software to measure stone density. All patients had negative urine culture before operation. A single intravenousdoseof first/second-generation cepha-losporin orciprofloxacinwasadministered30minbefore andaftereachsurgeryforprophylaxis.

Allthe procedureswere performedbyone designated experienced surgeon (100 procedures per year in both Resultsandlimitations: The1980intention-to-treatpatientswererandomized.The mPNLgroupachievedanoninferiorone-sessionSFRtothesPNLgroupbytheone-side noninferioritytest(0.5%[difference],p<0.001).Thetransfusionandembolizationrates werecomparable;however,thesPNLgrouphadahigherhemoglobindrop(5.2g/l,p< 0.001).ThesPNLyieldedshorteroperatingtime(–2.2min,p=0.008)butahigherVAS score(0.8,p<0.001).PatientsinthesPNLgroupalsohadlongerhospitalization(0.6d, p< 0.001). There was no statistically significant difference in fever or urosepsis occurrences.Thestudy’smainlimitationwasthatonly18For24Ftractsizeswereused. Conclusions: MiniPNLachievesnoninferiorSFRoutcomestosPNL,butwithreduced bleeding,lesspostoperativepain,andshorterhospitalization.

Patientsummary: Weevaluatedthesurgicaloutcomesofpercutaneousnephrolithotomy usingtwodifferentsizesofnephrostomytractsinalargepopulation.Wefoundthatthe smallertractmightbeasensiblealternativeforpatientswith20–40mmrenalstones.

©2020PublishedbyElsevierB.V.onbehalfofEuropeanAssociationofUrology.

Standard;

Renalstone;

sPNLandmPNL)percenter.Eachprocedurewascompleted undergeneralanesthesiaandintheproneposition.A5F open-ended ureteral catheter was first inserted into the renalpelvis. The renalpuncture wasperformedusing an 18-gauge needle with fluoroscopic and/or ultrasonic guidanceasperthesurgeon’spreference.Thenephrostomy tractwasgraduallydilated withfascialdilatorsupto18F (mPNL)or24F(sPNL).Acorrespondingpeel-awaysheath wasused(Fig.1).A12Fnephroscope(Wolf)waschosenfor themPNLanda20.8Fone(Wolf)forthesPNL.Thestone was fragmented by a pneumatic lithotripter or/and a holmium laser with a 550

m

m laser fiber (with energy settingat30–50W)and/oranultrasoniclithotripter(only thesPNLgroup).Thestatusofresidualstoneswasevaluated routinelybyfluoroscopy(radiopaquestone)orultrasound (radiolucent stone)attheendoftheprocedure.Then, an immediatesecondlookthroughtheinitialtractoranother puncturewasperformedifneeded.A6Findwelling double-Jstentwasplacedfor4wk.A16–18Fnephrostomytubewas insertedandthenremovedbeforedischarge.Indicationsfor atubelessprocedurewereasfollows:novisibleperforation, nosignificantbleeding,andcompletestoneclearance. 2.4. Outcomemeasuresanddatacollection

Plain kidney-ureter-bladder (KUB) radiograph and renal ultrasoundwereusedtoevaluatetheresidualstonesbefore dischargeandduringfollow-up.Iftherewasadiscrepancy betweentheKUBandultrasoundresults,2mmnoncontrast CTwasperformedtobetterassessthepresenceofresidual stonesandtheirclinicalmanagement.Theresidualstones wereassessedbytwoprotocol-blindedradiologists.If the largestresidualstonewas>6mm,shockwavelithotripsy, retrograde intrarenal surgery, or retrograde ureteroscope lithotripsywasrecommendedbeforeremovingthedouble-J stent.Residualstonesrangingfrom4to6mminsizewere recommended for conservative treatments [9]. The one-session SFR was defined as the presence of either no residualstoneor4mmasymptomatic,noninfectious,and nonobstructive residual stones [10] at 1 mo after the removal of the double-J stent and withoutany auxiliary procedures.

