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Clinical Transplantation. 2020;34:e13814.
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https://doi.org/10.1111/ctr.13814
clinicaltransplantation.com
1 | INTRODUCTION
Renal transplantation is the optimal treatment for end stage renal
disease; however, the lack of optimal donor organs remains a major
difficulty. In an attempt to overcome this hurdle, there has been a
recent increase in the use of grafts from donation after circulatory
death and extended criteria donors. While successfully increasing
the donor pool, these grafts have increased susceptibility to the
damage caused by ischemia and reperfusion and are therefore prone
to increased rates of delayed graft function (DGF) and poorer graft
survival.1-4
Received:17July2019
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Revised:27D ecember2019
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Accepted:3February2020
DOI : 10.1111 /ctr.13814
REVIEW ARTICLE
Hypothermic machine perfusion is superior to static cold
storage in deceased donor kidney transplantation: A meta-
analysis
Samuel J. Tingle1,2 | Rodrigo S. Figueiredo1 | John AG. Moir1 |
Michael Goodfellow1,2 | Emily R. Thompson1,2 | Ibrahim K. Ibrahim1,2 | Lucy Bates1,2 |
David Talbot1 | Colin H. Wilson1,2
©2020JohnWiley&SonsA/S.PublishedbyJ ohnWiley&SonsLtd
1Depar tmentofHPBandTransplant
Surger y, Freeman Ho spital, Newcas tle upon
Tyne,UnitedK ingdom
2Faculty of Medica l Sciences, Newcastle
University,NewcastleuponTyne,United
Kingdom
Correspondence
SamuelJ.Tingle,Depar tmentofHPBand
TransplantSurger y,FreemanHospital,
Freeman Rd , High Heaton, Newc astle upon
TyneNE77DN,UnitedKingdom.
Email:samjamestingle@gmail.com
Abstract
Background: Thereremainsalackof consensusonthe optimalstoragemethod for
deceaseddonorkidneys.Thismeta-analysiscomparesstoragewithhypothermicma-
chineperfusion(HMP)vstraditionalstaticcoldstorage(SCS).
Methods: TheCochraneKidneyandTransplantSpecialisedRegisterwassearchedto
identify(quasi-)randomizedcontrolled trials(RCTs)toincludeinourmeta-analysis.
PRISMAguidelineswereusedtoperformandwritethisreview.
Results: There is high-cert ainty evidence t hat HMP reduces the ris k of delayed graft
function(DGF) when comparedtoSCS (2138participants from14studies,RR=0.77;
0.67-0.90, P= .0006). This benefit issignificantin both donation following circulatory
death(DCD;772patientsfromsevenstudies,RR=0.75;0.64-0.87,P=.0002)anddona-
tionfollowingbrainstemdeath(DBD)grafts(971patientsfromfourstudies,RR=0.78;
0.65-0.93,P=.006).ThenumberofperfusionsrequiredtopreventoneepisodeofDGF
was7.26and13.60inDCDandDBDgrafts,respectively.Thereisstrongevidencethat
HMPalsoimprovesgraft survivalinbothDBDandDCDgrafts,atboth1 and 3years.
EconomicanalysessuggestHMPiscost-savingat1yearcomparedwithSCS.
Conclusion: Hypothermic machine perfusion is superior to SCS in deceased donor
renal transplantation. Direct comparisons with normothermic machine perfusion in
RCTsareessentialtoidentifyoptimalpreservationmethodsinkidneytransplantation.
KEY WORDS
kidney transplantation, machine perfusion, organ preservation, perfusion
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One avenue of research to prevent this damage involves the de-
velopment of organ preservation techniques to optimize conditions
during organ transport and storage. Static cold storage (SCS) in-
volves flushing the kidney with cold preservation solution followed
by storage in a container of preser vation solution surrounded by ice.
Hypothermic machine perfusion (HMP) is an alternative approach
which allows kidney grafts to be continuously per fused with cold
preservation solution during transport between donor and recipient
centers.Theaimofhypothermicmachineperfusionistoameliorate
damage caused by ischemia reperfusion injury and therefore im-
prove graft outcomes.
Inthedecade between 1985and1995,therewerea number
ofrelativelysmallrandomizedcontrolledtrials(RCTs)whichcom-
pare dSC SandHMP,manyofwhichwereinconclusive.5 -10A ssup-
ply and demand were relatively well matched at this time, there
waslimited need to use grafts prone to DGF.These studiespro-
videdinsufficientevidencetorecommendwidespreaduseofHMP
given its increased initial costs.5 -10 In the modern era, the disparit y
between supply and demand for kidney grafts continues to grow,
drivingtheuseof ma rg in al gr af t sw hi charepronetoD GF.Th ishas
resulted in a recent resurgence of interest in hypothermic machine
perfusion.11
O'Callaghan et al12 carried out a thorough and robust me-
ta-analysis of studies comparing hypothermic machine perfu-
sion and st atic cold storage prior to 2013. While demonstrating
an overall reduction in incidence of DGF, they found insufficient
evidence todemons tratea benefit of HMP in either the dona-
tionfollowingcirculatorydeath (DCD)or thedonationfollowing
brains tem death (DBD) su bgroup sepa rately and con cluded that
the impact on graf t survival is uncertain. Since this study, several
additionalRC Tshaveaddedevidencetothefield, providingara-
tionale for further review.
