ArticlePDF AvailableLiterature Review

Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation

March 2019
Cochrane Database of Systematic Reviews 3(3)

March 2019
3(3)

DOI:10.1002/14651858.cd011671.pub2

Authors:

Samuel James Tingle

Newcastle University

Rodrigo Figueiredo

The Newcastle upon Tyne Hospitals NHS Foundation Trust

John Moir

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Michael Goodfellow

Newcastle University

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Background: Kidney transplantation is the optimal treatment for end-stage kidney disease. Retrieval, transport and transplant of kidney grafts causes ischaemia reperfusion injury. The current accepted standard is static cold storage (SCS) whereby the kidney is stored on ice after removal from the donor and then removed from the ice box at the time of implantation. However, technology is now available to perfuse or "pump" the kidney during the transport phase or at the recipient centre. This can be done at a variety of temperatures and using different perfusates. The effectiveness of treatment is manifest clinically as delayed graft function (DGF), whereby the kidney fails to produce urine immediately after transplant. Objectives: To compare hypothermic machine perfusion (HMP) and (sub)normothermic machine perfusion (NMP) with standard SCS. Search methods: We searched the Cochrane Kidney and Transplant Register of Studies to 18 October 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria: All randomised controlled trials (RCTs) and quasi-RCTs comparing HMP/NMP versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD), standard and extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion. Data collection and analysis: The results of the literature search were screened and a standard data extraction form was used to collect data. Both of these steps were performed by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was incidence of DGF. Secondary outcomes included: one-year graft survival, incidence of primary non-function (PNF), DGF duration, long term graft survival, economic implications, graft function, patient survival and incidence of acute rejection. Main results: No studies reported on NMP, however one ongoing study was identified.Sixteen studies (2266 participants) comparing HMP with SCS were included; 15 studies could be meta-analysed. Fourteen studies reported on requirement for dialysis in the first week post-transplant (DGF incidence); there is high-certainty evidence that HMP reduces the risk of DGF when compared to SCS (RR 0.77; 95% CI 0.67 to 0.90; P = 0.0006). HMP reduces the risk of DGF in kidneys from DCD donors (7 studies, 772 participants: RR 0.75; 95% CI 0.64 to 0.87; P = 0.0002; high certainty evidence), as well as kidneys from DBD donors (4 studies, 971 participants: RR 0.78, 95% CI 0.65 to 0.93; P = 0.006; high certainty evidence). The number of perfusions required to prevent one episode of DGF (number needed to treat, NNT) was 7.26 and 13.60 in DCD and DBD kidneys respectively. Studies performed in the last decade all used the LifePort machine and confirmed that HMP reduces the incidence of DGF in the modern era (5 studies, 1355 participants: RR 0.77, 95% CI 0.66 to 0.91; P = 0.002; high certainty evidence). Reports of economic analysis suggest that HMP can lead to cost savings in both the North American and European settings.Two studies reported HMP also improves graft survival however we were not able to meta-analyse these results. A reduction in incidence of PNF could not be demonstrated. The effect of HMP on our other outcomes (incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain. Authors' conclusions: HMP is superior to SCS in deceased donor kidney transplantation. This is true for both DBD and DCD kidneys, and remains true in the modern era (studies performed in the last decade). As kidneys from DCD donors have a higher overall DGF rate, fewer perfusions are needed to prevent one episode of DGF (7.26 versus 13.60 in DBD kidneys).Further studies looking solely at the impact of HMP on DGF incidence are not required. Follow-up reports detailing long-term graft survival from participants of the studies already included in this review would be an efficient way to generate further long-term graft survival data.Economic analysis, based on the results of this review, would help cement HMP as the standard preservation method in deceased donor kidney transplantation.RCTs investigating (sub)NMP are required.

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Cochrane Database of Systematic Reviews

Machine perfusion preservation versus static cold storage for

deceased donor kidney transplantation (Review)

Tingle SJ, Figueiredo RS, Moir JAG, Goodfellow M, Talbot D, Wilson CH

Tingle SJ, Figueiredo RS, Moir JAG, Goodfellow M, Talbot D, Wilson CH.

Machine perfusion preservation versus sta tic cold storage for deceased donor kidney transplantation.

Cochrane Database of Syst ematic Reviews 2019, Issue 3. Art. No.: CD011671.

DOI: 10.1002/14651858.CD011671.pub2.

www.cochranelibrary.com

Machine perfusion preservation versus static cold storagefo rdeceased donor kidney transplantation (Review)

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

20DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 1 Delayed graft

function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 1.2. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 2 Delayed graft function:

type of donor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 1.3. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 3 Delayed graft function:

era of study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 1.4. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 4 Delayed graft function:

preservation times. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Analysis 1.5. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 5 Primary non-

function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Analysis 1.6. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 6 Duration of DGF. 69

Analysis 1.7. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 7 One year patient

survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Analysis 1.8. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 8 Treated acute rejection

in the ﬁrst year. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

71ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iMachine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

[Intervention Review]

Machine perfusion preservation versus static cold storage for

deceased donor kidney transplantation

Samuel J Tingle1, Rodrigo S Figueiredo2, John AG Moir3, Michael Goodfellow4, David Talbot5, Colin H Wilson6

1Faculty of Medical Sciences, Newcastle University Medical School, Newcastle upon Tyne, UK. 2Northern Deanery, The Freeman

Hospital, Newcastle upon Tyne, UK. 3The Freeman Hospital, Newcastle upon Tyne, UK. 4Newcastle Medical School, Newcastle

University, Newcastle upon Tyne, UK. 5The Liver/Renal Unit, The Freeman Hospital, Newcastle upon Tyne, UK. 6Institute of

Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK

Contact address: Samuel J Tingle, Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle

upon Tyne, Tyne and Wear, NE2 4HH, UK. samjamestingle@gmail.com,s.j.tingle@newcastle.ac.uk.

Editorial group: Cochrane Kidney and Transplant Group.

Publication status and date: New, published in Issue 3, 2019.

Citation: Tingle SJ, Figueiredo RS, Moir JAG, Goodfellow M, Talbot D, Wilson CH. Machine perfusion preservation versus static

cold storage for deceased donor kidney transplantation. Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.: CD011671.

DOI: 10.1002/14651858.CD011671.pub2.

A B S T R A C T

Background

Kidney transplantation is the optimal treatment for end-stage kidney disease. Retrieval, transport and transplant of kidney grafts causes

ischaemia reperfusion injury. The current accepted standard is static cold storage (SCS) whereby the kidney is stored on ice after removal

from the donor and then removed from the ice box at the time of implantation. However, technology is now available to perfuse or

“pump” the kidney during the transport phase or at the recipient centre. This can be done at a variety of temperatures and using

different perfusates. The effectiveness of treatment is manifest clinically as delayed graft function (DGF), whereby the kidney fails to

produce urine immediately after transplant.

Objectives

To compare hypothermic machine perfusion (HMP) and (sub)normothermic machine perfusion (NMP) with standard SCS.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies to 18 October 2018 through contact with the Information

Specialist using search terms relevant to this review. Studies in the Register are identiﬁed through searches of CENTRAL, MEDLINE,

and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

All randomised controlled trials (RCTs) and quasi-RCTs comparing HMP/NMP versus SCS for deceased donor kidney transplantation

were eligible for inclusion. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD), standard and

extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion.

Data collection and analysis

The results of the literature search were screened and a standard data extraction form was used to collect data. Both of these steps

were performed by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% conﬁdence

intervals (CI). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for

1Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

data analysis. The primary outcome was incidence of DGF. Secondary outcomes included: one-year graft survival, incidence of primary

non-function (PNF), DGF duration, long term graft survival, economic implications, graft function, patient survival and incidence of

acute rejection.

Main results

No studies reported on NMP, however one ongoing study was identiﬁed.

Sixteen studies (2266 participants) comparing HMP with SCS were included; 15 studies could be meta-analysed. Fourteen studies

reported on requirement for dialysis in the ﬁrst week post-transplant (DGF incidence); there is high-certainty evidence that HMP

reduces the risk of DGF when compared to SCS (RR 0.77; 95% CI 0.67 to 0.90; P = 0.0006). HMP reduces the risk of DGF in

kidneys from DCD donors (7 studies, 772 participants: RR 0.75; 95% CI 0.64 to 0.87; P = 0.0002; high certainty evidence), as well

as kidneys from DBD donors (4 studies, 971 participants: RR 0.78, 95% CI 0.65 to 0.93; P = 0.006; high certainty evidence). The

number of perfusions required to prevent one episode of DGF (number needed to treat, NNT) was 7.26 and 13.60 in DCD and DBD

kidneys respectively. Studies performed in the last decade all used the LifePort machine and conﬁrmed that HMP reduces the incidence

of DGF in the modern era (5 studies, 1355 participants: RR 0.77, 95% CI 0.66 to 0.91; P = 0.002; high certainty evidence). Reports

of economic analysis suggest that HMP can lead to cost savings in both the North American and European settings.

Two studies reported HMP also improves graft survival however wewere not able to meta-analyse these results. Areduction in incidence

of PNF could not be demonstrated. The effect of HMP on our other outcomes (incidence of acute rejection, patient survival, hospital

stay, long-term graft function, duration of DGF) remains uncertain.

Authors’ conclusions

HMP is superior to SCS in deceased donor kidney transplantation. This is true for both DBD and DCD kidneys, and remains true in

the modern era (studies performed in the last decade). As kidneys from DCD donors have a higher overall DGF rate, fewer perfusions

are needed to prevent one episode of DGF (7.26 versus 13.60 in DBD kidneys).

Further studies looking solely at the impact of HMP on DGF incidence are not required. Follow-up reports detailing long-term graft

survival from participants of the studies already included in this review would be an efﬁcient way to generate further long-term graft

survival data.

Economic analysis, based on the results of this review, would help cement HMP as the standard preservation method in deceased donor

kidney transplantation.

RCTs investigating (sub)NMP are required.

P L A I N L A N G U A G E S U M M A R Y

The use of machines to preserve kidneys from deceased donors prior to transplantation

What is the issue?

Kidney transplantation is the best treatment for patients with end-stage kidney disease. However, there are not enough donated organs

to go around. In addition, whilst a donated kidney is outside of the body it is starved of oxygen, the halting of circulation allows small

clots to form, which damages the organ. This damage remains a major barrier to transplantation as it renders many organs unusable and

is associated with decreased survival of the kidneys which are transplanted. Traditionally kidneys were kept in ice (termed static cold

storage). Machines which drive cold (hypothermic machine perfusion) or warm (normothermic machine perfusion) solutions through

donated kidneys aim to decrease the damage done during transport and therefore improve the outcomes for these kidneys.

What did we do?

We performed a rigorous search for studies which compared hypothermic machine perfusion, normothermic machine perfusion and

standard static cold storage. Data from included studies could then be combined to allow further analysis. Our primary outcome was

rate of delayed graft function (DGF) (the number of patients who needed extra dialysis support in the week following transplant). Our

main secondary outcome of interest was one-year kidney survival (the number of transplanted kidneys functioning at one year).

What did we ﬁnd?

2Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Sixteen studies (2266 participants) comparing hypothermic machine perfusion with static cold storage were included. The use of

hypothermic machine perfusion instead of standard static cold storage reduces the risk of DGF by approximately 23%. Two reports

performed economic analysis, in the USA and European settings, and both estimated cost savings with the use of hypothermic machine

perfusion. Two studies reported hypothermic machine perfusion prolongs the length of time that donated kidneys survive in the

recipient, however we were unable to perform an analysis to conﬁrm this. The effect of HMP on other outcomes (incidence of acute

rejection, patient survival, hospital stay, long-term kidney function, duration of DGF) remains uncertain.

No completed studies investigating normothermic machine perfusion were identiﬁed, but one ongoing study was identiﬁed.

Conclusions

Compared with standard static cold storage, hypothermic machine perfusion reduces the rate of DGF in kidneys from deceased donors,

and likely results in increased survival of the transplanted kidney and overall cost savings. Studies looking at normothermic machine

perfusion are required to assess if this results in superior outcomes.

3Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Hypothe rmic machine perfusion versus static cold storage f or deceased donor k idney t ransplantat ion

Patient or population: deceased donor kidney t ranspl ant atio n

Intervention: hypot h er m ic m achi ne perf u sio n

Comparison: s t atic c old st o rage

Outcomes Anticipat ed absolut e effe cts∗(95% CI) Relati ve ef fect

(9 5% CI )

No. of participants

(studi es)

Certai nty of the evi-

dence

(GRADE)

Comments

Risk with static cold

storage

Risk with hypothermic

machine perfusion

DGF 40 9 per 1,000 31 5 per 1,000

(2 74 to 368 )

RR 0.77

(0 .67 t o 0.90 )

21 38 (1 4) ⊕⊕⊕⊕

HIGH

DGF: DCD gro up 50 1 per 1,000 37 6 per 1,000

(3 21 to 436 )

RR 0.75

(0 .64 t o 0.87 )

77 2 (7) ⊕⊕⊕⊕

HIGH

DGF: DBD gro up 342 per 1,00 0 266 per 1,000

(2 22 to 318 )

RR 0.78

(0 .65 t o 0.93 )

97 1 (4) ⊕⊕⊕⊕

HIGH

DGF: mod er n era st ud-

ies

37 2 per 1,000 28 6 per 1,000

(2 45 to 338 )

RR 0.77

(0 .66 t o 0.91 )

13 55 (5 ) ⊕⊕⊕⊕

HIGH

DGF: pre-2008 s t udi es 47 4 per 1,000 37 0 per 1,000

(2 89 to 470 )

RR 0.78

(0 .61 t o 0.99 )

78 3 (9) ⊕⊕⊕⊕

HIGH

One year graft survi val See comm en ts See c om m ent s - - - M eta -anal ys i s was not

po ssib le. There i s

st rong evidence o f im -

proved g raf t surviva l

wit h HM P

PNF 65 p er 1,00 0 57 p er 1 ,00 0

(3 8 to 86)

RR 0.88

(0 .58 t o 1.33 )

13 87 (7 ) ⊕⊕⊕⊕

HIGH

4Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Durat ion of DGF The m ea n dur ati on o f

DGF wa s 11. 8 d ays

Mean du rat ion of DGF

was 1 .23 f ewer days (5 .