Transfusionwasimplementedwhenthehemoglobinwas <70g/lorprogressivelydecreasingaftersurgery.Indications for angiography and selective angioembolization were

continuous significant bleeding and progressive decrease inhemoglobinwithhemodynamicinstability.VASwasused forquantificationofpainat24haftersurgery[11].VASscore wasevaluatedbytwoprotocol-blindednurses.Patientswith aVASscoreof>5weregivennonsteroidal anti-inflamma-torymedication.Thestonecompositionwasanalyzedusing thesameinfraredspectrometerandmethodology[12]inall centers.

Patients’ characteristics and clinical outcomes were recorded on apre-establishedcase report form (Supple-mentarymaterial).Surgicaloutcomeswereassessedusing stone size,tract length,obstruction, numberofinvolved calices, and stone density (STONE) nephrolithometry

[13].Thestonesizewasthelargestdiameterforasingle stone and the summation of the largest diameters for multiple stones. The operating time was defined as the timefromapuncturetotheplacementofthenephrostomy tube or theremoval of access sheathsin tubeless cases. Septic shock was identified using the clinical criteria of persisting hypotension requiring vasopressor therapy to maintain the mean artery pressure of 65 mmHg and havingaserumlactatelevelof2mmol/ldespiteadequate fluidresuscitation[14].

2.5. Statisticalanalysis

TheSFRsofsPNLandmPNLwerepresumedtobe89%and 83%,respectively,basedonpreviousdata[15–19].Ournull hypothesiswasthatmPNLhadaninferiorSFRtosPNL;–10% was consideredasanoninferior margin.Thesample size was calculated with the formulas of a two-sample noninferior test comparing two proportions. The type-1 error(

a

)wassetat0.05andthepower(1–

b

)at0.8.The samplingratio was1.The minimumsamplesize foreach group was 923. The number was increased to 1000 in each group to offset the patient loss to follow-up and withdrawals.

StatisticalanalysiswasperformedusingSPSS20.0. Out-comeswere analyzedinbothintention-to-treat (ITT)and per-protocol (PP) populations. A one-side noninferiority testwasusedtoevaluatewhethermPNLhadanoninferior one-session SFRto sPNL.Othercategoricaloutcomes (eg, ratesoftransfusion,embolizationandfever,and complica-tion asperClavien-Dindogrades)werecomparedusinga fisher’sexactorchi-squaretest.Themeansofcontinuous

outcomes(eg,VASscore,hemoglobindrop,operatingtime, andlengthofpostoperativehospitalization)werecompared using a Student t test. Differencesbetween proportions/ meansand95%confidence intervalswere presented.Ap valueof<0.05wasconsideredstatisticallysignificant. 3. Results

3.1. Patientrecruitmentandbaselinecharacteristics

Ofthe2465patientsassessedforeligibility,2000underwent randomization. After excluding patients due to canceled surgeries and withdrawn consent, 1980 patients received randomly assigned interventions and formed the ITT population (988 in the sPNL group and 992 in the mPNL group;Fig.2).OftheITTpopulationinthesPNLgroup,five patientswereconvertedtomPNLbecausethecalycealneck wastoonarroworseverebleedingoccurredafterdilationto 18F. Besides,11 patientsin the sPNL groupand 12 inthe mPNLgroupwereconvertedtosecond-stagePNLs.Excluding

cases lost to follow-up, the PP population included 966patientsinthesPNLgroupand978inthemPNLgroup. PatientdemographicsareshowninTable1.

3.2. Efficacy

ThemPNLgroupachievedanoninferiorone-sessionSFRto thesPNLgroup(ITT:0.5%[difference],p< 0.001;PP:0.1% [difference], p< 0.001; Table 2); sPNL yielded shorter operatingtimesthanmPNL (ITT:–2.2min,p= 0.008;PP: –2.3min,p= 0.007;Table2).