The incre ased initial cost s of HMP compared wit h SCS mean
that high-certainty evidence is required in order to recommend its
widespreaduse.Thissystematicreviewandmeta-analysisaimedto
reviewcurrentevidencefromRC TstocompareHMPandSC Sinde-
ceased donor kidney transplantation.
2 | METHODS
Guidance from the Cochrane Handbook for Interventional
Systematic Reviews and the PRISMA guidelines (including the
PRISMA checklist)were followedfor this review.13,14 The protocol
forthereviewwaspublishedprospectivelythroughCochrane.15,16
TheCochraneKidney andTransplantRegister of Studieswas
searched using terms relevant to this review (supplementary dig-
italcontent:SDC TableS1)inOctober2018.17 Studies contained
in the Register are identified through searches of CENTRAL ,
MEDLINE,and EMBASE, as well as a selection of handsearched
journals, conference proceedings, and current awareness alerts.
Where necessary, we attempted to contact authors for further
information.
Weincluded(quasi-)RCTs whichdirectlycomparedHMPwith
SC Sofhu ma nkidneysp rior totransplantation,w it hn ores tr ic tion s
onda te ofpub lic ation .An ima lm ode lsand multi vis ce r altra nsp lants
wereexcluded.Bothpairedandunpairedstudieswereincluded.
Identified studies were screened by two independent authors
(Samuel T ingle and Rodri go Figueiredo), and d ata from inclu ded
studies was extracted by these authors using a standardized form.
Our primary outcome was incidence of delayed graft function
(DGF; defined as the requirement for dialysis in the first week
post-transplant). Secondary outcomes included graft survival, inci-
denceofprimarynonfunction(PNF),patientsurvival,economicim-
plications, graf t function, and acute rejection.
Quality of included studies was analyzed by two independent au-
thors(S amuelT in gl ea ndRodrigo Figu eiredo)usingtheCochraner is k
ofbiasassessmenttool,foundwithintheCochranehandbook.13The
certaintyofevidenceisgiveninaccordancewithGR ADEcriteria.18
2.1 | Statistical analysis
Statistical analysis was performed using RevMan (version 5.3).19
Meta-analysis of dichotomous outcomes DGF and PNF was per-
formed using a random-effects model. Results are expressed as rela-
tiverisks(RR)with95%confidenceintervals.
Heterogeneity was assessed using the I2 test, with values of
>25%,>50%,and>75%takentoindicatelow,medium,andhighlev-
els of heterogeneity.20Thefollowing subgroups wereanalyzedfor
anydifferingtreatmenteffects:DCDvsDBD,eraofstudy,anddu-
rationofcoldischemictime(CIT).
3 | RESULTS
3.1 | Search results
Our search returned 69 records, with 14 independent studies
suitable for inclusion in both qualitative and quantitative synthe-
sis.5-1 0, 21 -3 2 Further details can be found in Figure 1, repor ted as per
PRISMAguidelines.14 Individual reasons for study exclusion can be
foundinSDCTableS2.
3.2 | Details of included studies and risk of bias
Details of included studies, including the type of hypothermic ma-
chine used and the relevant reference(s) associated with each study,
canbefoundinTable1.Atotalof2138 participantsfrom14stud-
ies were included, covering the following locations: United States,
Europe, China,Japan, Canada,South Africa,andBrazil.Allbutone
study(Hall or an1985)usedapaire ddesign .6T hefol lowin gper fusio n
machine s were used: Waters Mox-100 pulsat ile, LifePor t pulsatile
perfusion machine, Gambro pulsatile perfusion machine, and the
APS-02(Nikkiso)machine.
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As u m ma r y o ft h er i s ko f bi a s in e ac h s tu d y c an b ef o u nd i n Fi g u re 2 .
Some of the older manuscripts lacked many methodological details,
making risk of bias difficult to assess. However, where bias could be
assessed, studies were generally well designed leading to a low risk
ofbias.Threestudieswerefelttobeathighriskofperformancebias
(Kwiatkowski 1999; Mat suno 1994; Mozes 1985) as kidneys in t he
HMPgrouphadsignificantlylongerCITs,whichlikelyleadstounder-
estimatesinthetreatmenteffectofHMPinthesestudies.Another
potential source of bias is the use of differing perfusion solutions in
theHMPand SCS studyarm (furtherinformationinSDCTableS3).
Repo rte db enefi t sofHMP co ul dbedu etodif fer ingef fe c tsofvar io us
coldstoragesolutionsratherthanaHMPspecificef fect.