87 f ewer to 3. 4 m o re)

- 22 0 (4) ⊕

VERY LOW 1

One year p atient sur-

vival

96 5 per 1,000 95 5 per 1,000

(9 17 to 994 )

RR 0.99

(0 .95 t o 1.03 )

92 0 (3) ⊕⊕

LOW 2

Treated acut e rejec tio n

in t he f irs t year

24 4 per 1,000 16 1 per 1,000

(9 0 to 285)

RR 0.66

(0 .37 t o 1.17 )

24 8 (2) ⊕⊕

LOW 3

*The risk in the inte rve ntion group (and it s 95% con f idence i nterval) i s b ased on the a ssum ed ris k in t he co m p arison g rou p and the relat ive ef f ect of the i nterven t ion (an d i t s

95 % CI).

CI: c onf iden ce int erval ; DBD: d ono r af t er brai nst em deat h; DCD: d ono r af t er ci rcu lat ory deat h; DGF: delayed graf t fun ctio n; M D: mean dif f erenc e; P NF: prim ary no n-fun ctio n;

RR: risk r ati o

GRADE Working Group grades of evidence

High certainty: We are very conf i dent t hat th e tru e ef fec t lies c lose t o that of th e es t im ate o f the eff ec t

Moderate certainty: We are m o derat ely c o nfid ent in the ef f ect es t im ate: The true ef fec t is likel y to b e clos e t o the esti m ate of th e effec t , but t here is a p oss i bil ity th at it i s

su bst a nti all y dif ferent

Low certainty: Our con f idence in the ef f ect es t im ate i s l imit ed: The t r ue e f f ect m ay be s ubs t ant ial ly di f f erent from the es timat e o f the ef f ect

Very low ce rt ainty: We have ver y li t tle conf idenc e in t he ef f ect es t im ate: The true ef f ect i s l ikely t o be sub s tan t ially d iff er en t f rom th e es t imat e o f ef f ect

1Dow n graded three levels : not all st u dies r ep ort i ng DGF dur ati on co uld b e i ncluded in t he m eta-an alysi s an d hi gh level of

hetero genei ty bet w een stud ies

2Dow ngra ded tw o level s: not al l stud ies rep ort ing patient su rvival d uratio n coul d be i ncl uded in t he m et a-anal ys is, and none

of t he stud ies were pow ered to al low ana lysis of pa tie nt s urvival

3Dow n graded tw o levels: repo rti ng a t diff er en t time p oin t s prevent ed inc l usi on o f severa l s t udies into met a-analys is. In

addit ion d if f erent st udi es used dif fer en t d efin itio ns f o r acut e rejec t ion, som e being dep en dent o n b iops ies a nd som e on

cl inical j udg em ent.

5Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

B A C K G R O U N D

Description of the condition

End-stage kidney disease (ESKD) is deﬁned as an irreversible de-

cline in kidney function that is severe enough to be fatal without

renal replacement therapy (RRT). ESKD is a major debilitating

condition with a drastic effect on patients’ quality of life, as well as

being associated with signiﬁcant morbidity and death. It is a con-

dition with growing worldwide prevalence, affecting an estimated

3.2 million people (Fresenius 2013). The maintenance treatment

for such patients is regular RRT. The impact of dialysis on the abil-

ity of patients to lead normal lives is signiﬁcant, requiring frequent

hospital visits, as well as severely restricting travel. It is now widely

accepted that kidney transplantation offers a survival advantage

over all forms of RRT (Wolfe 1999). In addition, there is also an

economic beneﬁt of transplantation when compared with the high

cost of dialysis. It has been estimated that kidney transplantation

costs GBP £241,000 less than dialysis over a 10-year period for a

single patient (NHSBT 2009).

An estimated 77,818 kidney transplants were carried out in 2012

(GODT 2012). Potential recipients can be transplanted with a

kidney graft (simply termed ’graft’ for the remainder of the review)

from a living or deceased donor. Deceased donors may be certiﬁed

dead on the basis of brainstem death (donation after brainstem

death; DBD) criteria or circulatory death (donation after circula-

tory death; DCD). However, kidneys from deceased donors have

a higher incidence of delayed graft function (DGF) and primary

non-function (PNF) due to the trauma of brainstem death or cir-

culatory arrest, as well as reperfusion injury when compared with

live donor kidneys.

The growing disparity between supply and demand has led to in-

creasing use of DCD organs and marginal organs from donors

outside traditional transplantation protocols. A well-accepted def-

inition of extended/expanded criteria donor (ECD) is age over

60 years or over 50 years with a history of hypertension, kidney

impairment or cause of death secondary to stroke (Port 2002).

Most studies have shown that transplantation of organs from ei-

ther DCD or ECD are associated with inferior short- and long-

term outcomes (Glyda 2012;Hwang 2014;Metzger 2003;Pascual

2008). This has focused attention on organ preservation tech-

niques and ways to recondition organs in the donor and ex vivo

prior to transplantation to potentially improve outcomes for re-

cipients. However, the signiﬁcant increase in cost of machine per-

fusion (MP) means that its widespread use depends on the demon-

stration of superiority, over the relatively inexpensive static cold

storage (SCS). Although it is also important to note that at least

some of the additional cost may be offset by reduced hospitalisa-

tion, complications, or both.

The use of MP brings with it further questions, such as what is

the optimum perfusion temperature, preservation solution; pul-

satile versus non-pulsatile ﬂow; and oxygenated versus non-oxy-

genated perfusate. The main focus of this review will be to compare

(sub)normothermic and hypothermic MP (HMP) versus SCS.

Description of the intervention

From the early days of organ transplantation, hypothermia was

an effective means of preserving the organ in the absence of oxy-

genated circulation. Belzer 1968 successfully preserved human

kidneys using HMP; although the machine was large, bulky and

difﬁcult to transport. Shortly thereafter, an electrolyte solution

was developed that enabled preservation of a kidney for 24 hours

in a container surrounded with ice, now termed SCS (Collins

1969). Subsequently, various other preservation solutions have

superseded Euro-Collins, most notably University of Wisconsin

(UW), histidine-tryptophan-ketoglutarate (HTK), and Marshall’s

hyperosmolar citrate. The preservation solution used has an effect

on the incidence of DGF, which may affect long-term outcomes.

In a meta-analysis both UW and HTK were found to have similar

DGF incidence, when compared with older preservation solutions

like Euro-Collins (O’Callaghan 2012,Table 1).

As organ preservation solutions have evolved so have extracorpo-

real MP technologies. There are now several commercially avail-

able HMP devices which are broadly similar with minor varia-

tions in perfusion temperature (4oC to 10oC), ﬂow (pulsatile ver-

sus non-pulsatile) and provision of oxygenation (oxygenated ver-

sus non-oxygenated). The most popular machines currently avail-

able are the LifePort® (Organ Recovery Systems; Itasca, Illinois),

the KidneyAssist® (OrganAssist; Gronigen, Netherlands) and the

Waters RM3® system (Rochester, Minnesota). The Gambro MP

devices (Gambro, Lund, Sweden) were previously available alter-

natives. Once the kidney has been removed from the donor, the

kidney is cannulated and connected to a disposable circuit de-

signed speciﬁcally for the device. The donor kidney is then con-

tinuously perfused typically at temperatures between 6oC and 12

oC within the battery-operated device, whilst the kidney is trans-

ported to a suitable recipient.

The older Waters and Gambro pumps rely on continuous ﬂow

of cold perfusate to sustain hypothermia. This risks graft loss in

the unlikely event of pump failure. In contrast, the newer LifePort

perfusion device is able to revert to SCS in the event of pump

failure, mitigating this risk.

More recently Professor Nicholson in Leicester, United Kingdom,

has pioneered a technique of normothermic machine perfusion

(NMP) using modiﬁed cardiopulmonary bypass equipment. This

preservation technique is static and can be used to complement

either SCS or HMP; as the kidney still has to be transferred to

the recipient centre (Nicholson 2013). In the future commercially

available transportable kidney normothermic perfusion machines

may become available as there is now for the liver (OrganOx®

metra™ device). Whilst NMP uses a perfusion temperature of 35

oC to 37oC, further studies may employ (sub)NMP; deﬁned as

20oC to 34oC.

6Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

How the intervention might work

Hypothermia slows the metabolism of cells. In general, for every

10oC drop, the metabolism rate halves (Wilson 2006). SCS works

by removing blood and clots from the kidney graft and replacing

this with an acellular preservation solution in a hypothermic envi-

ronment. Pulsatile preservation up-regulates nitric oxide produc-

tion by vascular endothelium (Gallinat 2013), as well as clearing

the microcirculation of debris and toxic metabolites. Proponents

hypothesise that the ultimate result of MP is a reduced intra-re-

nal resistance at the time of in vivo reperfusion and better earlier

transplant function.

NMP or EVNP (ex vivo normothermic perfusion; as it is also

known) technology is in its infancy and the exact beneﬁcial mech-

anism of action debated. In brief, whilst the recipient is under-

going anaesthesia and preliminary surgery, the kidney is prepared

and connected to a modiﬁed cardiopulmonary bypass circuit us-

ing a red-cell based perfusate (Nicholson 2013). The perfusate

lacks mediators of reperfusion injury like leukocytes, complement,

platelets but includes vasodilators and heparin. Experimental work

has shown that this combination improves early transplant func-

tion in a porcine model (Bagul 2008).

Why it is important to do this review

Ischaemia reperfusion injury in a kidney transplant manifests as

DGF with PNF if the injury is severe. In a recent review look-

ing at ECD/DCD kidneys one year graft survival was only 73%

and PNF rate of 12.5% in one subset that had been transplanted

(Kosmoliaptsis 2015). In addition, DGF leads to an increased

requirement for RRT, prolonged hospitalisation and often more

investigations - incurring signiﬁcant extra ﬁnancial costs. In our

own institution these extra peritransplant ﬁnancial costs for DCD

recipients with DGF have been estimated to be GBP £4500 per

patient (Wilson 2014). In cases of PNF the recipient requires a

second operation to remove the kidney and returns to dialysis with

an immune system sensitised and difﬁcult to match for repeat

transplantation.

DGF is most commonly deﬁned as the requirement for dialysis

within the ﬁrst week after implantation (Mallon 2013), although

common measures of kidney function estimationmay b e used such

as estimated glomerular ﬁltration rate (eGFR; Cockcroft-Gault or

MDRD).

SCS is a simple method of storage, and is relatively cheap compared

to MP. Robust evidence for the beneﬁts of MP are required to jus-

tify these increased initial costs. This review will critically appraise

and summate the current randomised controlled trial (RCT) lit-

erature to analyse the potential beneﬁt of novel preservation tech-

nologies in kidney transplantation, both in terms of patient cen-

tred outcomes and the ﬁnancial implications at a societal level.

O B J E C T I V E S

To compare hypothermic HMP and (sub)NMP with standard

SCS.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All RCTs and quasi-RCTs (RCTs in which allocation to treatment

was obtained by alternation, use of alternate medical records, date

of birth or other predictable methods) looking at normothermic

and HMP versus SCS for kidney transplantation from deceased

donors were eligible for inclusion. For a study to be included,

one group must have been randomised to cold storage with a

commercially available preservation solution (Table 1) and one to

a MP technique.

Types of participants

Inclusion criteria

All RCTs and quasi-RCTs comparing HMP or NMP with SCS

for donor human kidneys were eligible for inclusion. We antici-

pated that some studies would be limited to ECD or DCD kid-

neys, whereas others would not be selective. We further antici-

pated that some studies would randomise one kidney in a pair to

one modality and the other kidney to the control group: in other

unpaired studies both organs from the same donor will have been

randomised. We included both paired and unpaired studies.

We also included studies where a recipient received dual kidney

transplants as long as the same modality (HMP, NMP or SCS)

was used for both grafts.

Exclusion criteria

We planned to exclude studies where the kidney graft was used as

part of a composite or multi-visceral transplantation, although no

such studies were identiﬁed. The meta-analysis was restricted to

human studies, as although there are good animal transplantation

models available, we did not anticipate that these would examine

the inter-relationship of immunosuppression, ischaemia-reperfu-

sion injury and preservation modality over the required length of

follow-up to provide data with direct clinical applicability.

7Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Types of interventions

We searched for studies comparing the following interventions.

1. HMP versus SCS

2. HMP versus (sub)NMP

3. (Sub)NMP versus SCS.

This initial version of the review will only include comparison of

HMP and SCS, as (sub)NMP RCTs are yet to be completed.

Types of outcome measures

Primary outcomes

•Incidence of DGF (deﬁned as requirement for

postoperative dialysis)

Secondary outcomes

•One-year graft survival

•Duration of DGF

•Episodes of biopsy-proven rejection

•Incidence of PNF

•Patient survival

•Presence of ﬁbrosis on biopsy

•Economic implications

•Quality of life

•Hospital stay

•Early hospital costs

•Number of allograft ultrasound scans

•Number of allograft biopsies

•Incidence of acute rejection

•Kidney function at three, six, nine and 12 months (serum

creatinine (SCr) and glomerular ﬁltration rate (GFR))

•Two, three, and ﬁve-year graft survival.

Search methods for identiﬁcation of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of

Studies up to 18 October 2018 through contact with the Infor-

mation Specialist using search terms relevant to this review. The

1. Monthly searches of the Cochrane Central Register of

Controlled Trials CENTRAL

2. Weekly searches of MEDLINE OVID SP

3. Handsearching of kidney-related journals and the

proceedings of major kidney and transplant conferences

4. Searching of the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected kidney journals

6. Searches of the International Clinical Trials Register

(ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identiﬁed through searches

of CENTRAL, MEDLINE, and EMBASE based on the scope

of Cochrane Kidney and Transplant. Details of search strategies,

as well as a list of handsearched journals, conference proceedings

and current awareness alerts, are available in the Specialised Register

section of information about Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of review articles, relevant studies and

clinical practice guidelines.