3.3. Safety

Although the sPNL procedure had a significantly higher hemoglobin drop (ITT: 5.2g/l, p< 0.001; PP: 4.6 g/l, p< 0.001;Table2),thetransfusionandembolizationrates ofthetwogroupswerecomparable.Arterialembolization was requiredmainlyinpatients with complicatedstones (STONE score 10) or in those with more than one

Und

erwent rando

mizati on (

n = 2000

)

Lost to foll

ow-up

(

n = 7)

Intenti

on-to-trea

t analysis (

n = 99

2)

Per-protocol analysis (

n = 97

8)

All

oca

ted to mPNL group

(

n = 100

0)

8 exclud

ed

3 surgeries ca

ncell

ed

5 withd

rew consent

5 requ

ired fURL

Rece

ived intervention

(

n = 99

2)

12 conv

erted to sec

ond-stage PNL

9 pyon

eph

rosis/severe infecti

on

2 severe blee

ding

after tract dil

ati on

1 li

fe-threatening

arrhy

thmia

All

oca

ted to sPNL grou

p (

n = 1000)

Lost to foll

ow-up

(

n = 6)

Intenti

on-to-trea

t analysis (

n = 98

8)

Per-protocol analysis (

n = 96

6)

12 excluded

4 surgeries ca

ncell ed

8 withd

rew con

sent

5 requ

ired mPNL

3 requ

ired fURL

Rece

ived intervention

(

n = 98

8)

11 conv

erted to sec

ond-stage PNL

6 pyon

eph

rosis/severe infecti

on

3 severe blee

ding

after tract dil

ati on

2 li

fe-threatening

arrhy

thmia

5 conv

erted to mPNL

2465 patients ass

ess

ed for eli

gibilit y

465 exclud

ed

378 did not mee

t inclusion crit

eria

75 decli

ned to parti

cipate

12 other rea

son

s

Fig.2–Trialprofile.fURL=flexibleureteroscopelithotripsy;mPNL=minipercutaneousnephrolithotomy;PNL=percutaneousnephrolithotomy;

Table1–Characteristicsoftheintention-to-treatpopulationatbaseline. sPNL(n=988) mPNL(n=992) Age(yr) 51.0(44.0,60.0) 51.0(43.0,59.0) Gender,n(%) Male 531(54) 526(53) Female 457(46) 466(47) BMI(kg/m2 ) 24.7(22.7,26.6) 24.4(22.3,26.4) Stonesize(mm) 29.0(25.0,35.0) 29.0(23.0,35.0) Stonesurface(mm2_{) 1122.0(899.0,1295.0) 1116.0(900.0,1260.0)} Numberofstones 1 878(89) 856(86) 2 110(11) 136(14)

CTvalueofstone(HU) 1105.1(880.3,1275.0) 1086.5(865.0,1254.5)

STONEscore 7.0(6.0,8.0) 7.0(6.0,8.0)

Pre-Hb(g/l) 145.0(134.0,157.0) 144.0(133.0,155.0)

Pre-WBC(mmol/l) 6.4(5.2,7.8) 6.6(5.4,8.0)

Pre-Cr(mmol/l) 83.0(71.0,95.0) 82.3(70.1,94.9)

Comorbidity,n(%) 311(32) 329(33)

Initialpositiveurineculture,n(%) 188(19) 200(20)

Laterality,n(%) Left 501(51) 492(50) Right 487(49) 500(50) Hydronephrosisgrade,n(%) G0 156(16) 167(17) Mild(G1orG2) 654(66) 637(64) Moderate(G3) 127(13) 142(14) Severe(G4) 51(5.0) 46(5.0)

BMI=bodymassindex;Cr=creatinine;CT=computedtomography;G0=grade0;G1=grade1;G2=grade2;G3=grade3;G4=grade4;Hb=hemoglobin;

mPNL=minipercutaneousnephrolithotomy;sPNL=standardpercutaneousnephrolithotomy;WBC=whitebloodcell.

Dataarepresentedasmedian(firstquartile,thirdquartile),ornumber(proportion).

Theformulaforcalculationofstonesurfaceisthatthelargestlengthofstoneismultipliedbywidth.

Table2–Primaryandsecondaryoutcomesinintention-to-treatandper-protocolpopulation.