Further details on all included studies, including justification for
theriskofbiasassessments,canbefoundinSDCTableS3.
3.3 | Incidence of delayed graft function
All14includedstudiesreportedDGFastheirprimaryoutcome.All
studies used the definition stated in our methods section, or pro-
vided data on how many patients required dialysis in the first year
post-transplant.Thismeantthat2138participantscouldbeincluded
inthemeta-analysis.Theuseofhypothermicmachineperfusionre-
duces the relative risk of DGF (high-certainty evidence; Figure 3; RR
0.77,95%CI0.67-0.90,P=.0006).Thisequatesto10.35hypother-
micmachineperfusions required toprevent onecase of DGF.The
level of heterogeneity between studies as measured by I2 test was
low and not statistically significant (Figure 3; I2 = 33%, P = .11). A
funnel plot was symmetrical and does not suggest the presence of
publicationbias(SDCFigureS1).
Sensitivity analysis was performed. Moers 2009 was the largest
study and contributed 752 of 2138 participants. When Moers was
excluded from the met a-analysis, the relative risk of DGF (RR 0.77,
95%CI 0.65-0.91,P=.003)andthelevelofheterogeneity(I2=39%,
P=.08)werebarelyeffected.Fourstudieswereassessedtohavehigh
riskofbiasinatleastonecategory(Halloran1985;Kwiatkowski1999;
Matsuno1994;Mozes 1985;see Figure2).Removingallfourof these
studiesfrom themeta-analysis,therelative riskofDGF(RR0.79,95%
CI0.64- 0.97,P=.03)remainedsimilar,butamediumlevelofheteroge-
neity was found (I2=52%,P=.03).Toensurerobustnessofthemodel,
the full da taset was also anal yzed using a fixed-e ffects mod el; this made
littledifferencetotheresults(RR0.76,95%CI0.68-0.86,P < .00001).
Subgroupanalyses were performedtocompare DBD with DCD
donors.SixstudieslookedpurelyatDCD(Chen2014c;Kwiatkowski
1999; Matsuno 1994; Watson 2010; van der Vliet 2001; Zhong
2017), three s tudies looke d purely at DBD (M ozes 1985;Tedesco -
Silva 2017; Veller 1994), four studies did not specify the donor t ype
(Alijani1985;Halloran1985;Heil1987;Merion1990),andonestudy
(M oers 2009)re p orte dbot hDC Dan dDBD dat asep a rat ely.A s sho w n
inFigure 4,HMPsignificantly reducedDGFintheDCDgroup (772
patientsfromsevenstudies,RR0.75, 95%CI0.64-0.87,P= .0002),
aswellasintheDBDgroup(971patientsfromfourstudies,RR0.78,
95%CI 0.65-0.93, P=.006).Thenumberofperfusionsrequiredto
prevent one episode of DGFwas7.26and 13.60 in DCD and DBD
FIGURE 1 PRISMAflowdiagram.14
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TABLE 1 Characteristicsofincludedstudies
Study nam e Refs Study design Country Number of participants
Perfusion machine
used Cold ischemic tim e
Alijani1985 5Paired,quasi-randomized;alternatingleftand
right kidneys placed in machine perfusion
group
USA 58kidneysfrom29donors.
AssumedallDBD
Waters Mox-100 29.7hSCSgroup,
32.5hHMPgroup(P=ns)
Halloran1985 6MulticenterRCT.Notpaired;eachdonor
randomized to have both kidneys r andomized
toSCSorHMP
Canada 181 kidneys from 107 donor s Waters Mox-100 27.7±12hSCS,
30.5±10hHMP(P=ns)
Mozes1985 7PairedmulticenterRCT USA 187kidneysfrom96DBD
donors
Waters Mox-100 32.7hSCSgroup,
35.2hMPgroups(P=.09)
Hei l 1987 21 PairedRC T USA 54kidneysfrom27donors.
AssumedallDBD
Waters Mox-100 Not reported
Merion 1990 8Paired,quasi-randomized;alternatingleftand
right kidneys placed in machine perfusion
group
USA 102kidneysfrom51donors.
AssumedallDBD
Waters Mox-100 21.8hSCSgroup,
21.0hMPgroup(P=ns)
Veller 1994 10 Pairedtrial.Unclearwhetherrandomizedor
quasi-randomized.
SouthAfrica 36kidneysfrom18DBDdonors Waters Mox-100 8(7-34)hSCS,
19(7-33)hHMP(P=ns)
Mat su no 19 94 9Pairedtrial.Nodetailsonwhether
randomization took place.
Japan 26kidneysfrom13DCDdonors APS-02(Nikkiso) 6.08±2.93hSCS,
11.9±3.20hHMP
(P<.05)
Kwiatkowski
1999
22,23,25 PairedRC T Poland 74kidneysfrom37DCDdonors Waters Mox-100 27. 5hSCS,34.5hHMP
(P<.05).