2. Letters seeking information about unpublished or

incomplete studies to investigators known to be involved in

previous studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and ab-

stracts of studies that may have been relevant to the review. Titles

and abstracts were screened independently by two authors, who

discarded studies that were not applicable, however studies and

reviews which were thought to include relevant data or informa-

tion on studies were retained initially. Two authors independently

assessed retrieved abstracts and, if necessary, the full text of these

studies to determine which studies satisﬁed the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by two authors us-

ing standard data extraction forms. Where more than one publi-

cation of one study existed, reports were grouped together and the

publication with the most complete data was used in the analyses.

Where relevant outcomes were only published in earlier versions

these data were used.

Assessment of risk of bias in included studies

The following items were independently assessed using the risk of

bias assessment tool (Higgins 2011) (see Appendix 2).

•Was there adequate sequence generation (selection bias)?

•Was allocation adequately concealed (selection bias)?

•Was knowledge of the allocated interventions adequately

prevented during the study (detection bias)?

◦Participants and personnel

◦Outcome assessors

•Were incomplete outcome data adequately addressed

(attrition bias)?

•Are reports of the study free of suggestion of selective

outcome reporting (reporting bias)?

8Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

•Was the study apparently free of other problems that could

put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. incidence of DGF or PNF) re-

sults were expressed as risk ratio (RR) with 95% conﬁdence inter-

vals (CI). Where continuous scales of measurement were used to

assess the effects of treatment (e.g. duration of DGF), the mean

difference (MD) was used.

Missing standard deviations were imputed from data presented in

the published data (P values). Imputation of standard deviations

from other studies (Furukawa 2006), as described in our protocol,

was not appropriate . We recognise that all imputation techniques

involve making assumptions about unknown statistics, and we

avoided their use where possible.

As speciﬁed in our protocol we attempted to analyse graft survival

and patient survival by extracting time-to-event data from publi-

cations and entering the O-E and V statistics into RevMan and

then performing analysis with a log rank approach. Unfortunately

there was insufﬁcient reporting of time-to-event data to allow this.

Unit of analysis issues

We did not anticipate any challenges with non-standard designs

such as cross-over or cluster RCTs. In the future, there may be

studies in which a graft is initially transported with either SCS or

HMP and then subjected to NMP prior to implantation. These

will be analysed by the “dominant” preservation type.

Dealing with missing data

Any further information required from the original author was

requested by written correspondence (e.g. emailing correspond-

ing author). Evaluation of important numerical data such as

screened, randomised patients as well as intention-to-treat, as-

treated and per-protocol population was carefully performed. At-

trition rates, for example drop-outs, losses to follow-up and with-

drawals were investigated. Issues of missing data and imputation

methods (for example, last-observation-carried-forward) were crit-

ically appraised (Higgins 2011).

Assessment of heterogeneity

Statistical heterogeneity was explored and potential sources iden-

tiﬁed (including subgroup analysis as described below). Hetero-

geneity was analysed using a Chi2test on N-1 degrees of freedom,

with an alpha of 0.05 used for statistical signiﬁcance and with the I

2test (Higgins 2003). I2values of 25%, 50% and 75% were taken

to indicate low, medium and high levels of heterogeneity.

Assessment of reporting biases

Where possible, funnel plots were used to assess for the potential

existence of small study bias (Higgins 2011).

Data synthesis

Data was pooled using the random-effects model, but the ﬁxed-

effects model was also used to ensure robustness of the model

chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was used to explore possible sources of hetero-

geneity (e.g. inclusion of ECD or DCD kidneys). Potential sub-

group analyses included:

•DCD versus DBD criteria donors kidneys

•ECD versus standard criteria kidneys

•HMP at the time of donation versus HMP at the recipient

centre

•Long preservation times (≥24 hours) versus short (< 24

hours)

•Era of study (those performed in the ’modern era’ with

newer MP devices such as the LifePort device versus studies

performed previously; ’pre-2008’).

Sensitivity analysis

We performedsensitivity analyses in order to explore the inﬂuence

of the following factors on effect size.

•Repeating the analysis taking account of risk of bias, as

speciﬁed

•Repeating the analysis excluding any very long or large

studies to establish how much they dominate the results.

’Summary of ﬁndings’ tables

The main results of the review are presented in a ’Summary of

ﬁndings’ table. This table presents key information concerning

the quality of the evidence, the magnitude of the effects of the

interventions examined, and the sum of the available data for the

main outcomes (Schünemann 2011a). The ’Summary of ﬁndings’

table also includes an overall grading of the evidence related to

each of the main outcomes using the GRADE (Grades of Recom-

mendation, Assessment, Development and Evaluation) approach

(GRADE 2008;GRADE 2011). The GRADE approach deﬁnes

the quality of a body of evidence as the extent to which one can

be conﬁdent that an estimate of effect or association is close to the

true quantity of speciﬁc interest. The quality of a body of evidence

involves consideration of within-trial risk of bias (methodological

quality), directness of evidence, heterogeneity, precision of effect

estimates and risk of publication bias (Schünemann 2011b). The

following outcomes are presented in the ’Summary of ﬁndings’

table.

9Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

•Incidence of DGF (deﬁned as requirement for

postoperative dialysis)

•One-year graft survival

•Incidence of PNF

•Duration DGF

•One-year patient survival

•Incidence of acute rejection.

R E S U L T S

Description of studies

The following section contains broad descriptions of the studies

considered in this review. For further details on each individual

study please see the characteristics ofstudies tables; Characteristics

of included studies,Characteristics of excluded studies.

No studies reported on NMP, however one ongoing study was

identiﬁed. The rest of this review therefore deals entirely with

HMP.

Results of the search

A PRISMA ﬂow chart for the studies included in this review can

be found in Figure 1.

Figure 1. Study ﬂow diagram

After searching the Register we identiﬁed 71 records. After du-

plicates were removed and titles and abstracts screened we re-

trieved 68 full-text articles for further assessment. Of these, 16

studies (48 records) were included and 10 studies (13 records)

were excluded. Five ongoing studies were identiﬁed (Hosgood

2017;ISRCTN35082773;ISRCTN63852508;NCT02525510;

NCT02621281). Two studies were completed prior to publica-

tion, however no results are as yet available (ISRCTN50082383;

NCT01170910). These seven studies will be assessed in a future

update of this review

Included studies

In total 2266 recipients of cadaveric kidney transplants from 16

different studies (Alijani 1985;Amaduzzi 2011;Chen 2014c;

Halloran 1985;Heil 1987;Kwiatkowski 1996;Matsuno 1994;

Merion 1990;Moers 2009;Mozes 1985;PPART 2010;Tedesco-

Silva 2017;van der Vliet 2001;Veller 1994;Wang 2017;Zhong

10Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

2017) included in this review; full details for each study can be

found in the Characteristics of included studies table.

Insufﬁcient information was provided in the abstract by Amaduzzi

2011. Attempts to gain further information by contacting the

corresponding author failed and therefore results of this study

could not be included in the meta-analyses.

Of the 16 studies, four were performed in the USA (Alijani 1985;

Heil 1987;Merion 1990;Mozes 1985), ﬁve in Europe (Amaduzzi

2011;Kwiatkowski 1996;Moers 2009;PPART 2010;van der

Vliet 2001), three in China (Chen 2014c;Wang 2017;Zhong

2017), one in Japan (Matsuno 1994), one in Canada (Halloran

1985), one in South Africa (Veller 1994), and one in Brazil (

Tedesco-Silva 2017).

All but one of the included studies used a paired design, with

one kidney from each donor being preserved with MP and one

preserved with SCS. Halloran 1985 was the only study to not use

a paired design, instead randomising a donor to have both kidneys

preserved with MP or SCS.

The type of MP device used varied between studies. The most

commonly used device was the Waters Mox-100 pulsatile, which

was used by seven studies (Alijani 1985;Halloran 1985;Heil 1987;

Kwiatkowski 1996;Merion 1990;Mozes 1985;Veller 1994). The

LifePort Pulsatile Perfusion machine was used in six studies (Chen

2014c;Moers 2009;PPART 2010;Tedesco-Silva 2017;Wang

2017;Zhong 2017), the Gambro Pulsatile Perfusion machine was

used in van der Vliet 2001, and the APS-02 (Nikiso) machine was

used in Matsuno 1994.Amaduzzi 2011 did not report the type of

MP device used.

Excluded studies

Full details for individual studies can be found in the

Characteristics of excluded studies table.

Three studies compared different cold storage solutions (Alijani

1987;Baatard 1993;Wamser 1990); two compared different MP

solutions (Guarrera 2004;Guarrera 2004a); one compared re-

ﬂush solutions (Lodge 1993); two compared different MP addi-

tives (Polyak 1998;Polyak 2002); and two compared different MP

techniques (Tisone 1999;Wszola 2013).

Risk of bias in included studies

The following section contains an overview of some of the com-

mon biases present in the included studies. For further details on

each individual study please see Characteristics of included studies;

a summary of the risk of bias information for each study can be

found in Figure 2, and a summary of the of the total risk of bias

in different domains can be found in Figure 3.

11Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.

12Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.

Allocation

Four of the studies (Heil 1987;Moers 2009;PPART 2010;

Tedesco-Silva 2017) described appropriate methods of randomi-

sation and allocation concealment, resulting in a low risk of bias.

One study (Zhong 2017) did not describe randomisation or allo-

cation in detail, however all consecutive donors were assessed for

inclusion, with valid reasons given for any exclusions. Therefore,

the risk of bias remained low. Two studies (Alijani 1985;Merion

1990) described quasi-RCTs, with a paired alternating design; each

donor had one kidney preserved with SCS and the other with MP,

alternating between left and right. However, as these studies used

a paired design with consecutive donors, and good explanations

for any exclusions, our assessment was that the risk of selection

bias remained low.

In seven studies (Amaduzzi 2011;Chen 2014c;Kwiatkowski

1996;Matsuno 1994;Mozes 1985;van der Vliet 2001;Veller

1994) there was insufﬁcient information on randomisation and

allocation techniques to make a judgement of the risk of bias.

However, as these studies are all paired RCT, it is unlikely that

selection bias will be present unless the decision to include a donor

in the study was made after visualisation of the organs by the organ

retrieval team.

For the single study which did not use a paired design (Halloran

1985), the potential for selection bias is potentially higher. No

information was given regarding how patients were randomised,

however inclusion and randomisation of each donor happened

prior to procurement. This lowers the risk of selection bias, as

donors could not be selected based on features only apparent at

surgery.

Wang 2017 gave no informationon how kidneys were randomised,

and the authors were allowed to swap kidneys between groups. As

no intention-to-treat analysis was performed it was considered to

be at high risk of allocation bias. On the advice of referees during

the peer review process this study was included.

Blinding

Nine studies were considered to be at low risk of performance

bias; Moers 2009 performed adequate blinding at the time of or-

gan offer; PPART 2010 did not perform blinding, but did per-

form randomisation for which kidney was transplanted ﬁrst; the

remaining seven studies (Alijani 1985;Halloran 1985;Merion

1990;Tedesco-Silva 2017;van der Vliet 2001;Veller 1994;Zhong

2017) did not perform blinding but showed no signiﬁcant dif-

ference in CIT, suggesting that the organs preserved by different

methods were treated similarly.

Four studies (Kwiatkowski 1996;Matsuno 1994;Mozes 1985;

Wang 2017) were considered to be at high risk of performance

bias. In three of these studies (Kwiatkowski 1996;Matsuno 1994;

Mozes 1985) the CIT was signiﬁcantly longer in the MP group.

Kwiatkowski 1996 describes routinely transplanting the SCS kid-

ney prior to the MP kidney. As increased CIT is known to be detri-

13Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

mental, this generates a performance bias which may lessen the

predicted positive effects of MP. Wang 2017 perform no blinding

and no reporting of CIT. Therefore, one group may have routinely

been transplanted ﬁrst, adding bias to the results. In addition, it

is not stated whether assessors of acute rejection were blinded.

In three studies (Amaduzzi 2011;Chen 2014c;Heil 1987) there

was insufﬁcient information on blinding and CIT to make a judge-

ment of the risk of performance bias.

Although none of the studies performed blinding of the outcome

assessors, we deemed this to be an unlikely source of bias, given

the outcome measures chosen by most studies. For this reason,

14 studies were deemed to be at low risk of detection bias. Wang

2017 did not report blinding of outcome assessors however it’s

outcomes (non-standard deﬁnition of DGF and acute rejection)

put it at higher risk of detection bias.

Incomplete outcome data

Ten studies (Alijani 1985;Chen 2014c;Matsuno 1994;Merion

1990;Moers 2009;Mozes 1985;PPART 2010;Tedesco-Silva

2017;Veller 1994;Zhong 2017) provided either full follow-up

data for all included patients, or valid reasons for any exclusions,

and were therefore considered to be at low risk of attrition bias.

Three studies (Halloran 1985;Kwiatkowski 1996;Wang 2017)

were considered to be at high risk of attrition bias. In the Halloran

1985 study, 13 patients which were originally randomised to MP,

instead received SCS; no follow-up information was provided for

these patients so intention to treat analysis could not be performed.

In Kwiatkowski 1996, data on DGF was missing for six patients

with no explanation. In addition, the 10-year graft survival data

gave only percentages with no absolute numbers to indicate level of

follow-up. Wang 2017 had “time-zero biopsies” as an outcome, but

no data was given for the groups as a whole; only H+E stains and

electron microscopy from a single pair of kidneys are presented.

In three studies (Amaduzzi 2011;Heil 1987;van der Vliet 2001)

there was insufﬁcient information to make a judgement of the risk

of attrition bias.

Selective reporting

The majority of the studies (Alijani 1985;Chen 2014c;Heil

1987;Matsuno 1994;Merion 1990;Moers 2009;Mozes 1985;

PPART 2010;Tedesco-Silva 2017;van der Vliet 2001;Veller

1994;Zhong 2017) reported all expected outcomes in a complete

and unambiguous fashion.