Intentiontotreat Perprotocol

sPNL (n=988) mPNL (n=992) Difference (95%CI) pvalue sPNL (n=966) mPNL (n=978) Difference (95%CI) pvalue One-sessionSFR,N(%) 848(86) 856(86) 0.50a _<0.001b 831(86) 842(86) 0.10a _<0.001b Transfusion,N(%) 13(1.3) 11(1.1) 0.21(–0.76to1.2) 0.7 11(1.1) 11(1.1) 0.014(–0.93to0.96) 1 Embolization,N(%) 10(1.0) 8(0.81) 0.21(–0.63to1.0) 0.6 9(0.93) 8(0.82) 0.11(–0.72to0.94) 0.8 Hemoglobindrop(g/l) 17.0 (10.0,29.0) 13.0 (5.0,22.0) 5.2 (3.8–6.6) <0.001 17.0 (9.0,28.0) 13.0 (5.0,22.0) 4.6(3.2–6.1) <0.001

Operatingtime(min) 35.0

(28.0,48.0) 36.0 (27.0,51.0) –2.2 (–3.9to–0.6) 0.008 35.0 (28.0,48.0) 37.0 (28.0,51.0) –2.3 (–3.9to–0.60) 0.007

VASscorepostop24h 6.0(5.0,7.0) 5.0(4.0,6.0) 0.8(0.7–1.0) <0.001 6.0(5.0,7.0) 5.0(4.0,6.0) 0.8(0.7–1.0) <0.001

Analgesics(NSAIDs),N(%) 368(37) 284(29) 8.6(4.5–13) <0.001 359(37) 272(28) 9.4(5.2–14) <0.001

Fever(38_{C),N(%) 81(8.2) 97(9.8) –1.6(–4.1to0.94) 0.2 79(8.2) 96(9.8) –1.6(–4.2to0.91) 0.2}

Septicshockrequired

ICUtreatment,N(%) 6(0.61) 8(0.81) –0.20(–0.94to0.54) 0.8 5(0.52) 8(0.82) –0.30(–1.0to0.42) 0.4 Postoperative hospitalization(d) 5.0(4.0,7.0) 5.0(3.0,6.0) 0.6(0.4-0.8) <0.001 5.0(4.0,7.0) 5.0(3.0,6.0) 0.5(0.3–0.8) <0.001 Clavien-Dindo,N(%) GradeI 409(41) 385(39) – 0.7 406(42) 377(39) – 0.4 GradeII 16(1.6) 11(1.1) 16(1.7) 10(1.0) GradeIIIa 12(1.2) 11(1.1) 11(1.1) 11(1.1) GradeIVa 4(0.40) 6(0.60) 3(0.30) 6(0.60) GradeIVb 2(0.20) 2(0.20) 2(0.20) 2(0.20) Tubeless,N(%) 180(18) 344(35) –16(–20to–13) <0.001 180(19) 339(35) –16(–20to–12) <0.001 Auxiliaryprocedure (SWLorRIRSorURL),N(%) 63(6.4) 53(5.3) 1.0(–1.0to3.1) 0.3 62(6.4) 51(5.2) 1.2(–0.88to3.3) 0.3

CI=confidence interval; ICU=intensive care unit; mPNL=mini percutaneous nephrolithotomy; NSAID=nonsteroidal anti-inflammatory drug;

postop=postoperative; RIRS=retrograde intrarenal surgery; SFR=stone-free rate; sPNL=standard percutaneous nephrolithotomy; SWL=shock wave

lithotripsy;URL=ureteroscopelithotripsy;VAS=visualanalogpainscale.