Van der Vliet
2001
24 PairedmulticenterRCT Netherlands 76kidneysfrom38DCDdonors Gambro pulsatile
perfusion
23.0±1.3hSCS,
25.0±1.0hHMP(P=ns)
Moers 20 09 26,27,29,33,3 4 International,pairedRCT Europe;Netherlands
Germany,Belgium
752kidneysfrom376donors
Of these 164 kidneys were
from82DCDdonors
LifePor tpulsatile
perfusion
15hoursinbothgroups
(P=ns)
Wats on 2010 28 PairedmulticenterRCT UK 90kidneysfrom45DCD
donors
LifePor tpulsatile
perfusion
14.3hSCSgroup,
13.9hHMPgroup(P=ns)
Chen2014 30 PairedsinglecenterRCT China 72kidneysfrom36DCD
donors
LifePor tpulsatile
perfusion
Not reported
Zhong 2017 32,38 PairedsinglecenterRCT China 282kidneysfrom153DCD
donors
LifePor tpulsatile
perfusion
11.8(6.3-22.5)hSCS,
10.3(5.1-24.0)hHMP
(P=.063)
Tedesco-Silva
2017
31 PairedmulticenterRCT Brazil 160kidneysfrom80DBD
donors
LifePor tpulsatile
perfusion
25.6±6.6hSCS,
25.1±6.3hHMP(P=ns)
Note: Pairedtrialsrefertothosewherebothkidneysfromeachdonorareused:Oneispreservedwithstaticcoldstorageandtheotherwithhypothermicmachineperfusion.
Abbreviations:DBD,deceasedfollowingbrainstemdeath;DCD,deceasedfollowingcirculatorydeath;HMP,hypothermicmachineperfusion;SCS,staticcoldstorage.
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grafts,respectively.ThelevelofheterogeneityinboththeDCDand
DBDsubgroupswaslow(I2=1%,P=.42andI2=0%,P=.83,respec-
tivel y).Th er ewasn oeviden ceforadifferingt re atmente ffec ti nDBD
andDCDdonors(P=.72).Ofnote,duetothepublicationdateofthe
fourstudieswhichdidnotspecifydonortype(Alijani1985;Halloran
1985;Heil 1987;Merion 1990)these likelyrepresentDBD donors.
Aseparateanalysis wasperformed to assess the robustnessofthe
subgroupfindingsincludingthesestudiesintheDBDsubgroup;sim-
ilarresultswerefoundwithHMPleadingtoarelativeriskreduction
(RR0.82,95%CI0.66-1.02,P=.07),andthereremainednoevidence
ofdifferingtreatmenteffectsinDCDandDBDgrafts(P=.51).
Subgroupanalysiswasper formedlookingatera ofstudy(SDC
Figure S2). Five of the studies were performed in the last decade
(“modernera”)andusedthenewerLifePortmachine(Chen2014c;
Moers 20 09; Watson 2010; Tedesco-Silva 2017; Zhong 2017).
Studies performed over a decade ago (“pre-2008”) used older per-
fusion machines (Waters Mox-100, Gambro pulsatile perfusion ma-
chine,orNikkisomachine).HMPsignificantlyreducedincidenceof
DGFwh en comparedw it hSCSinstudiespe rformedi nthe“mo de rn
era”;(1355patients from fivestudies,RR 0.77,95% CI 0.66-0.91,
P=.002).Therewasnoevidenceforadifferingtreatmenteffectin
studies performed in the “modern era” vs studies performed “pre-
2008” (P = .97).The level ofheterogeneity in studies performed
in the “modern era” was low (I2=15%,P=.32).Watson2010con-
cludedthatHMPconfersnoadvantageoverSCS,astheyfoundno
signific ant differe nce in DGF rate. T his may be becaus e the me-
diandu ratio nofHMPwasrelative lysho rtint hisgroup(10.1hou rs).
Some patients only received HMP at the recipient center, not
during tr ansport ation, lead ing to a minimum dur ation of HMP of
only2.5hours.Wefeelthatthisrelatively shortduration ofHMP,
paired with the moderate sample size of the study, likely explains
the negative results.
Therewasnoevidenceofdifferingtreatmenteffectswithshort
(<24hours)vslong(≥24hours)coldischemictimes.OnlyMoers2009
reported on standard criteria vs extended criteria donors, and they
found no evidence of differing treatment effects in these groups.
3.4 | One year graft survival
Eight studies reported 1-year graft survival data (Chen 2014c;
Halloran1985;Moers2009;Watson2010;Tedesco-Silva2017;van
derVliet2001;Veller1994;Zhong2017).Table2providesinforma-
tion from all studies which reported on 1-year graft sur vival. Many
of the studies do not provide information on how the graft survival
percentages were calculated, or whether censoring was applied.