The remaining three studies (Halloran 1985;Kwiatkowski 1996;

Wang 2017) were considered to be at high risk of reporting bias.

Halloran 1985 used a complex and unusual deﬁnition for DGF,

for unclear reasons. However, data included in our analysis was

taken directly from the number of dialyses in week one table; so

their reporting anomaly has not directly impacted on this meta-

analysis. Amaduzzi 2011 and Kwiatkowski 1996 did not report all

relevant data, and most of the data which was reported was either

incomplete or reported ambiguously with percentages rather than

absolute values. Wang 2017 used a non-standard deﬁnition of

DGF and failed to provide data on the number of participants

requiring dialysis in the ﬁrst week post-transplant. There were also

issues with selective reporting of the outcome ’time-zero biopsies’

described in further detail in the characteristics of included studies

table.

Other potential sources of bias

Several manuscripts had very short methods sections making full

assessment of further biases difﬁcult. Matsuno 1994 did not state

the duration of the study, whether they were consecutive cases, or

how inclusion/randomisation took place and was therefore con-

sidered to be at high risk of bias. Kwiatkowski 1996 was consid-

ered to be at high risk of bias- as the CIT was different between

the groups.

Another potential source of bias is the lack of intention-to-treat

analysis. Only one of the studies (PPART 2010) described using

intention to treat analysis. In two studies (Alijani 1985;Halloran

1985) a change in perfusion technique led to exclusion from the

study. In Moers 2009 a “switch in preservation methods changed

the initial randomization”. In Wang 2017 several kidneys were

swapped between groups and intention to treat analysis not per-

formed. In Zhong 2017 no grafts were swapped between groups

therefore intention to treat analysis was not performed. For the

remaining 10 studies (Amaduzzi 2011;Chen 2014c;Heil 1987;

Kwiatkowski 1996;Matsuno 1994;Merion 1990;Mozes 1985;

Tedesco-Silva 2017;van der Vliet 2001;Veller 1994) there was

insufﬁcient information to assess whether intention-to-treat anal-

ysis had been performed.

One potential source of bias in all studies was the lack of blinding-

the surgical team performing the transplant were aware of treat-

ment allocation. This information may have changed the decision

threshold to dialyse in the early post-operative period, depending

on physician and surgeon pre-conceptions.

Effects of interventions

See: Summary of ﬁndings for the main comparison

Hypothermic machine perfusion versus static cold storage for

deceased donor kidney transplantation

Hypothermic machine perfusion versus static cold

storage

See Summary of ﬁndings for the main comparison

The results for Amaduzzi 2011 could not be included in any of

the meta-analyses.

14Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Delayed graft function

All studies reported DGF as their primary outcome. Other than

Wang 2017, all studies used the deﬁnition stated in our methods

section, or provided data on how many patients required dialysis in

the ﬁrst week post transplant. This meant that 2138 participants

could be included in the meta-analysis. The use of HMP reduces

the risk of DGF (Analysis 1.1 (14 studies, 2138 participants): RR

0.77, 95% CI 0.67 to 0.90; P = 0.0006; I2= 33%; high certainty

evidence). This equates to 10.35 HMPs required to prevent one

case of DGF. The level of heterogeneity between studies as mea-

sured by I2test was low. A funnel plot including data on DGF

incidence can be found in Figure 4. This plot is symmetrical and

does not suggest the presence of publication bias.

Figure 4. Funnel plot of comparison: 1 Hypothermic machine perfusion versus static cold storage,

outcome: 1.1 Delayed graft function.

Sensitivity analysis was performed. Moers 2009 was the largest

study, and contributed 752 of 2138 participants. When this study

was excluded from the meta-analysis, the risk of DGF (RR 0.77,

95% CI 0.65 to 0.91; P = 0.003) and the level of heterogeneity (I

2= 39%; P = 0.08) were not affected. Four studies were assessed

to have high risk of bias in at least one category (Halloran 1985;

Kwiatkowski 1996;Matsuno 1994;Mozes 1985 (Figure 2). Re-

moving all four of these studies from the meta-analysis, the risk of

DGF (RR 0.79, 95% CI 0.64 to 0.97; P = 0.03) remained similar,

but a medium level of heterogeneity was found (I2= 52%; P =

0.03).

15Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Wang 2017 did not report on the number of patients requiring

dialysis in the ﬁrst week post-transplant (the deﬁnition of DGF

used in this review) and therefore could not be included in our

meta-analysis. Using their non-standard deﬁnition of DGF they

reported a signiﬁcant improvement in DGF incidence with HMP.

Sensitivity analysis was performed, adding the Wang 2017 data

(using their non-standard deﬁnition of DGF) to the rest of the

studies; the relative risk of DGF (RR 0.77, 95% CI 0.66 to 0.89;

P = 0.0003) remained similar, and the level of heterogeneity re-

mained low (I2= 32%; P = 0.11).

Amaduzzi 2011 reported “No statistically signiﬁcant difference

was found between graft preserved by machine perfusion and

cold storage in terms of DGF rate (37,8% vs 30%, respectively

p>0.05).”

To ensure robustness of the model, the main analysis (Analysis

1.1) was repeated using a ﬁxed effects model; HMP continued to

demonstrate a signiﬁcant relative risk reduction when compared

to SCS (RR 0.76, 95% CI 0.68 to 0.86; P < 0.0001), and hetero-

geneity remained low (I2= 33%; P = 0.11).

Subgroup analyses were performed to look for differing treatment

effects in various groups. Initial subgroup analysis compared DBD

with DCD donors. Six studies looked at DCD (Chen 2014c;

Kwiatkowski 1996;Matsuno 1994;PPART 2010;van der Vliet

2001;Zhong 2017), three studies looked at DBD (Mozes 1985;

Tedesco-Silva 2017;Veller 1994), four studies did not specify

the donor type (Alijani 1985;Halloran 1985;Heil 1987;Merion

1990), and one study (Moers 2009) reported both DCD and DBD

data separately. HMP reduces DGF in the DCD group (Analysis

1.2.1 (7 studies, 772 participants): RR 0.75, 95% CI 0.64 to 0.87;

P = 0.0002; I2= 1%; high certainty evidence), as well as in the

DBD group (Analysis 1.2.2 ( 4 studies, 971 participants): RR

0.78, 95% CI 0.65 to 0.93; P= 0.006; I2= 0%; high certainty evi-

dence). The number of perfusions required to prevent one episode

of DGF was 7.26 and 13.60 in DCD and DBD grafts respectively.

The level of heterogeneity in both the DCD and DBD subgroups

was low. There was no evidence for a differing treatment effect in

DBD and DCD donors (P = 0.72). Of note, due to the publication

date of the four studies which did not specify donor type (Alijani

1985;Halloran 1985;Heil 1987;Merion 1990) these likely repre-

sent DBD donors. A separate analysis was performed to assess the

robustness of the subgroup ﬁndings including these studies in the

DBD subgroup; similar results were found with HMP leading to

a relative risk reduction (RR 0.82, 95% CI 0.66 to 1.02; P = 0.07)

and there remained no evidence of differing treatment effects in

DCD and DBD grafts (P = 0.51).

Subgroup analysis was performed looking at the era of study. Five

studies reporting DGF in a standard fashion were performed in

the last decade (Chen 2014c;Moers 2009;PPART 2010;Tedesco-

Silva 2017;Zhong 2017). All ﬁve of these ’modern era’ studies used

the LifePort perfusion machine. Studies performed over a decade

ago (’pre 2008’) used older perfusion machines (Waters Mox-100,

Gambro pulsatile perfusion machine, or Nikiso machine). HMP

reduced the risk of DGF when compared with SCS in studies

performed in the ’modern era’; (Analysis 1.3.1 (5 studies, 1355

participants): RR 0.77, 95% CI 0.66 to 0.91; P = 0.002; I2=

15%; high certainty evidence). Studies published ’pre-2008’ also

demonstrated a reduction in the risk of DGF with HMP (Analysis

1.3.2 (9 studies, 783 participants): RR 0.78, 95% CI 0.61 to

0.99; P = 0.04; I2= 46%; high certainty evidence). There was no

evidence for a differing treatment effect in studies performed in

the ’modern era’ vs studies performed ’pre-2008’ (P = 0.97).

Subgroup analysis basedon shor t (< 24 hours) or long (≥24 hours)

mean cold ischaemic times (CIT) was also performed. Six studies

reported short CIT (Matsuno 1994;Merion 1990;Moers 2009;

PPART 2010;Veller 1994;Zhong 2017), six studies reported long

CIT (Alijani 1985;Halloran 1985;Kwiatkowski 1996;Mozes

1985;Tedesco-Silva 2017;van der Vliet 2001), and two studies did

not report CIT (Chen 2014c;Heil 1987). There was a reduction

in the risk of DGF with HMP using a long CIT (Analysis 1.4.2

(6 studies, 725 participants): RR 0.69, 95% CI 0.57 to 0.83; P

< 0.0001; I2= 16%). In the six studies reporting a short CIT

(1288 participants), There was little or no reduction in the risk

of DGF with HMP and short CIT (Analysis 1.4.1 (6 studies,

1288 participants): RR 0.86, 95% CI 0.70 to 1.04; P = 0.11; I

2= 28%). When the two studies which did not report CIT were

removed from the analysis, a test for differing treatment effects

provided no evidence that the effect of HMP was different between

subgroups with short versus long CIT (P = 0.11). The most highly

powered study (Moers 2009) reported short mean CIT (15 hours)

and found a signiﬁcant reduction in DGF incidence with HMP

(adjusted odds ratio, 0.57; P = 0.01).

Although initially planned in the protocol, subgroup analyses sep-

arating standard versus ECD, and HMP during transport versus

HMP at the recipient centre, were not completed. This was due to

insufﬁcient reporting of these subgroups across the included stud-

ies. We feel this does not limit the review, as the original reason for

considering these analyses was to investigate sources of signiﬁcant

heterogeneity, and heterogeneity was found to be low as described

above.

The highly powered Moers 2009 performed subgroup analysis to

compare SCD with ECD. Incidence of DGF was found to be

lower with HMP versus SCS in both the SCD (n = 484, adjusted

OR 0.59, 95% CI 0.35 to 1.02) and ECD (n = 188, adjusted OR

0.51, 95% CI 0.24 to 1.09) subgroups. There was no evidence for

different treatment effect in these two subgroups (P = 0.75).

Overall, there is high certainty evidence that HMP reduces the

risk of DGF.

One-year graft survival

Eight studies reported one-year graft survival data (Chen 2014c;

Halloran 1985;Moers 2009;PPART 2010;Tedesco-Silva 2017;

van der Vliet 2001;Veller 1994;Zhong 2017) (see Table 2). Many

of the studies did not provideinformation on how the graft survival

16Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

percentages were calculated. Often only a percentage is given with

no indication of statistical signiﬁcance or the number of people

who were followed up to one year. There is not enough informa-

tion in the studies to analyse the data in a time-to-event fashion,

as recommended by Cochrane and as speciﬁed in our protocol.

Unfortunately, it was not possible to meta-analyse the data; many

studies do not provide raw data and studies use different deﬁni-

tions of graft survival (some censoring for death, others not, some

providing raw data, others giving the output of a Cox regression

model which adjusts for other factors).

The two most powerful studies (Moers 2009 and Zhong 2017)

both reported statistically signiﬁcant beneﬁts in one-year graft sur-

vival with HMP versus SCS. Moers 2009, which included mostly

DBD kidneys, used appropriate time-to-event analysis and re-

ported a statistically signiﬁcant improvement with HMP (90%

SCS versus 94% HMP, log-rank P = 0.04; Cox HR for one-year

graft loss, 0.52; P = 0.03). Zhong 2017, which included only DCD

kidneys, used log-rank test analysis and also reported a statisti-

cally signiﬁcant improvement with HMP (93% SCS versus 98%

HMP; P = 0.026). As described in Table 2, the remaining studies

report non-signiﬁcant differences in one-year graft survival (Chen

2014c;Halloran 1985;PPART 2010;Tedesco-Silva 2017), or do

not provide P values (van der Vliet 2001;Veller 1994).

Whilst Mozes 1985 does not report one-year graft survival directly,

there is a table reporting graft loss. Using this table, one-year graft

survival estimates of 60.7% and 65.4% in SCS and HMP groups

respectively were calculated. However, mathematical inconsisten-

cies were identiﬁed in the table, so these calculations are likely

inaccurate.

Heil 1987 only provided graft survival data onth ose kidneyswhich

experienced DGF. They reported that kidneys which experienced

DGF had one-year graft survival rates of 74% and 89% for SCS

and HMP respectively (P < 0.05). However, they did not state how

many of the 25 kidneys which experienced DGF were followed

up for the full year.

Primary non-function

Seven studies (Halloran 1985;Matsuno 1994;Moers 2009;Mozes

1985;PPART 2010;Tedesco-Silva 2017;van der Vliet 2001) re-

ported on PNF. There was no evidence that the use of HMP af-

fected the risk of developing PNF when compared to SCS (Anal-

ysis 1.5 (7 studies, 1387 participants): RR 0.88, 95% CI 0.58 to

1.33; P = 0.55; I2= 0%; high certainty evidence). A funnel plot

showed no signs of asymmetry (Figure 5). The results remained

unchanged when studies assessed to have a high risk of bias in at

least one area (Halloran 1985;Matsuno 1994;Mozes 1985) were

removed from the analysis (RR 1.05, 95% CI 0.37 to 3.02; P =

0.92).

17Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Figure 5. Funnel plot of comparison: 1 Hypothermic machine perfusion versus static cold storage,

outcome: 1.5 Primary non-function.

Duration of delayed graft function

Six studies (Heil 1987;Matsuno 1994;Moers 2009;Mozes 1985;

PPART 2010;Tedesco-Silva 2017) reported on duration of DGF.