Dataarepresentedasmedian(firstquartile,thirdquartile),ornumber(proportion).

a

Difference=PT–PS;PT(proportionoftestgroup):one-sessionSFRofmPNL;PS(proportionofstandardgroup):one-sessionSFRofsPNL.

b

nephrostomytract(Table3).InthesPNLgroup,VASscore washigher(ITT:0.8,p< 0.001;PP:0.8,p< 0.001;Table2) andmorepatientsneededanalgesics(ITT:8.6%,p< 0.001; PP: 9.4%, p< 0.001; Table 2). According to the Clavien-Dindo grading system [20], complication rates were comparablebetweenthetwogroups.GradeIcomplications accountedfornearly40%,occurringinpatientstakingeither antipyreticoranalgesicmedication.GradeIIcomplications occurred in patients requiring transfusions except that three patients required total parenteral nutrition for persistent abdominal distension. Patients with grade IIIa complications included those who underwent arterial embolizationorureteroscopyunderlocalanesthesia.Grade IVaand IVbcomplications were present inpatients who requiredintensivecareunit (ICU)treatment forsingle or multipleorganfailurescausedbyurosepsis.Therewasno statistically significant difference in fever and urosepsis (Table2).ThesPNLgrouphadlongerhospitalizationperiods (ITT:0.6d,p< 0.001;PP:0.5d,p< 0.001;Table2). 4. Discussion

Therearearisingnumberofstudiesdebatingthemeritsof minimally invasive PNLs [21]. There are considerable debatesregardingthemeritsofmPNLandsPNL.Weaimed toperformahigh-qualityRCTcomparingmPNLandsPNL forthetreatmentof20–40mm renalstonestosettlethis debate. Since the treatment algorithm was decided according to stone size in the guideline on urolithiasis

[22], we used stone size as an inclusion criterion. We measuredthelargestdiameterinboththecoronalandthe sagittalviewontheCTscantoincreaseaccuracy.

Ourdata demonstrated that mPNL wasnoninferior to sPNL in the treatment of 20–40mm stones. The SFR achievedbymPNL wassimilar to thatbysPNL,butwith less blood loss, less postoperative pain, and shorter hospitalization.Therewasnoincreaseinthecomplication ratewith mPNL, albeit asmall increase in the operating time. This study reaffirmed the findings of the previous trials[1].Weselected18Fand24Fnephrostomytractsfor thisstudy.Whentractsizeincreasedfrom18Fto24F,the actualsurfaceareaofthetractincreasedby77.8%.However, thenephroscopeusedinsPNL(20.8F)hada150%increase relativetomPNL(12F)intermsofsurfacearea.Thespace between the tract and the nephroscope was greater in mPNL,whichprovidedbettervisualizationandevacuation

of fragments or dust during the procedure. Different lithotripters usedbetweenthegroupsmight havecaused abias,becauseofthedifferentmethodsoflithotripsyand thedifferentspacesintheworkingchannelofscopeafter inserting the lithotripter. However, the use of different lithotripsydevicesdidnotresultinadifferenceinthe one-sessionSFR(SupplementaryTable1).Wedidnotroutinely useCTtoexaminetheresidualstones,eventhoughithas the highest sensitivity and specificity [23]. This was intended to decrease the cost and radiation exposure to the patients. Furthermore, most studies reporting SFRs reliedonKUBormultiplemodalities,ratherthanonCTonly

[24]. In our study, two protocol-blinded radiologists assessed the SFR using KUB and ultrasound; CT was optional.

The main purpose of miniaturized PNL was to offer comparableSFRoutcomeswithlowermorbidity.Thisstudy demonstrated that mPNL was associated with a lower hemoglobindropthansPNL.Furtherreductionintractsize mightevenheightenthisdifference[3].Whiletherewasno statisticallysignificantdifferenceintransfusionand embo-lizationrates,mPNLhadahighertubelessrateowingtoless bleeding.Thehighertubelessratemightalsocontributeto thelowerpostoperativepainandthelowerproportionof patientsrequiringpainmedication.Inaddition,thepatients whounderwentmPNLhadshorterhospitalizationperiods. In a recent meta-analysis, it was reported that patients recoveredfasterfromthetubelessprocedures[25].

Although more than half of the punctures were supracostal (Table 4), no thoracic complications were encountered. Ultrasonic guidance was used for most of thesepunctures,whichmighthavecontributedtothelower incidence [26]. All 10th intercostal rib punctures had nephrostomy tubes placed for 1wkto safeguard against missedpleuralinjuries.