Often only a percentage is given with no indication of statistical
significance or the number of people who were followed up to one
year.Otherstudiesrepor ttheresultsofadjustedCoxregression,but
lack the raw data. It was therefore not possible to analyze the data
ineitheratime-to-eventfashion,asrecommendedintheCochrane
Handbook,13 or a dichotomous fashion.
Thetwomos tpower fulst udies(Moers2009andZhong2017 )
both reported st atistically significant benefits in 1-year graft
survi val with HMP vs S CS. Moer s 2009 use d appropriat e time-
to-event analysis and reported a statistically significant improve-
ment in 1-year graftsurvival with HMP(90% SCSvs94%HMP,
log-rank P=.04;CoxHRfor1-yeargraftloss,0.52,P=.0 3).Zhong
2017 used log-rank test analysis and also reported a statistically
significant improvement in 1-yeargraftsurvivalwith HMP (93%
FIGURE 2 Riskofbiasinincludedstudies.Positivesymbol=low
riskofbias,negativesymbol=highriskofbias,andquestion
mark=unclearriskofbias.RiskofbiascalculatedusingCochrane
riskofbiastool,foundwithintheCochranehandbook.13
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FIGURE 3 Forrest plot showing overall relative risk of developing delayed graft function with hypothermic machine perfusion compared
with static cold storage. Results display relative risk with corresponding confidence inter vals for each study. Diamonds represent pooled
datafrommultiplestudies.Arandom-effectsmodelwasemployedwithI2testsusedtoassessheterogeneit y.CI,confidenceinterval;HMP,
hypothermicmachineperfusionandSCS,staticcoldstorage
FIGURE 4 Forrest plot showing relative risk of developing delayed graf t function with hypothermic machine perfusion compared with
staticcoldstorage,withseparatesubgroupsforDCDandDBDgrafts.Resultsdisplayrelativeriskwithcorrespondingconfidenceintervals
foreachstudy.Diamondsrepresentpooleddatafrommultiplestudies.Arandom-effectsmodelwasemployedwithI2 tests used to assess
heterogeneity.CI,confidenceinterval;DBD,deceasedfollowingbrainstemdeath;DCD,deceasedfollowingcirculatorydeath;HMP,
hypothermicmachineperfusionandSCS,staticcoldstorage
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SCSvs98%HMP,P=.026).Asdescr ibedinTab le2,t heremaining
studies report nonsignificant differences in 1-year graft survival
(Chen 2014c; Halloran1985;Watson2010;Tedesco-Silva 2017)
or do not provide P-values (van der Vliet 2001; Veller 1994).
3.5 | Longer term graft survival
Threestudies(Kwiatkowski1999;Moers2009;Zhong2017)pro-
vided data on longer term graft survival. Moers 2009 followed up
all 672 participants from their main analysis as well as an addi-
tional80participantsfromtheirextendedDCDdatasetforthree
years. Overall, 3-year graft survival was significantly improved by
HMP vs SCS (91% vs 87%; a djusted HR for gr aft failure, 0 .60;
P=.04).TheDBDcohortbenefittedfromsignificantlyimproved
3-year graf t survival (91% vs 86%; a djusted hazard r atio, 0.54;
P=.02).Overall,thesurvivalbenefitwasmostpronouncedinthe
subgroupofgraftsfromECD(86%vs76%;adjustedhazardratio,
0.38; P=.01).29
Zhong 2017 followed all 282 included participants for three
years.InthislargecohortofDCDrecipients,the3-yeargraftsurvival
rateintheHMPgroupwassignificantlyhigherthanthatintheSCS
group(93%vs82%,P=.036).
Kwiatkowski 1999providedthelongest follow-updata, report-
ing10-yeargraftsurvival.ThecohortwhichhadreceivedHMPhad
improved 10-yeargraft survivalwhen compared to the SCS group
(68.2% vs 43.0%); however, this was not statistically significant
(P= .08). This may be a resultofthelow power of the study,with
only 37 patients in each arm.
3.6 | Incidence of PNF
Seven studies(Halloran1985;Matsuno 1994;Moers 2009;Mozes
1985;Watson2010;Tedesco-Silva2017;vanderVliet2001)witha
totalof1387 participantsreportedon PNF.Meta-analysisof these
studiescanbefoundinSDCFigureS3.Therewasnoevidencethat
theuseofHMPeffectedtherelative risk ofdevelopingPNFwhen
comparedtoSCS(RR0.88, 95%CI0.58-1.33, P= .55).Thelevelof
heterogeneity was low (I2=0%, P= .44).Noneofthestudieswere
powered to identify differences in primary nonfunction, and this
may represent a type 2 statistical error.
TABLE 2 Summary of study data on 1-y renal graft sur vival
Study nam e
Number of
participants 1-y graft survival result s Information
Halloran19856181 69.5%SCS,74.9%HMP
(“not significant”)
Survival%isfromCoxregressiontime-to-eventanalysis.NoP-value
or further information was provided which may allow inclusion in a
meta-analysis. Death counted as graf t failure. Most patients were not
followed up for a full year, but no further information was given on this.