Only four of these studies could be included in the meta-analy-

sis; three included mean and SD data (Heil 1987;Mozes 1985;

Tedesco-Silva 2017), and Matsuno 1994 provided means and a P

value which allowed imputation of a conservative SD estimate. It

is uncertain whether HMP reduces the duration of DGF (Analysis

1.6 (4 studies, 220 participants): MD -1.23 days, 95% CI -5.87

to 3.40; P = 0.60; very low certainty evidence). The level of het-

erogeneity was high (I2= 88%), with two studies reporting statis-

tically signiﬁcant reductions in DGF duration with HMP (Heil

1987;Matsuno 1994) and one study reporting statistically sig-

niﬁcant increases in DGF duration with HMP (Mozes 1985). It

is important to note that Analysis 1.6 does not display all of the

available evidence on DGF duration, only that evidence presented

in a way to allow meta-analysis.

Means and SD could not be imputed for Moers 2009 or PPART

2010 which only reported median, range and a P value for the

duration of DGF. Whilst this prevented their inclusion in the

meta-analysis, they do provide further evidence. PPART 2010

reported no signiﬁcant difference in duration of DGF; 7 days

(range 1 to 33) for SCS versus 5 days (range 1 to 92) for HMP (P

= 0.40). However, the European study by Moers 2009 did report a

signiﬁcant reduction in DGF duration with HMP; 13 days (range

1 to 41) for SCS versus 10 days (range 1 to 48) for HMP (P =

0.04).

Overall, three studies report a signiﬁcant reduction in DGF (Heil

1987;Matsuno 1994;Moers 2009) duration with HMP, one re-

ports an increase in DGF duration (Mozes 1985), and two were

inconclusive (PPART 2010;Tedesco-Silva 2017).

Long-term graft survival

Three studies (Kwiatkowski 1996;Moers 2009;Zhong 2017) pro-

vided data on longer term transplant survival. Moers 2009 con-

tinued to follow up all 672 participants from their main analysis

as well as an additional 80 participants from their extended DCD

dataset for three years. Overall, three-year graft survival was signif-

icantly improved by HMP versus SCS (91% versus 87%; adjusted

hazard ratio for transplant failure, 0.60; P = 0.04). This beneﬁt

was most pronounced in the subgroup of grafts from ECD (86%

versus 76%; adjusted hazard ratio, 0.38; P = 0.01). Interestingly,

18Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

the authors state that a signiﬁcant three-year graft survival beneﬁt

was not seen in the DCD subgroup, but no further data or expla-

nation was given. This could simply represent a lack of power due

to the smaller number of patients in this subgroup (164 partici-

pants).

Zhong 2017 followed all 282 included participants for three years.

The log-rank test was used to analyse three-year graft survival,

censoring for death (in those who died with a functioning graft). In

their large cohort of DCD recipients, the three-year graft survival

rate in the HMP group was signiﬁcantly higher than that in the

SCS group (93% versus 82%; P = 0.036).

Kwiatkowski 1996 provided the longest follow up data, reporting

10-year graft survival. The group which received HMP had im-

proved 10-year graft survival when compared to the SCS group

(68.2% versus 43.0%), however this was not statistically signif-

icant (P = 0.08). This may be a result of the low power of the

study, with 37 patients in each arm. The study did report a signiﬁ-

cant difference in the frequency of “return to dialysis” between the

groups (50% SCS versus 25% HMP; P = 0.02), however this does

not appear to be a pre-speciﬁed outcome and may suffer selective

reporting bias.

Patient survival

Four studies reported on one-year patient survival (Halloran 1985;

Moers 2009;PPART 2010;Tedesco-Silva 2017). Halloran 1985

reported survival data calculated from Cox regression. As this was

the only study to provide time-to-event data, meta-analysis using

this could not be applied. Three studies (Moers 2009;PPART

2010;Tedesco-Silva 2017) reported the number of patients who

had died at one year. These studies could be combined. There

no evidence that HMP has an effect on one-year patient survival

(Analysis 1.7 (3 studies, 920 participants): RR 0.99, 95% CI 0.95

to 1.03; P = 0.58; I2= 20%; low certainty evidence). Halloran

1985 also reported a non-signiﬁcant impact on one-year patient

survival (88.8% SCS versus 94.9% HMP; P = “not signiﬁcant”).

Whilst Mozes 1985 does not report one-year patient survival di-

rectly, there is a table reporting patient survival. Using this table,

one-year patient survival estimates of 89.0% and 89.7% in SCS

and HMP groups respectively were calculated. However, mathe-

matical inconsistencies were identiﬁed in the table, so these calcu-

lations are likely inaccurate.

Two studies (Kwiatkowski 1996;Moers 2009) provided longer

follow-up of patients. Moers 2009 simply states that there were no

signiﬁcant differences in th ree-year patient survival between HMP

and SCS groups (n = 752). Kwiatkowski 1996 reports that there

were no signiﬁcant differences in 10-year patient survival between

HMP and SCS groups (86.5% versus 83.7%, n = 72; P = ns).

Economic implications

Two reports performed economic evaluation. Both of these per-

formed their analysis based on the results of Moers 2009. Both

reports conﬁrm cost savings with HMP, one in the US and one

in the European setting. Groen 2012 reported estimated mean

total costs of $8668 with HMP versus $11,294 with SCS in the

European setting. Garﬁeld 2009 performed US projections and

reported that HMP improved mean costs when compared to SCS

in both standard criteria donors ($92,561 versus $104,118) and

ECD ($106,012 versus $114,530). One of the main reasons for

the cost savings, were lower dialysis costs in the HMP group due

to decreased incidence of DGF.

Quality of life

No studies reported quality of life.

Hospital stay

Four studies (Chen 2014c;Moers 2009;Tedesco-Silva 2017;

Wang 2017) reported on length of hospital stay. Reporting was

insufﬁcient to allow meta-analysis. Chen 2014c reported a signif-

icantly shorter hospital stay with HMP compared to SCS (16.8

days versus 21.4 days; P = 0.046), but did not state whether these

values were means or medians, and did not provide standard de-

viations or inter-quartile ranges. Wang 2017 reported a signiﬁ-

cantly shorter mean hospital stay with HMP compared with SCS

(12.3 ± 4.4 versus 19.4 ± 7.2 respectively; P = 0001). Moers 2009

found no signiﬁcant difference in the median length of hospital

stay between groups (18 days SCS versus 19 days HMP; P = 0.78).

Tedesco-Silva 2017 also found no signiﬁcant difference in hospital

stay between groups (15.6 ± 11.7 days SCS versus 13.5 ± 10.5

HMP; P = 0.629).

Graft function

Five studies reported on graft function (Moers 2009;PPART

2010;Tedesco-Silva 2017;van der Vliet 2001;Zhong 2017). The

following measures were reported: SCr, creatinine clearance, esti-

mated glomerular ﬁltration rate (eGFR), area under the curve of

creatinine for the ﬁrst two weeks post-transplant, creatinine reduc-

tion ratio post-transplant, and urine output. These were reported

at time points ranging from seven days to one year. As studies

reported different outcomes at different time points meta-analysis

could not be completed.

Moers 2009 reported creatinine clearance at 14 days, and area

under the creatinine curve during the ﬁrst 14 days. Median cre-

atinine clearance at 14 days was not signiﬁcantly different in the

HMP group compared with the SCS group (42 HMP versus 40

SCS; P = 0.25). By performing daily SCr measurements, Moers

2009 was able to calculate area under the curve for the ﬁrst 14

days post-transplant, with a lower value equating to better graft

function. HMP signiﬁcantly decreased the median area under the

curve compared to SCS (1456 HMP versus 1787 SCS; P = 0.01).

19Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

This difference is to be expected given the decreased incidence of

DGF with HMP which was reported by the same study.

Zhong 2017 reported SCr and urine output in the ﬁrst week post-

transplant. Data was collected on both of these outcomes every

day for the ﬁrst seven days post-transplant. “Analysis for repeated

measurement data” was used to compare SCS with HMP. They

reported that HMP led to a signiﬁcant decrease in median SCr (F

= 5.165; P = 0.024), and a signiﬁcant increase in median urine

output (F = 3.962; P = 0.047), in the ﬁrst seven days post-trans-

plant.

PPART 2010 reported on the creatinine reduction ratio between

day one and day two, and the creatinine reduction ratio between

immediately pre-transplant and day ﬁve. They also reported eGFR

at day seven, three months, and one year. There were no signiﬁcant

differences in any of these values between the HMP and SCS

groups, in keeping with similar DGF rates in each group.

Tedesco-Silva 2017 provide data for mean SCr and eGFR (± SD)

at time points of 7, 14, 21, 28, and 365 days. They reported that

“mean serum creatinine was signiﬁcantly lower in the HMP group

compared with the SCS at both 14 days (3.0 ± 2.2 HMP versus 4.1

± 3.2 mg/dL; P = 0.005) and 21 days (2.3 ± 1.8 HMP versus 3.0 ±

2.6 mg/dL; P = 0.021)”. Although these results are signiﬁcant, they

did not perform statistical corrections for multiple comparisons,

and found no evidence for differences in SCr at any of the other

three time points, or signiﬁcant differences in eGFR at any of the

ﬁve time points.

van der Vliet 2001 reported mean SCr (± SD) at 3 months post-

transplant; there was no signiﬁcant difference between HMP and

SCS groups (174 ± 25 HMP versus 162 ± 11 µmol/L SCS group;

P = 0.68).

Overall there is no evidence that long-term graft function is af-

fected. The signiﬁcant improvements seen in short-term graft

function are analogous to the signiﬁcant improvements seen in

DGF incidence.

Episodes of acute rejection or ﬁbrosis on biopsy

Five studies (Kwiatkowski 1996;Moers 2009;PPART 2010;

Tedesco-Silva 2017;Wang 2017) reported acute rejection. As they

reported on acute rejection over different time periods meta-anal-

ysis including all studies was not possible. Only PPART 2010 and

Tedesco-Silva 2017 had a shared time point; acute rejection within

one year. HMP may make little or no difference to acute rejection

at one year (Analysis 1.8 (2 studies, 248 participants): RR 0.66,

95% CI 0.37 to 1.17; P = 0.15; I2= 13%; low certainty evidence).

In addition to the one year data, PPART 2010 also reported a lower

incidence of biopsy-proven acute rejection in the HMP group

within the ﬁrst three months (n = 90; 22% SCS versus 7% HMP; P

= 0.06), although this is not signiﬁcant. Tedesco- Silva 2017 reports

incidence of treated acute rejection within the ﬁrst month (n = 160;

16.3% SCS versus 8.8%; P = 0.151); again the lower incidence of

acute rejection in the HMP group is not signiﬁcant. Moers 2009

reported on incidence of biopsy-proven acute rejection at 14 days,

and found similar rates between the groups (n = 672; 13.7% SCS

versus 13.1% HMP; P = 0.91).

Kwiatkowski 1996 reported incidence of treated acute rejection

during the full duration of follow-up (median 22 months, range

7 to 37 months). They found that incidence of acute rejection

was lower with HMP (n = 74; 51% SCS versus 35% HMP) but

this was not statistically signiﬁcant. Kwiatkowski 1996 did not

state whether the follow-up duration was similar between groups,

therefore the validity of these results are questionable.

Wang 2017 reported on incidence of acute rejection, however it

is not stated whether this is biopsy-proven rejection or clinical

rejection. It is also not stated over what time period acute rejection

data was collected over. They report acute rejection in 1/24ki dneys

undergoing HMP and 2/24 kidneys undergoing SCS (P = 0.551),

Fibrosis on biopsy was not reported by any studies.

Number of allograft ultrasound scans

No studies reported the number of ultrasound scans.

Number of allograft biopsies

No studies reported the number of allograft biopsies.

Normothermic machine perfusion versus

hypothermic machine perfusion or static cold storage

To date no RCT has been published which includes a NMP arm.

Our search identiﬁed one ongoing RCT comparing NMP with

SCS which could be included in future updates of this review

(Hosgood 2017).

D I S C U S S I O N

Summary of main results

Overall, 16 studies (2266 participants) were included. These stud-

ies all compared HMP with standard SCS. None of the included

studies investigated (sub)NMP, however one ongoing normother-

mic study was identiﬁed (Hosgood 2017).

The use of HMP reduced the rate of DGF compared to SCS (RR

0.77, 95% CI 0.67 to 0.90; P = 0.0006, high certainty evidence).

This result was also observed for both DCD (7 studies, 772 par-

ticipants: RR 0.75, 95% CI 0.64-0.87; P = 0.0002), and DBD

subgroups (7 studies, 971 participants: RR 0.78, 95% CI 0.65-

0.93; P = 0.006). There was no evidence for differing treatment

effect between these groups (P = 0.72). That said, as the overall

incidence of DGF is higher in the DCD subgroup, HMP pre-

vents more episodes of DGF in DCD grafts in absolute terms.

Therefore, the number of HMP required to prevent one episode

20Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

of DGF (number needed to treat; NNT) is lower in DCD grafts;

7.26 and 13.60 in DCD and DBD grafts respectively. There was

no evidence that the beneﬁcial effect of HMP varies depending

on duration of CIT (Analysis 1.4). Studies published in the last

decade (’modern era’) all used the LifePort HMP device. Clearly

these studies are especially relevant for practice today. In these

’modern era’ studies, HMP with LifePort decreased the incidence

of DGF compared with SCS (5 studies, 1355 participants: RR

0.77, 95% CI 0.66 to 0.91; P = 0.002; high certainty evidence).

Economic analysis based on results from the large Moers 2009

study suggest that HMP is cost effective in both the European and

US setting. The main reason for cost savings in the HMP group

was the lower incidence of DGF. The reported risk of DGF with

HMP reported by Moers 2009 (RR 0.77) was similar to the overall

risk from our meta-analysis (RR 0.78). Therefore, the cost savings

reported based on results from Moers 2009 are generalisable to

our meta-analysis as a whole; we feel it is almost certain that HMP

results in cost savings.