AspartofChinesecustoms,manyofourpatientschoseto be fully recovered and without external tubes before discharge.Consequently,postoperativehospitalization per-iodsinbothgroupswerelongerthanthepublisheddata[8]. 4.1. Strengthsandlimitations

The major strength of this study is its large number of participatingpatientsandcenters,andthesurgerieswere performedbyonlyonedesignatedexperiencedsurgeonin eachcenter,leadingtoamuchmorereliablecomparison.

Thisstudyhaditslimitations.Weonlyselectedtwotract sizes, 18Fand24F,whicharemostcommonlyusedinChina. The central randomized allocation method caused an uneven distribution of cases among the participating centers. This method was practical and used widely in multicenter RCTs with a large number of participants

[27].Auxiliaryprocedureswouldincuradditionalexpenses inChina;thus,morethanhalfofthepatientswithresidual stones decided to follow them expectantly. With the surgeries performedonlybyone designated experienced surgeon in each high-volume center, itis uncertain how this study will translate to lower-volume centers with less experienced PNL surgeons. Furthermore, this was a

Table3–Featuresofpatientsrequiringembolization.

　 sPNL mPNL STONEscore <10 3 3 10 7 5 Numberoftract 1 4 3 >1 6 5

mPNL=mini percutaneous nephrolithotomy; sPNL=standard

noninferior trial, and some centers might need to be equippedwithasecondsetofdevices,whichmightnotbe sufficienttochangethetreatmentparadigm.

5. Conclusions

This RCTdemonstrates thatmPNL achievesanoninferior SFRtosPNL,butwiththeadvantagesofreducedbloodloss, lesspostoperativepain,andshorterhospitalization. Addi-tionally,mPNLdoesnotcauseanincreaseintheinfectious complications. Hence,18F mPNL should beconsidered a sensiblealternativeto24FsPNLforthetreatmentof20– 40mmrenalstones.

Authorcontributions: GuohuaZeng andJeande laRosettehadfull

accesstoallthedatainthestudyandtookresponsibilityfortheintegrity

ofthedataandtheaccuracyofthedataanalysis.

Studyconceptanddesign:delaRosette,Zeng.

Acquisitionofdata:Duan,X.Xu,Mao,X.Li,Nie,Xie,JiongmingLi,Lu,Zou,

Mo,C.Li,JianzhongLi,Wang,Yu,Fei,Gu,EnciXu,Kong,Wu,Sun,Liu.

Analysisandinterpretationofdata:Cai,Zhao,Zhu.

Draftingofthemanuscript:Cai,Zhao,Zhu.

Criticalrevisionofthemanuscriptforimportantintellectualcontent:dela

Rosette,Zeng.

Statisticalanalysis:Cai,Zhao,Zhu.

Obtainingfunding:Zeng.

Administrative,technical,ormaterialsupport:Duan,X.Xu,Mao,X.Li,Nie,

Xie,JiongmingLi,Lu,Zou,Mo,C.Li,JianzhongLi,Wang,Yu,Fei,Gu,Enci

Xu,Kong,Wu,Liu.

Supervision:Cai,Zeng.

Other:None.

Financialdisclosures:GuohuaZengcerti_fiesthatallcon_flictsofinterest,

includingspeci_{ficfinancial}interestsandrelationshipsandaf_filiations

relevanttothesubjectmatterormaterialsdiscussedinthemanuscript

(eg,employment/affiliation,grantsorfunding,consultancies,honoraria,

stockownershiporoptions,experttestimony,royalties,orpatentsfiled,

received,orpending),arethefollowing:None.

Funding/Supportandroleofthesponsor:Thisworkwas_financedby

grants from high-leveldevelopment funding ofGuangzhou Medical

University (2017160106). The fundingorganizationhas aroleinthe

preparationofthisstudy.