Veller 199410 36 82%SCS,83%MP Noinformationonhowpercentageswerecalculated.Thereforelikely
not time-to-event analysis, and unknown whether graft survival was
censored for death . Insufficient information to assess how many
patient s were followed up for a full year. No P-value was reported.
Van der Vliet
200124
76 84.2%SCS,76.3%MP Noinformationonhowpercentageswerecalculated.Thereforelikely
not time-to-event analysis, and unknown whether graft survival was
censored for death . Insufficient information to assess how many
patient s were followed up for a full year. No P-value was reported.
Moers 20 0926 672 in graft
survival
analysis
90%SCS ,94%HMP
(P=.04).CoxHR0.52
(P=.03)
Usedlog-rankandCoxproportionalhazardsmodel.Graftsur vival
censored for death (in those dying with a functioning graft). Graft
survival rates are a result of this time-to-event death censored analysis.
Wats on 201028 90 44/45(97.8%)SCS,42/45
(93.3%)MP(P=.3)
Theygiveactualnumbersfornumbersofgraftswhichfailedby1y.
Deathwasnotcountedasgraftfailure.T ime-to-eventanalysisnot
performed.
Chen201430 72 91.7%SCS,97.2%HMP
(P=.307)
Noinformationonhowpercentageswerecalculated.Thereforelikely
not time-to-event analysis, and unknown whether graft survival was
censored for death . Insufficient information to assess how many
patient s were followed up for a full year.
Tedesco-Silva
201731
160 72/78(92.3%)SCSvs72/80
(90%)HMP(P=1.000)
Theygiveactualnumbersfornumbersofgraftswhichfailedby1y.Death
wasnotcountedasgraf tfailure.Time-to-eventanalysisnotperformed.
Zhong 201732 282 93%SCS,98%HMP
(P=.026)
Graft survival was analyzed using a log-rank test. G raft survival was
censored for death (in those dying with a functioning graft). Graft
survival estimates are based on time-to-event analysis, and raw dat a for
number of graft losses were not given. Hazard ratios were not reported.
Note: Survival rates and associate d P-values are all those repor ted in the original study manuscript.
Abbreviations:HMP,hypothermicmachineperfusion;SCS,staticcoldstorage.
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3.7 | Patient survival
Six studies repor ted on patient survival (Halloran 1985;
Kwiatkowski 1999; Moers 2009; Watson 2010; Tedesco-Silva
2017; Zhong 2017). None of the four studies that reported on
1-year patient survival (Halloran 1985; Moers 2009; Watson
2010;Tedesco-Silva2017)foundsignificantdifferencesbetween
HMP and SC S. Three stud ies (Kwiatkowski 1999; Moers 2 009;
Zhong 2017) provided longer follow-up of patients at 10, 3, and
3 years, respectively. None found any significant dif ferences in
patient survival at these time points.
3.8 | Economic implications
Two reports performed economic evaluation.33,34 Both of these
performedtheir analysisbasedon the resultsofMoers20 09.Both
reportsconfirmcostsavingswithHMP,oneintheUnitedStatesand
one in theEuropean setting.In 2012, Groen et al34 reported esti-
matedmeantotalcostsof$8668withHMPvs$11294withSCSin
theEuropeansetting.Gar fieldetal33performedUSprojectionsand
reportedthatHMPimprovedmeancostswhencomparedtoSCSin
bothstandardcriteria donors($92 561vs $104118)andextended
criteriadonors($106012vs$114530).Oneofthemainreasonsfor
thecost savingswaslowerdialysiscosts inthe HMP group dueto
decreased incidence of DGF.
3.9 | Graft function
Five studies repor ted on graft function (Moers 2009; Watson 2010;
Tedesco-Silva 2017; van der V liet 2001; Zhong 2017). A s studies
reported different outcomes at different time points, meta-analysis
could not be completed.
Moers 2009 performed daily serum creatinine measurements
and calculated area under the creatinine curve for the first 14 days
post-transplant.HMPsignificantlydecreasedthemedianareaunder
thecurvecomparedtoSCS(1456HMPvs1787SCS,P=.01).
Zhong 2017 reported the HMP cohort had significantly de-
creased median serum creatinine (F=5.165,P=.024),andasignifi-
cant increase in median urine output (F=3.962,P=.047),inthef irst
7 days post-transplant.
Watson 2010 rep orted on the creat inine reductio n ratio between
day 1 and day 2, and the creatinine reduction ratio between immedi-
atelypretransplantandday5.Theyalsoreportedestimatedglomer-
ularfiltrationrate(eGFR)atday7,3months,and1year.Therewere
nosignificantdif ferencesin anyofthesevalues betweentheHMP
andSCSgroups,inkeepingwithsimilarDGFratesineachgroup.