Although graft survival was reported in some form by 10 studies,

it was insufﬁciently accurately reported to allow meta-analysis. A

summary of all studies reporting on overall one-year graft survival

is provided in Table 2. The EuroTransplant study (Moers 2009)

reported a signiﬁcant graft survival beneﬁt of HMP compared

with SCS, at both one year (90% SCS versus 94% HMP, log-rank

P = 0.04; Cox HR for one-year graft loss, 0.52; P = 0.03) and

three years (87% SCS versus 91% HMP; adjusted hazard ratio for

transplant failure, 0.60; P = 0.04). It is important to note that this

study included predominantly DBD kidneys. Zhong 2017 used

log-rank test analysis and also reported a statistically signiﬁcant

survival beneﬁt of HMP compared with SCS, at both one (93%

SCS versus 98% HMP; P = 0.026) and three years (82% SCS

versus 93% HMP; P = 0.036) in their cohort of DCD kidney

recipients. Both of these studies were well designed, and well pow-

ered. Together they provide strong evidence that HMP improves

graft survival in kidneys from both DBD and DCD donors. Other

studies reporting graft survival were less well powered and did not

report signiﬁcant differences in transplant survival.

Overall, we feel that transplant centres should consider the use of

HMP in all kidney transplants on the basis of the beneﬁts listed

above (reduced incidence of DGF, cost savings, and improved

graft survival), which have all been demonstrated/conﬁrmed by

studies in the modern era (those performed in the last decade).

This is especially important in DCD kidneys, where the number

of perfusions needed to prevent one episode of DGF is far lower

(7.26 versus 13.60 in DBD kidneys).

Four studies reported on patient survival and none of these found

signiﬁcant differences between HMP and SCS. It is likely that any

effect on patient survival is small, and beyond the detection size

of these samples.

Based on high quality evidence from 7 studies, there was no evi-

dence that HMP has an impact on incidence of PNF (RR 0.88,

95% CI 0.58 to 1.33; P = 0.55). There are two explanations for

this. PNF is an inevitable event which HMP has no effect. Alter-

natively, this is a type 2 statistical error, as the incidence of PNF is

low and it may be difﬁcult to demonstrate signiﬁcant differences

in PNF incidence.

There is some good evidence that HMP reduces the duration of

DGF, with three studies ﬁnding reductions in DGF duration (in-

cluding the highly powered Moers 2009). However, one study

contradicts this (Mozes 1985) and two found no signiﬁcant dif-

ferences. Not all studies provided mean and SD data, and these

could not be imputed due to evidence of positive skew, therefore

meta-analysis was not possible. The contradictory evidence from

these studies may be due to hospital and physician differences in

criteria for dialysis. Further studies looking at duration of DGF

would likely change the estimate therefore this evidence is very

low certainty.

Five studies reported on transplant function. This was reported

in various ways (based on SCr or urine output), at various time

points, preventing meta-analysis. Three studies reported signiﬁ-

cant improvements in graft function in the short term with HMP

(Moers 2009;Tedesco-Silva 2017;Zhong 2017). This is in keep-

ing with the lower incidence of DGF in the HMP group reported

by these studies. The three studies (PPART 2010;Tedesco-Silva

2017;van der Vliet 2001) which looked at graft function at time

points greater than one month, found no signiﬁcant differences

in long-term graft function, although the level of certainty is low.

Five studies reported on acute rejection. All of these reported a

lower incidence of acute rejection with the use of HMP, however

this result was not signiﬁcant in any studies. Reporting at various

time points prevented meta-analysis of all ﬁve studies. Only two

studies could be included in meta-analysis; HMP may make little

or no difference to acute rejection at one year (RR 0.66, 95% CI

0.37 to 1.17; P = 0.15).

Four studies reported length of hospital stay. Two reported no

signiﬁcant differences between HMP and SCS (Moers 2009;

Tedesco-Silva 2017). Two small studies (Chen 2014c;Wang 2017)

reported a signiﬁcant reduction in hospital stay with HMP.

Other secondary outcomes (quality of life, number of ultrasound

scans, number of biopsies) were not reported by any studies.

Overall completeness and applicability of

evidence

The 16 studies included in this review were from a range of differ-

ent locations (USA, Europe, China, Japan, Canada, South Africa

and Brazil). Some studies reported on the use of HMP in DCD

kidneys and some on DBD kidneys. Studies with both short and

long mean CIT were also well represented. Many of the studies

were reported in the last decade. Overall, this makes the results of

this review generalisable and therefore applicable to many differ-

ent transplant settings.

DGF data was available from all studies, although reporting by

Wang 2017 was incompatible with the standard deﬁnition of DGF

21Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

used in this review. Our main secondary outcome, one-year graft

survival, was only reported by seven studies, and insufﬁcient re-

porting prevented meta-analysis. With the exception of one-year

graft survival and PNF, our secondary outcomes were reported by

a minority of studies, and differences in reporting often prevented

meta-analysis. The authors of several studies were contacted to try

and gather additional unreported data. Unfortunately, none of the

corresponding authors responded to inquiries. In one instance this

prohibited the inclusion of the results of this study in our meta-

analyses (Amaduzzi 2011).

Moers 2009 was a large study and contributed to a lot of the

outcomes included in this review. It could therefore be argued that

this study dominates our results. However, the evidence from this

study was gathered from 60 different hospitals throughout Europe,

and included DBD, DCD, SCD and ECD, so results from this

study are generalisable to the current European setting.

We have reported numbers of perfusions needed to prevent one

episode of DGF in our results. This number depends on the inci-

dence of DGF, so these ﬁgures may not be applicable to transplant

centres which have particularly high or low rates of DGF.

Quality of the evidence

A summary of identiﬁed biases can be found in the Risk of bias

in included studies section above. Where bias could be assessed,

studies were generally well designed leading to a low risk of bias.

Wang 2017 was considered to be at high risk of bias. In some

studies there was a tendency to leave the HMP kidney for longer.

The resulting increase in CIT introduces bias, and may lead to

an underestimate of the positive effect of HMP in these studies.

Many of the older studies (especially those published before 2000)

had very short manuscripts making risk of bias difﬁcult to assess.

The primary outcome of all included studies was incidence of

DGF. This outcome is measured in the ﬁrst week post-transplant,

whilst the patient is still in hospital. This means that participants

were very unlikely to be lost to follow-up and there was virtually no

missing data for the outcome of DGF. In addition, this outcome

tended to be reported in a standardised fashion, with studies simply

reporting raw data for the numbers of patients with DGF in each

group, allowing inclusion of all studies except Wang 2017 in meta-

analysis. This resulted in high certainty evidence for this outcome.

None of our other outcomes were reported by all studies. In ad-

dition, other outcomes tended to be reported in different ways

by different studies, which often prevented inclusion of all studies

into meta-analysis. This meant that the quality of evidence for

outcomes other than incidence of DGF was lower (see Summary

of ﬁndings for the main comparison for more information).

Potential biases in the review process

We attempted to limit biases at every stage in our review. The

search for studies was performed in a systematic fashion using the

Cochrane Kidney and Transplant Specialised Register. Two inde-

pendent authors screened the identiﬁed studies prior to inclusion

in the review. A standardised data extraction form was used to

collect data from included studies. This was done independently

by two authors, and any discrepancies were resolved. Subgroup

analysis was only performed if pre-speciﬁed in our protocol, to

limit bias from multiple comparisons. There is however always a

possibility that we failed to identify some relevant studies.

Agreements and disagreements with other

studies or reviews

O’Callaghan 2013 was the previous large meta-analysis comparing

HMP with SCS. They also used incidence of DGF as their primary

outcome. They included seven RCTs in their meta-analysis, all of

which are also included in our review. O’Callaghan 2013 reported

a signiﬁcant decrease in DGF with HMP, reporting a RR of 0.81

(similar to our meta-analysis). As our review was able to include

more studies we were able to demonstrate a signiﬁcant reduction

in DGF in both DCD and DBD subgroups, which O’Callaghan

2013 did not demonstrate. As in our review, O’Callaghan 2013

was not able to perform meta-analysis of graft survival data. In

contrast to O’Callaghan 2013, there are now sufﬁcient studies to

provide strong evidence that HMP leads to improved graft survival

compared to SCS.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There is high certainty evidence that HMP reduces the incidence

of DGF when compared to SCS, in both DBD and DCD kid-

neys. The number of perfusions required to prevent one episode of

DGF was 7.26 and 13.60 in DCD and DBD kidneys respectively,

demonstrating that HMP is especially beneﬁcial in DCD grafts.

Previous economic analysis suggests that this alone makes HMP a

cost-effective intervention. HMP may also decrease the duration

of DGF when it develops.

There is strong evidence that HMP has a positive impact on trans-

plant survival in both the short and long term, in both DBD

and DCD grafts. This is to be expected given previous research

has shown the DGF is associated with higher rates of kidney loss

(Yarlagadda 2009).

Overall, there is high certainty evidence for the beneﬁts of HMP

in terms of incidence of DGF, the cost savings that this has been

shown to produce, and the improved transplant survival (all of

which have been demonstrated/conﬁrmed by studies published in

22Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

the last decade). This is especially important in DCD kidneys,

where the number of perfusions needed to prevent one episode of

DGF is far lower (7.26 versus 13.60 in DBD kidneys).

Implications for research

Further studies comparing HMP with SCS and reporting only

DGF incidence are not required. Any new studies should include

data on duration of DGF and incidence of acute rejection. Data

should also be included to allow meta-analysis of transplant sur-

vival in a time-to-event fashion.

Follow-up reports detailing long-term graft survival from partic-

ipants of the studies already included in this review would be an

efﬁcient way to generate long-term graft survival data. This is vital

in assessing the long-term beneﬁts of HMP.

Economic analysis based on the results of this review would help

cement HMP as the standard preservation method in deceased

donor kidney transplantation.

RCTs investigating (sub)NMP are required.

As described above, current studies fail to provide evidence of a

beneﬁt in terms of PNF. Research investigating the use of per-

fusion parametrics such as ﬂow, pressure and resistance, to per-

form viability assessment may be useful in preventing incidences

of PNF.

A C K N O W L E D G E M E N T S

The author team would like thank the referees and to acknowl-

edge the ongoing help and assistance of the Cochrane Kidney

and Transplant group. The research was funded in part by the

National Institute for Health Research Blood and Transplant Re-

search Unit (NIHR BTRU) in Organ Donation and Transplan-

tation at the University of Cambridge in collaboration with New-

castle University and in partnership with NHS Blood and Trans-

plant (NHSBT). The views expressed are those of the author(s)

and not necessarily those of the NHS, the NIHR, the Department

of Health or NHSBT.

R E F E R E N C E S

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References to other published versions of this review

Figueiredo 2015

Figueiredo RS, Moir JA, Talbot D, Wilson CH.

Normothermic and hypothermic machine perfusion

preservation versus static cold storage for deceased

donor kidney transplantation. Cochrane Database of

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14651858.CD011671

∗Indicates the major publication for the study

28Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Alijani 1985

Methods •Study design: quasi-RCT

•Duration of study: not reported

•Duration of follow-up:

Participants •Country: Washington USA

•Setting: paired kidneys were transplanted at 22 institutions

•58 kidneys from 29 donors. Originally there were 38 donors, but 8 were excluded

because one kidney was discarded and 1 was excluded because preservation method was

changed

•Donor characteristics

◦Mean age ± SD (years): not reported

◦Number of DCD: not reported

◦Number of ECD: not reported

◦Donor sex (M/F); not reported

◦Inclusion criteria: not explicitly stated

◦Exclusion criteria: not explicitly stated

•Recipient characteristics

◦Inclusion criteria: not explicitly stated

◦Exclusion criteria: not explicitly stated

◦Recipient sex (M/F): not reported

◦Mean age ± SD (years): not reported

Interventions •One kidney from each pair assigned to MP and the other to SCS, alternating

between left and right kidneys

Machine perfusion

•Waters Mox-100 pulsatile perfusion machine using plasma protein fraction

perfusate

Static cold storage

•Solution: Euro-Collins

Mean CIT

•Time did not differ signiﬁcantly between the groups: 29.68 hours in the SCS

group and 32.50 hours in the MP group

Outcomes •DGF: requirement for dialysis during the ﬁrst week; labelled as post-transplant

ATN by the study

Notes •A study with long CIT, which could explain the positive result despite small

sample size. Although it is quasi-randomised, it is 38 consecutive donors and the

reasons for exclusions are clear and appropriate

•Kidneys which swapped groups were excluded

•Funding source: not reported

Risk of bias

29Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Alijani 1985 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Although it is quasi-randomised, it is 38

consecutive donors and the reasons for ex-

clusions are clear and appropriate. The fact

that it is 38 consecutive donors means that

selection bias is likely not a large source of

bias

Allocation concealment (selection bias) Low risk See random sequence generation above

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding, but CIT was not signiﬁcantly

longer in either group

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Data reported for all kidneys, and reason

for exclusion of donors and discarding of

kidneys was explained clearly

Selective reporting (reporting bias) Low risk Appropriate outcome clearly reported

Other bias Unclear risk Short methods section, as expected given

the date of the study. Intention to treat anal-

ysis not performed, but this only affected

one kidney pair

Amaduzzi 2011

Methods •Study design: quasi-RCT (consecutive donors; kidneys randomised)

•Duration of study: October 2008 to February 2011

•Duration of follow-up: not reported

Participants •Country: Italy

•Setting: not reported

•All ECD

•Donor characteristics

◦Age range: 18 to 79 years

◦Number of DCD: not reported

◦Sex (M/F): not reported

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

30Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Amaduzzi 2011 (Continued)

◦Sex (M/F): not reported

◦Mean age ± SD (years): not reported

Interventions Machine perfusion

•Machine and solution not reported

Cold static storage

•Solution not reported

Outcomes •DGF

•DGF length

•PNF

•SCr

•CrCl

•Acute rejection

•ATN

•Length of hospital stay

•Patient survival

Notes •59 paired kidneys; 11 excluded for technical/logistic issues or renal artery

unavailability

•Insufﬁcient information provided in the abstract. Attempts to gain further

information by contacting the corresponding author failed

•Results could not be meta-analysed

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Insufﬁcient information to permit judge-

ment

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to permit judge-

ment

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Insufﬁcient information to permit judge-

ment

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Insufﬁcient information to permit judge-

ment

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Insufﬁcient information to permit judge-

ment

Selective reporting (reporting bias) High risk Not all outcomes listed were reported; data

presented could not be meta-analysed

31Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Amaduzzi 2011 (Continued)