Acknowledgments:Wethanktheclinicaltrialteam,allinvestigators,

andpatientsandtheirfamilies.WealsothankProfessorWanforhis

assistanceineditingthismanuscriptandProfessorJinxiangMaforher

contributiontothequalitycontrolofthistrial.

AppendixA. Supplementarydata

Supplementary material related to this article can be found,intheonlineversion,atdoi:https://doi.org/10.1016/j. eururo.2020.09.026.

References

[1]RuhayelY,TepelerA,DabestaniS,etal.Tractsizesinminiaturized percutaneousnephrolithotomy:asystematicreviewfromthe Eu-ropeanAssociation ofUrology UrolithiasisGuidelinesPanel.Eur Urol2017;72:220–35.

[2]SeitzC,DesaiM,HäckerA,etal.Incidence,prevention,and man-agementofcomplicationsfollowingpercutaneous nephrolithola-paxy.EurUrol2012;61:146–58.

[3]YamaguchiA,SkolarikosA,BuchholzNP,etal.Operatingtimesand bleedingcomplicationsinpercutaneousnephrolithotomy:a com-parisonoftractdilationmethodsin5,537patientsintheClinical Research Office of the Endourological Society Percutaneous NephrolithotomyGlobalStudy.JEndourol2011;25:933–9.

[4]JackmanSV,DocimoSG,CadedduJA,BishoffJT,KavoussiLR,Jarrett TW.The"mini-perc"technique:alessinvasivealternativeto per-cutaneousnephrolithotomy.WorldJUrol1998;16:371_–4.

[5]HelalM,BlackT,LockhartJ,FigueroaTE.TheHickmanpeel-away sheath:alternativeforpediatricpercutaneousnephrolithotomy.J Endourol1997;11:171–2.

[6]KangSK,ChoKS,KangDH,JungHD,KwonJK,LeeJY.Systematic reviewandmeta-analysistocomparesuccessratesofretrograde

Table4–Othervariablesinintention-to-treatandper-protocolpopulation.

Intentiontotreat Perprotocol

　 sPNL(n=988) mPNL(n=992) pvalue sPNL(n=966) mPNL(n=978) pvalue Accessunder,N(%) X-ray 222(23) 238(24) 0.7 218(23) 239(24) 0.6 Ultrasound 734(74) 722(73) 715(74) 707(73) Combined 32(3.0) 32(3.0) 32(3.0) 32(3.0) Siteofpuncture,N(%) 10thintercostalspace 15(2.0) 26(3.0) 0.4 15(2.0) 26(3.0) 0.4 11thintercostalspace 520(53) 517(52) 505(52) 509(52) under12thspace 443(44) 439(44) 436(45) 433(44) 2sites 10(1.0) 10(1.0) 10(1.0) 10(1.0) Stonecomposition,N(%) Calciumoxalate 748(76) 747(75) 0.8 731(76) 735(75) 0.9 Uricacid 130(13) 126(13) 129(13) 125(13) Carbonateapatite 75(7.6) 79(8.0) 73(7.6) 79(8.1)

Ammoniummagnesiumphosphate 20(2.0) 27(2.7) 19(2.0) 27(2.8)

Others 15(1.4) 13(1.3) 14(1.4) 12(1.1)

mPNL=minipercutaneousnephrolithotomy;sPNL=standardpercutaneousnephrolithotomy.

intrarenalsurgeryversuspercutaneousnephrolithotomyforrenal stones>2cm:anupdate.Medicine(Baltimore)2017;96:e9119.

[7] PelitES, AtisG, KatiB,etal. Comparisonofmini-percutaneous nephrolithotomyandretrogradeintrarenalsurgeryin preschool-agedchildren.Urology2017;101:21_–5.

[8] Ba_şO,DedeO,AydogmusY,etal.Comparisonofretrograde intrar-enalsurgeryandmicro-percutaneousnephrolithotomyin moder-atelysizedpediatrickidneystones.JEndourol2016;30:765–70.

[9] HübnerWA,IrbyP,StollerML.Naturalhistoryandcurrentconcepts forthetreatmentofsmallureteralcalculi.EurUrol1993;24:172–6.