Tedesco-Silva 2017 provides data for mean serum creatinine
and eGFR (± standard deviation) at time point s of 7, 14, 21, 28, and
365 days. The y reported t hat “mean ser um creatinin e was signifi-
cantly lower in the HMP group compared with the SCS at both
14days (3.0 ± 2.2 HMP vs 4.1±3.2mg/dL, P=.005) and 21days
(2.3±1.8HMPvs3.0±2.6mg/dL,P=.021).”Alt ho ughth esere sults
are significant, they did not perform statistical corrections for mul-
tiple comparisons and found no evidence for differences in serum
creatinine at any of the other three time points or significant dif fer-
ences in eGFR at any of the five time points.
Van der Vliet 2001 reported mean serum creatinine (± stan-
dard deviation) at 3 months post-transplant; there was no signifi-
cant differencebetweenHMP and SCS groups (174± 25 HMPvs
162±11µmol/LSCSgroup,P=.68).
Overall, there is no evidence that long-term graft function is
affected. The significant improvements seen in short-term graft
function are analogous to the significant improvements seen in DGF
incidence.
3.10 | Acute rejection
Four studies (Kwiatkowski 1999; Moers 2009; Watson 2010;
Tedesco-Silva 2017) re ported on incid ence of acute rejec tion. As
they reported on acute rejection incidence over different time peri-
ods, meta-analysis including all studies was not possible.
Moers 20 09 reported on incidence of biopsy-proven acute rejec-
tionat14 daysandfoundsimilarrate sb et weengroups(n=672,13.7%
SCS vs 13.1% HMP,P=.91).Tedesco-Silva2017reportslowerinci-
denceoftreatedacuter ejec tionwi th inthefir st mo nt h(n =16 0,16.3%
SCSvs8.8%HMP,P=.151).Wat so n2 010 re po rts alowerincidenceof
biopsy-provenacuterejectionintheHMPgroupwithinthefirstthree
months(n=90,22%SCSvs7%HMP,P=.06).Ted esco-S ilva2017and
Watson 2010 both report rejection at 1 year, and meta-analysis of this
dat ashowedal owe rrateofac uterejec tioni ntheHMPgrou p,b utt his
wasnotsignificant(RR0.66,95%CI0.37-1.17,P=.15).
Kwiatkowski 1999 reported incidence of treated acute rejec-
tion during the full duration of follow-up (median 22 months, range
7-37 months). They found that incidence of acute rejection was
lower with HMP(n= 74, 51%SCS vs 35% HMP), but thiswas not
statisticallysignificant.Kwiatkowski1999didnotstatewhetherthe
follow-up duration was similar bet ween groups; therefore, the valid-
ity of these result s is questionable.
4 | DISCUSSION
Thisstudyperformedmeta-analysesofRCTstoinvestigatetheef-
fect of HMP i n deceased do nor kidney tr ansplantat ion. Overal l,
14trials (2138 participants)wereincluded. The use of HMPsig-
nifica ntly reduced the rate of DGF compared to SCS (RR 0.77,
95%CI0.67-0.90,P=.0006,high-certaintyevidence).Thisresult
wasstatisticallysignificant in boththeDCD (P=.0002)andthe
DBD subgroups (P=.006).Therewasnoevidencefordiffering
treatment effect between these groups (P=.72).Thatsaid,asthe
overall in cidence of DGF is highe r in the DCD subgroup, H MP
preventsmore episodesofDGF inDCDgraftsinabsoluteterms.
Therefore,thenumberofHMPsrequiredtopreventoneepisode
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ofDGFislowerin DCD grafts,7.26and13.60inDCDandDBD
grafts, respectively.
Stu di espublishedinthelastde cadeal lusedtheL if ePor thypo-
thermic machine perfusion device.26, 28,30-32Clearly,thesestudies
are especially relevant for practice today. In these “modern era”
studies, HMP with the LifePort machine significantly decreased
theincidenceofDGFcomparedwithSCS(1355patientsfromfive
studies,RR0.77,95%CI0.66-0.91,P=.002).Economicanalysis
based on results from the large Moers 20 09 trial suggest s that
HMPwithLifePortiscost-effectiveinboththeEuropeanandUS
setting.33,34
Although 1-year graft sur vival was repor ted by eight studies ,
it was insuf ficiently a ccurately rep orted to allow m eta-analysis . A
summary of all trials reporting on overall 1-year graft survival is pro-
vided in Table 2. T he EuroTra nsplant trial (Moe rs 2009) repor ted
asignificant graft sur vival benefitof HMP compared with SCS, at
both 1 year (90 % SCS vs 94% HMP,l og-rank P = .0 4; Cox HR for
1-yeargraftloss, 0.52,P=.03)and3years(87% SCSvs91%HMP;
adjusted hazard ratio for graf t failure, 0.60; P= .04). These grafts
were most ly from DBD don ors, and a ben efit in 3-year graf t was
demons trated in their D BD cohort (91% vs 86%; adjus ted hazard
ratio,0.54;P=.02).29
Zhong 2017 used log-rank test analysis and also reported a sta-
tistically significant survivalbenefit of HMPcomparedwith SCS in
DCDgrafts,atboth1year(93%SCSvs98%HMP,P=.026)an dt hre e
years(82%SCSvs93%HMP,P=.036).Bothofthesetrialswerewell
designedandwellpowered.Together,theyprovidestrongevidence
thatHMPimprovesgraftsurvivalinbothDBDandDCDgrafts.