Other bias Unclear risk Insufﬁcient information to permit judge-

ment

Chen 2014c

Methods •Study design: parallel RCT

•Duration of study: not reported

•Duration of follow-up: 1 year

Participants •Country: China

•Setting: single centre

•Donor characteristics

◦Mean age ± SD (years): not reported

◦Number of DCD: 36 (72 kidneys)

◦Sex (M/F); not reported

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): not reported

◦Mean age ± SD (years): not reported

Interventions Machine perfusion

•LifePort pulsatile perfusion machine; solution not reported

Static cold storage

•Preservation solution not reported (presumed to be UW)

Mean CIT

•Not reported

Outcomes •DGF

•Acute rejection

•Length of hospital stay

•One-year graft survival

Notes •72 kidneys from 36 donors. All were DCD

•One kidney from each pair assigned to MP and the other to SCS

•CIT for the two groups was not given

•This is a recent abstract and the full paper has not yet been published

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Insufﬁcient information to permit judge-

ment

32Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Chen 2014c (Continued)

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to permit judge-

ment

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Insufﬁcient information to permit judge-

ment

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Blinding not discussed, but outcome mea-

surements are unlikely to be affected by the

lack of blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk All patients were followed up

Selective reporting (reporting bias) Low risk Study outcomes were appropriate,and con-

cisely reported

Other bias Unclear risk As this is only an abstract, thorough analysis

of biases is impossible

Halloran 1985

Methods •Study design: parallel RCT

•Duration of study: 29 January 1983 to 15 January 1984

•Duration of follow-up: 12 months

Participants •Country: Canada

•Setting: multicentre (9 centres)

•Donor characteristics

◦Mean age ± SD (years): MP group (38.0 ± 16); SCS group (29.7 ± 15)

◦Unclear as to whether the donors were DBD/DCD or SCD/ECD

◦Sex (M/F): not reported

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): MP group 55/35; SCS group: 65/26

◦Mean age ± SD (years): MP group (38.1 ± 16); SCS group (38.7 ± 16)

Interventions Machine perfusion

•Waters pulsatile perfusion machine using plasmate solution, except in 10 kidneys

where the Gambro machine was used

Static cold storage

•Collins’ solution

Mean CIT

•Although slightly higher in the MP group mean CIT did not differ signiﬁcantly

between the study arms: 27.7 ± 12 hours in the SCS group and 30.5 ± 10 hours in the

33Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Halloran 1985 (Continued)

MP group

Outcomes •DGF

•Number of dialyses in the ﬁrst week

•Graft and patient 1-year survival

•Cause of graft failure

•One week creatinine

Notes •This was not a paired study; each donor was randomised to have both kidneys

machine perfused or both kidneys SCS

•107 donors. 2 recipients weren’t followed up, 12 kidneys were discarded and 13

randomised to receive MP underwent SCS and were excluded. This left 181 kidneys

(90 received SCS, and 91 received MP)

•There are two manuscripts describing the same study, the more recent of the two

(1987) is far more detailed

•The study gives a complex deﬁnition for DGF. Data taken from the number of

dialyses in the ﬁrst week table can be used to ﬁnd rates of DGF consistent with the

current deﬁnition, allowing inclusion of this study in the meta analysis

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Insufﬁcient information to permit judge-

ment

Allocation concealment (selection bias) Low risk Patients were randomised before procure-

ment, immediately after consent for organ

donation

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding, but CIT was not statistically

signiﬁcantly different between groups

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

High risk 13 kidneys randomised to MP and were

then changed to SCS. These patients were

not reported and were excluded from the

study; intention to treat analysis was not

employed

Selective reporting (reporting bias) High risk They used a complex and unusual deﬁni-

tion for DGF, for unclear reasons. How-

ever, data included in our analysis will be

taken directly from the number of dialyses

34Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Halloran 1985 (Continued)

in week one table, so this bias will not im-

pact on the meta analysis

Other bias Unclear risk A relatively short methods section

Heil 1987

Methods •Study design: parallel RCT

•Duration of study: not reported

•Duration of follow-up: 1 year

Participants •Country: Minnesota, USA

•Setting: single centre

•Donor characteristics

◦Mean age ± SD (years): not reported

◦Number of DCD: not reported

◦Number of ECD: not reported

◦Sex (M/F); not reported

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): not reported

◦Mean age ± SD (years): not reported

Interventions Machine perfusion

•Waters Mox-100 pulsatile perfusion machine using silica gel fractionated plasma

Static cold storage

•Euro-Collins solution

Mean CIT

•Data on length of CIT was not reported, but there was a randomisation

procedure as to which organ was transplanted ﬁrst

Outcomes •DGF

•One year graft survival

Notes •54 kidneys from 27 donors

•One kidney from each pair assigned to MP and the other to SCS

•Very short manuscript, lacking a lot of information

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Insufﬁcient information to permit judge-

ment

35Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Heil 1987 (Continued)

Allocation concealment (selection bias) Low risk Sealed envelopes were used to decide which

kidney would receive MP

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk No information on blinding, or on differ-

ences in CIT between groups

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No information, but outcome measure-

ments are unlikely to be affected by the lack

of blinding

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk Insufﬁcient information to permit judge-

ment

Selective reporting (reporting bias) Low risk Appropriate outcomes, adequately re-

ported

Other bias Unclear risk Extremely short manuscript making thor-

ough analysis of biases impossible

Kwiatkowski 1996

Methods •Study design: parallel RCT

•Duration of study: not reported

•Duration of follow-up: 10 years

Participants •Country: Poland

•Setting: single centre

•Donor characteristics

◦Mean age (range): 36 years (5 to 70)

◦Number of DCD: 37 (74 kidneys)

◦Sex (M/F): 24/14

◦Inclusion criteria: DCD donors

◦Exclusion criteria: not reported.

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦sex (M/F): MP group (18/19); SCS group (21/16)

◦Mean age ± SD (years): MP group (37 ± 12); SCS group (40 ± 15)

Interventions Machine perfusion

•MOX-100 DCM disposable cassette using MPSII solution

Static cold storage

•Preservation solution was not reported

Mean CIT

•Signiﬁcantly different between the groups; 27.5 hours in the SCS and 34.5 hours

in the MP group (P < 0.05)

36Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Kwiatkowski 1996 (Continued)

Outcomes •DGF

•Creatinine

•10-year graft survival

•Return to dialysis

Notes •74 kidneys from 37 donors. All were DCD donors

•One kidney from each pair assigned to MP and the other to SCS

•There were two main manuscripts, one in 1999 which presented to original data,

and one in 2009 publishing the 10-year graft survival. Both manuscripts are vague and

ambiguous in places. The graft survival is given as a percentage only, with no

information on how many people were followed up for the full 10 years

•The MP kidneys were routinely transplanted after the SCS kidneys, and therefore

suffered signiﬁcantly longer CIT

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Very few details given, only that the kidneys

were paired and randomised

Allocation concealment (selection bias) Unclear risk Very few details given, only that the kidneys

were paired and randomised

Blinding of participants and personnel

(performance bias)

All outcomes

High risk No blinding and the kidneys were trans-

planted such that the SCS kidney was rou-

tinely transplanted before the MP kidney

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

High risk No reason given as to why there was no

DGF information on 6 patients. In terms

of 10-year graft survival, this was only given

as a percentage with no indication to how

many patients were followed up

Selective reporting (reporting bias) High risk A lot of data was not reported, and most

of the data reported was incomplete or re-

ported ambiguously

Other bias High risk A relatively short manuscript. CIT was sig-

niﬁcantly different between the groups

37Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Matsuno 1994

Methods •Study design: parallel RCT

•Duration of study: not reported

•Duration of follow-up: 1 month

Participants •Country: Japan

•Setting: single centre

•Donor characteristics

◦Mean age: 51.1 years

◦Number of DCD donors: 13

◦Donor sex (M/F): not reported

◦Inclusion criteria: DCD donors

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): not reported

◦Mean age ± SD (years): MP group (41 ± 7.9); SCS group (38.5 ± 10.1)

Interventions Machine perfusion

•APS-02 (Nikiso) machine using cryoprecipitated plasma

Static cold storage

•UW or Euro-Collins solution

Mean CIT

•Signiﬁcantly different between the groups; 6.08 ± 2.93 hours in the SCS and 11.9

± 3.20 hours in HMP (P < 0.05)

Outcomes •DGF: requirement for dialysis during the ﬁrst week; labelled as post-transplant

ATN by the study

•Requirement for dialysis at 2 weeks

•Duration of dialysis

•One month graft survival

Notes •26 kidneys from 13 donors

•One kidney from each pair assigned to MP and the other to SCS

•There was a signiﬁcantly longer CIT in the MP arm, suggesting that people were

happy to leave perfused organs for longer

•The rate of DGF found by this study was very high, which could explain how the

study achieved statistical signiﬁcance even with such a small sample size

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk The study does not specify how, or at what

time, the randomisation takes place. It only

actually mentions that the study is ran-

domised in the concluding paragraph

38Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Matsuno 1994 (Continued)

Allocation concealment (selection bias) Unclear risk The study does not specify how, or at what

time, the randomisation takes place. It only

actually mentions that the study is ran-

domised in the concluding paragraph

Blinding of participants and personnel

(performance bias)

All outcomes

High risk No blinding and there was a signiﬁcant dif-

ference in CIT, suggesting that the groups

were treated differently. Prolonged CIT is

likely to affect the primary outcome of

DGF

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Data available for all included donors

Selective reporting (reporting bias) Low risk The outcomes reported were appropriate

and expected

Other bias High risk The study does not state the duration of the

study, whether they are consecutive cases,

or how inclusion/randomisation took place

Merion 1990

Methods •Study design: quasi-RCT

•Duration of study: April 1987 to November 1987

•Duration of follow-up: 30 days

Participants •Country: Michigan, USA

•Setting:

•Donor characteristics

◦Mean age ± SD (years): not reported

◦Number of DCD: not reported

◦Number of ECD: not reported

◦Sex (M/F); not reported

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): not reported

◦Mean age ± SD (years): MP group (39 ± 14); SCS group (40 ± 10)

39Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Merion 1990 (Continued)

Interventions Machine perfusion

•Waters Mox-100 perfusion device using silica gel fraction solution

Static cold storage

•Euro-Collins solution

Mean CIT

•Mean time did not differ signiﬁcantly between the groups: 21.8 hours in the SCS

group and 21.0 hours in the MP group

Outcomes •Requirement for dialysis

•Creatinine at day 1, 7 and 30

Notes •102 kidneys from 51 donors

•One kidney from each pair assigned to MP and the other to SCS, alternating

between right and left

•The study used a paired alternating design, with all donors between April and

November 1987 being included, except for nine donors, for which good explanations

were given for their exclusion

•As this is an older study, the CIT are relatively long

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Although an alternating design was used,

all consecutive donors between two time

periods were considered for inclusion. 51

of the 60 donors were included, and clear

reasons were given for exclusion of the nine

donors. This and the fact that the study

used a paired design, means that the selec-

tion bias is unlikely to have altered the re-

sults of this study

Allocation concealment (selection bias) Low risk See random sequence generation above

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding but this is unlikely to affect

the outcome, especially as there was no dif-

ference in CIT between the groups

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Follow up data for all included patients and

clear explanations for the nine excluded pa-

tients

40Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Merion 1990 (Continued)

Selective reporting (reporting bias) Low risk Appropriate outcomes, well reported

Other bias Low risk A thorough descriptive methods section

Moers 2009

Methods •Study design: parallel RCT

•Duration of study: 1 November 2005 to 31 October 2006

•Duration of follow-up: 36 months

Participants •Country: Netherlands, Belgium and Germany

•Setting: multinational

•Donor characteristics

◦Mean age (range): 51 years (16 to 81)

◦Number of DCD: 82 (164 kidneys)

◦Number of ECD: 94 (188 kidneys)

◦Sex (M/F): not reported

◦Inclusion criteria: organ donors had to be 16 years of age or older. Only

kidney pairs from deceased donors were included in the study, either from donation

after brain death or donation after CCD. The category for donors without a heartbeat

had to be Maastricht category III (awaiting CCD after withdrawal of treatment) or IV

(CCD in a brain-dead donor).

◦Exclusion criteria: Kidney pairs were excluded if both organs were not

transplanted into two different recipients. If one kidney was transplanted into the same

recipient together with another organ, this kidney pair was excluded

•Recipient characteristics

◦Inclusion criteria: recipient of a single kidney

◦Exclusion criteria: only exclusion criterion for recipients was the death of the

patient in the ﬁrst week after transplantation, since a follow-up of at least 1 week was

required to determine the primary end point

◦Sex (M/F): not reported

◦Mean age, range (years): MP group (52, 2 to 79); SCS group (53, 11 to 79)

Interventions Machine perfusion

•LifePort transporter machines (pulsatile perfusion) using KPS-1 solution

Static cold storage

•UW or HTK solutions

Mean CIT

•Mean time was 15 hours, and did not differ signiﬁcantly between the groups

Outcomes •DGF

•Duration of DGF

•PNF

•SCr

•Creatinine clearance at day 14

•Acute rejection

•Length of hospital stay

•One-year patient survival

41Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Moers 2009 (Continued)

•One-year graft survival

•Three-year patient survival

•Three-year graft survival

Notes •672 kidneys from 336 donors (plus a further 80 kidneys from 40 donors which

were detailed in the 2010 report by Jochman et al.)

•One kidney from each pair assigned to MP and the other to SCS

•Many papers were published based on the original 2009 Moers study, including

in depth analysis of various subgroups. Some of these reports acted as useful sources for

subgroup analysis, and could be included in the meta-analysis. A letter submitted to the

New England Journal of Medicine in 2012 reported 3-year patient and graft survival

•The research was “supported by organ recovery systems”.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Randomisation lists for each study region

Allocation concealment (selection bias) Low risk All ocation happened prior to procurement,

whilst the donor was still in the ICU

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk They performed blinding at the time of or-

gan offer, so a centre could not turn down

a kidney on the basis of storage method

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Only 1 patient out of 672 was lost to fol-

low-up. The rest were followed up to at least

one year

Selective reporting (reporting bias) Low risk All outcomes reported were present in the

original study protocol except for PNF

Other bias Unclear risk Intention to treat analysis likely not com-

pleted

42Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Mozes 1985

Methods •Study design: parallel RCT

•Duration of study: not reported

•Duration of follow-up: 22 months.