[10]DelvecchioFC,PremingerGM.Managementofresidualstones.Urol ClinNorthAm2000;27:347_–54.

[11] Grant S, Aitchison T, Henderson E,et al. A comparison of the reproducibilityandthe sensitivitytochangeofvisual analogue scales,Borg scales,andLikert scalesinnormal subjectsduring submaximalexercise.Chest1999;116:1208–17.

[12]WuW.,YangD.,TiseliusH.G.,etal.Thecharacteristicsofthestone andurinecompositioninChinesestoneformers:primaryreportof asingle-centerresults.Urology83:732–737.

[13]OkhunovZ,FriedlanderJI,GeorgeAK,etal.S.T.O.N.E. nephrolitho-metry:novelsurgicalclassificationsystemforkidneycalculi. Urol-ogy2013;81:1154–69.

[14]SingerM,DeutschmanCS,SeymourCW,etal.TheThird Interna-tionalConsensusDe_finitionsforSepsisandSepticShock(Sepsis-3). JAMA2016;315:801_–10.

[15]MishraS,SharmaR,GargC,KurienA,SabnisR,DesaiM.Prospective comparativestudyofminipercandstandardPNLfortreatmentof 1to2cmsizerenalstone.BJUInt2011;108:896–9.

[16]KnollT,WezelF,MichelMS,HoneckP,Wendt-NordahlG.Dopatients bene_fitfromminiaturizedtubelesspercutaneousnephrolithotomy? Acomparativeprospectivestudy.JEndourol2010;24:1075_–9.

[17] ChengF,YuW,ZhangX,YangS,XiaY,RuanY.Minimallyinvasive tractinpercutaneousnephrolithotomyforrenalstones.JEndourol 2010;24:1579–82.

[18]LuY,PingJG,ZhaoXJ,HuLK,PuJX.Randomizedprospectivetrialof tubeless versus conventional minimally invasive percutaneous nephrolithotomy.WorldJUrol2013;31:1303–7.

[19] ZengG, ZhaoZ,WanS, etal. Minimallyinvasivepercutaneous nephrolithotomyforsimpleandcomplexrenalcalicealstones:a comparative analysis of more than 10,000 cases. J Endourol 2013;27:1203–8.

[20] MitropoulosD,ArtibaniW,GraefenM,etal.Reportingandgrading ofcomplicationsafterurologicsurgicalprocedures:anadhocEAU guidelines panel assessment and recommendations. Eur Urol 2012;61:341_–9.

[21] PietropaoloA,ProiettiS,GeraghtyR,etal.Trendsof_’urolithiasis: interventions, simulation, and laser technology’ over the last 16years(2000-2015)aspublishedintheliterature(PubMed):a systematic review from European section of Uro-technology (ESUT).WorldJUrol2017;35:1651–8.

[22] TürkC,PetríkA,SaricaK,etal.EAUguidelinesoninterventional treatmentforurolithiasis.EurUrol2016;69:475_–82.

[23] Smith-Bindman R, Moghadassi M, Griffey RT, et al. Computed tomographyradiationdoseinpatientswithsuspectedurolithiasis. JAMAInternMed2015;175:1413–6.

[24] Opondo D, Gravas S, Joyce A,et al. Standardization of patient outcomesreportinginpercutaneousnephrolithotomy.JEndourol 2014;28:767_–74.

[25] ZhongQ,ZhengC,MoJ,PiaoY,ZhouY,JiangQ.Totaltubelessversus standard percutaneous nephrolithotomy: a meta-analysis. J Endourol2013;27:420–6.

[26] NgFC,YamWL,LimTYB,TeoJK,NgKK,LimSK.Ultrasound-guided percutaneousnephrolithotomy:advantagesandlimitations. Inves-tigClinUrol2017;58:346_–52.

[27] HuY,HuangC,SunY,etal.Morbidityandmortalityoflaparoscopic versusopenD2distalgastrectomyforadvancedgastriccancer:a randomizedcontrolledtrial.JClinOncol2016;34:1350–7.