Overall, studies included in this review tended to be at low risk of
bias.Asourceofbiasinthreestudies (Kwiatkowski1999;Matsuno
1994;Mozes1985)waslongerCITintheHMPgroup.Insomecases,
the HMP ki dney was routi nely trans planted aft er the SCS ki dney;
this bias could cause us to underestimate the treatment effec t of
HMP. We attempted to limi t biases at every s tage in our review.
Systematic searches were performed, screening of studies was by
independent authors, and data were extracted in a standardized
fashion . The four teen studi es included i n this review we re from a
range of dif ferent locati ons (United States , Europe, China, Jap an,
Canad a, South Afric a, and Brazil) , with a range of DCD an d DBD
grafts. Studieswith bothshort andlong meanCITswerealso well
represented. Overall, this makes the above results generalizable and
therefore applicable to many different transplant settings.
We have reported numbers of perfusions needed to prevent
oneepisodeofDGF inourresults.Thisnumberdependsonthein-
cidence of DGF, so these figures may not be applicable to transplant
centers which have particularly high or low rates of DGF. However,
the RR reported by this study c an easily be used to calculate the
number of perfusions required to prevent one episode of DGF for
grafts with any DGF rate.
In recent years, transplantation researchers have shifted their
focus to normothermic machine perfusion (NMP), with a recent
trialshowingbenefitsofcontinuousNMPinlivertransplantation.35
Thereis also emergingevidencethat “end-ischemic”NMPmaybe
superiorto SCS inkidney transplantation, which has prompted an
ongoingRCT.36,37However,there arecurrentlyno completedRC Ts
to suppor t the use of NMP, and no mea ningful com parisons have
beenmadebetweenNMPandHMPintheclinicalsetting.HMPhas
severaltheoreticalbenefitsoverNMP;itgenerallycostsless,iseas-
ily portable, and is safer (technical failure simply means reverting to
SCSratherthanlossofapotentialgraft).26Thisreviewhasdemon-
strate d HMP as superio r to SCS. Ther efore, fur ther RCTs directl y
comparing NMP (either continuous or end-ischemic) with HMP
are essential to identify the optimal preservation method in renal
transplantation.
4.1 | Conclusions
Thereishigh-certainty evidencethathypothermicmachineperfu-
sion reduces the incidence of delayed graft function and improves
short- and long-term graft survival when compared to static cold
storage,inboth DBD andDCDgrafts. Previous economicanalysis
suggeststhatHMPisacost-effectiveinter vention.
Transplantation units should considerthe use of hypothermic
machine perfusion in all deceased donor kidney transplantation,
especially in grafts at high risk of DGF.Asnormothermic machine
perfusion is changing the landscape of transplantation, randomized
controlled trials must directly compare hypothermic and normother-
mic machine perfusion in kidney transplantation.
ACKNOWLEDGEMENTS
TheauthorteamwouldliketothanktheNIHRBloodandTransplant
ResearchUnit(NIHRBTRU)inOrganDonationfortheirsupport.
CONFLICT OF INTEREST
Theauthorsdeclarenoconflictsofinterest.
AUTHOR CONTRIBUTIONS
SJT,RSF,JAGM,DT,andCHW:Conceivedthestudy.SJT,RSF,JAGM,
MG, ERT,IKI,LB,DT,andCHW:Designedthestudy.SJTandRSF:
Carried out study selection, extracted the data, and performed
statistical analysis. SJT, RSF, and MG: Interpreted the data. SJT:
Preparedthemanuscript.SJT,RSF,andCHW:Editedthemanuscript.
SJT,R SF,JAG M,MG,ERT,IKI ,LB ,DT,andCHW:Reviewedtheman-
uscript.SJT,RSF,JAGM,MG,ERT,IKI, LB, DT,andCHW:Approved
the final version of the manuscript.
ORCID
Samuel J. Tingle https://orcid.org/0000-0001-5529-7815
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SUPPORTING INFORMATION
Additional suppor ting information may be found online in the
Supporting Information section.
How to cite this article:TingleSJ,FigueiredoRS,MoirJAG,
et al. Hypothermic machine perfusion is superior to static
coldstorageindeceaseddonorkidneytransplantation:A
meta-analysis. Clin Transplant. 2020;34:e13814. h t tp s : //d o i.
org /10.1111/ct r.13814