Participants •Country: Illinois, USA

•Setting: multicentre

•Mean age ± SD (years) Donor: 26.5 (3-61)

•Donor characteristics

◦Number of DCD: 0

◦Sex (M/F); not reported

◦Inclusion criteria: DBD donors with two kidneys suitable for transplant.

“Criteria for donor selection was uniform for all participants”

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): “There were no signiﬁcant differences between the groups with

respect to recipient characteristics such as sex”. Numbers of males in each group not

reported

◦Mean age ± SD (years): not given but there were “no signiﬁcant differences”

between the SCS and MP group

Interventions Machine perfusion

•Waters MOX-100 pulsatile perfusion machine using silica gel plasma perfusate

Static cold storage

•Euro-Collin’s solution.

Mean CIT

•Mean CIT was longer in the MP group although this was not signiﬁcant (P = 0.

09): 32.7 in the SCS group versus 35.2 in the MP group

Outcomes •DGF (called post-transplant ATN in the study but deﬁned as requirement for

dialysis in the ﬁrst week)

•One-year graft and patient survival

•90 day creatinine

Notes •One kidney from each pair randomised to MP and the other to SCS

•192 kidneys from 96 donors. However only 187 (94 SCS and 93 MP) kidneys

were included in the study. All donors were DBD donors

•Signiﬁcantly more kidneys in the MP group had CIT >36 hours, compared to the

SCS group (P = 0.01).

•In the SCS group, the rate of DGF increased as CIT increased, whereas in the MP

group rate of DGF was independent of CIT

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

43Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Mozes 1985 (Continued)

Random sequence generation (selection

bias)

Unclear risk Insufﬁcient information to permit judge-

ment

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to permit judge-

ment

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Recipient centres were informed of the

preservation method used and left MP kid-

neys for longer; more kidneys had a CIT >

36 hours in the MP group (P = 0.01)

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk The 5 kidneys not used were as a result of

“recipient unavailability” which is unlikely

to be a source of bias. Thorough outcome

data was reported for the remaining 187

patients

Selective reporting (reporting bias) Low risk Appropriate outcome measures, well re-

ported

Other bias Unclear risk Limited methods section, as expected due

to the date of the study

PPART 2010

Methods •Study design: parallel RCT

•Duration of study: August 2006 to October 2007

•Duration of follow-up: 12 months

Participants •Country: UK

•Setting: multicentre

•Donor characteristics

◦Mean age ± SD: 45.6 ± 29.2 years

◦Number of DCD: 45 (90 kidneys)

◦Number of ECD: 16 (32 kidneys)

◦Sex (M/F): 29/16

◦Inclusion criteria: “All adult DCD donors at the ﬁve participating UK

centers were eligible for the study although only controlled DCD donors, in whom

further active treatment had been deemed futile and life-supporting treatment

withdrawn (Maastricht category 3), were entered.”

◦Exclusion criteria: not reported

•Recipient characteristics

◦inclusion criteria: aged ≥18 years or over, and had a negative crossmatch.

◦Exclusion criteria: previous nonrenal organ transplant

44Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

PPART 2010 (Continued)

◦Sex (M/F): MP group (31/14); SCS group (33/12)

◦Mean age ± SD (years): MP group (50.3 ± 28.4); SCS group (48.6 ± 13.9)

Interventions Machine perfusion

•LifePort transporter machines (Organ Recovery Systems) using KPS-1 solution

Static cold storage

•UW solution.

Mean CIT

•Did not differ signiﬁcantly between the groups: 14.3 hours in the SCS group and

13.9 hours in the MP group.

Outcomes •DGF

•PNF

•Creatinine

•Incidence of biopsy proven acute rejection

•Patient and graft survival

•Other measures of graft function

Notes •One kidney from each pair assigned to MP and the other to SCS

•A few of the kidneys only received MP at the recipient centre, but most also

received it in transit. Relatively low rate of DGF overall, compared to DCDs in other

studies, which could explain why this study was negative

•Funding source: “ The Research described was funded by a large unrestricted

research grant from Novartis Pharmaceuticals UK and a smaller grant from Organ

Recovery Systems.”

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Computer generated random sequences

were used

Allocation concealment (selection bias) Low risk Central allocation at duty ofﬁce of NHS

blood and transplant

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding, but there was a randomisation

scheme to dictate which kidney would be

transplanted ﬁrst, therefore the MP kidney

was not always left to suffer longer CIT as

is the case in some other studies

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Full follow-up data for all patients, using

an intention to treat model

45Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

PPART 2010 (Continued)

Selective reporting (reporting bias) Low risk Outcomes suitable, with adequate report-

ing

Other bias Low risk All kidneys were transplanted, the indices

gained from the MP process were not used

to decide whether a kidney was trans-

planted

Tedesco-Silva 2017

Methods •Study design: parallel RCT

•Duration of study: 26 July 2014 to 22 August 2014; 26 January 2015 to 28

March 2015

•Duration of follow-up: 1 year

Participants •Country: Brazil

•Setting: multicentre

•Donor characteristics

◦Mean age (range): 50 years (20 to 71)

◦Some donors were ECD, but information on exact numbers was not

provided.

◦Sex (M/F): 46/34

◦Inclusion criteria: “We screened all adult brain dead deceased donors referred

to a single OPO during the enrollment period. To be included in the study it was

required the availability of the equipment and trained surgeons and sufﬁcient time to

recover the organs, considering the distance to travel at the time of referral. ”

◦Exclusion criteria: “We excluded donors younger than 18 years, with

unstable hemodynamic condition, and when combined transplants were anticipated.”

•Recipient characteristics

◦Inclusion criteria: not reported.

◦Exclusion criteria: not reported.

◦sex (M/F): MP group (45/35); SCS group (49/31)

◦Mean age ± SD (years): MP group (47.4 ± 15.6); SCS group (48.9 ± 12.3)

Interventions Machine perfusion

•LifePort transporter machines (Organ Recovery Systems) using KPS-1 solution

Static cold storage

•SPS-1 (Organ Recovery Systems) or Celsior preservation solution (Genzyme)

based on surgeon preference.

Mean CIT

•Mean time was long but did not differ signiﬁcantly between the groups: 25.6 ± 6.

6 hours in the SCS group and 25.1 ± 6.3 hours in the MP group

Outcomes •DGF

•PNF

•Duration of DGF

•Duration of hospital stay

•Incidence of acute rejection

46Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Tedesco-Silva 2017 (Continued)

•One-year graft survival

•One-year patient survival

•Kidney function at days 7, 14, 21, 28 and 365

Notes •160 kidneys from 80 donors. All were DBD donors

•One kidney from each pair assigned to MP and the other to SCS. Kidneys were

assessed to ensure that both kidneys were suitable for HMP/SCS before randomisation.

If either kidney could not be included, the pair was excluded from the study

•Due to various factors, including long CIT and relatively haemodynamically

compromised donors, the incidence of DGF is relatively high in Brazil. This increased

incidence improves the ability of the study to identify interventions which affect DGF

incidence

•Funding source: Organ Recovery Systems provided the Lifeport kidney

transporter machine, preservation solutions, perfusion kits and training of the organ

recovery team

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Randomisation using a web based program

(www.randomization.com)

Allocation concealment (selection bias) Low risk Once a random sequence was generated us-

ing a web based program allocations were

placed in opaque envelopes

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding but this is unlikely to affect

the outcome, especially as there was no dif-

ference in CIT between the groups

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Clear reasons given for excluded pairs of

kidneys. Primary outcome data reported

for all 160 included participants. Only 2/

160 were lost to follow up and were there-

fore not included in the graft/patient sur-

vival analysis

Selective reporting (reporting bias) Low risk Outcomes suitable, with adequate report-

ing

Other bias Low risk Kidneys were assessed to ensure that both

kidneys were suitable for HMP/SCS before

randomisation. This removes the potential

47Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Tedesco-Silva 2017 (Continued)

bias associated with excluding kidneys only

if a kidney with unusual vascular anatomy

is randomised to HMP

van der Vliet 2001

Methods •Study design: parallel RCT

•Duration of study: not reported

•Duration of follow-up: 18.3 ± 2.7 months

Participants •Country: Netherlands

•Setting: multicentre

•Donor characteristics

◦Mean age ± SD: 36.6 ± 5.4 years

◦Number of DCD: all 38 (76 kidneys)

◦Sex (M/F): not reported

◦Inclusion criteria: all consecutive DCD donors

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): not reported

◦Mean age ± SD (years): not given but there were “no signiﬁcant differences”

between the SCS and MP groups

Interventions Machine perfusion

•Gambro pulsatile perfusion machine using Belzer’s solution

Static cold storage

•UW solution

Mean CIT

•Longer in the MP groups, but this was not statistically signiﬁcant: 23.0 ± 1.3

hours in the SCS group and 25.0 ± 1.0 hours in the MP group

Outcomes •DGF

•One-year graft survival

•SCr at 3 months

Notes •One kidney from each pair assigned to MP and the other to SCS

•76 kidneys from 38 consecutive donors. All were DCD donors

•5 patients were lost to follow up, and data for their DGF rate was not reported.

Although not stated, further patients must have been lost to follow up before 1 year, as

only percentages are given for graft survival, and these do not result in integers for the

numbers of grafts lost, if all of the 71 recipients were followed up. This prohibits

survival data from being used in the meta analysis

•Funding source: not reported

Risk of bias

48Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

van der Vliet 2001 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Paired design with one kidney randomly

assigned to each group. No information on

how or at what stage the randomisation was

done

Allocation concealment (selection bias) Unclear risk Too little information was given to allow

assessment of allocation concealment

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding, but the difference in CIT be-

tween the arms was not statistically signif-

icantly different

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk 5/76 lost to follow-up, with no informa-

tion on DGF. No explanation given for the

patients lost to follow up, but similar num-

bers lost from each group

Selective reporting (reporting bias) Low risk Appropriate outcome measures, with each

reported in the results section

Other bias Unclear risk Very concise materials and methods section

so difﬁcult to assess level of bias

Veller 1994

Methods •Study design: unclear whether this study was randomised or quasi-randomised

•Duration of study: Total study duration was 35 months

•Duration of follow-up: not reported

Participants •Country: South Africa

•Setting: not reported

•Donor characteristics

◦Mean age ± SD (years): not reported

◦Number of DCD: 0

◦Sex (M/F); not reported

◦Inclusion criteria: DBD victims of trauma who were haemodynamically

stable and who continued to pass urine

◦Exclusion criteria: one of the kidneys was transplanted into a recipient who

had already received a kidney transplant

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported. one of the kidneys was transplanted into a

49Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Veller 1994 (Continued)

recipient who had already received a kidney transplant

◦Sex (M/F): not reported

◦Mean age, range (years): MP group (34, 11 to 53); SCS group (53, 1 to 56)

Interventions Machine perfusion

•Waters Inc. t000 pulsatile perfusion machine (Rochester, Minnesota, USA) using

cryoprecipitated plasma

Static cold storage

•UW solution

Mean CIT

•Did not differ signiﬁcantly between the groups; 18 (7-34) in the SCS group and

19 (7-33) in the MP group

Outcomes •DGF

•Functional DGF based on creatinine

Notes •36 kidneys from 18 donors. All were DBD donors.

•One kidney from each pair assigned to MP and the other to SCS

•The manuscript presents two studies, a paired study of 18 donors, and a

retrospective analysis of previous cases. Only the data from the paired population has

been collected.

•This study has a small sample size, and took place over a long duration.

•“Only donors of excellent quality were used for the study”.

•Funding source: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk It does not state how or at what stage the de-

cision was made as to which kidney would

receive MP and which would receive SCS.

Moreover it is unclear whether the study

was randomised or quasi-randomised

Allocation concealment (selection bias) Unclear risk Insufﬁcient information to permit judge-

ment

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk No blinding, but comparable CIT between

the groups, and the study does describe ran-

domisation of kidneys in terms of alloca-

tion to recipients

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

Incomplete outcome data (attrition bias)

All outcomes

Low risk Data is available for all included partici-

pants

50Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Veller 1994 (Continued)

Selective reporting (reporting bias) Low risk Suitable outcome measures with results re-

ported for each

Other bias Unclear risk Relatively short manuscript lacking details

of methods of randomisation

Wang 2017

Methods •Study design: parallel RCT

•Duration of study: June 2014 to June 2015

•Duration of follow-up: 6 months

Participants •Country: China

•Setting: single centre

•Donor characteristics

◦Mean age ± SD: 48.2 ± 12.6 years

◦Number of DCD: 48

◦sex (M/F): 18/6

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

•Recipient characteristics

◦Inclusion criteria: not reported

◦Exclusion criteria: not reported

◦Sex (M/F): MP group (15/9); SCS group (18/6)

◦Mean age ± SD (years): MP group (44.6 ± 8.1); SCS group 940.2 ± 6.2)

Interventions Machine perfusion

•Lifeport (ORS) system using KPS-1 at a constant pressure of 30 mmHg

Static cold storage

•Solution not reported

Mean CIT

•Poorly reported. CIT in the SCS group ranged from 1-8 hours, and mean CIT in

the MP group was 5.8 ± 2.8 hours

Outcomes •DGF is listed as the primary outcome, a non-standard deﬁnition was used (“DGF

was deﬁned as one of the following: postoperative anuria or oliguria and the need to

reinitiate hemodialysis in the ﬁrst week after surgery; or hemodialysis was not

reinitiated, but SCr was greater than 400 µmol/L at 7 days after surgery”)

•Acute rejection

•“time-zero biopsies”

•Length of hospital stay was not listed as an outcome, but was reported in the

results

Notes •One kidney from each pair assigned to MP and the other to SCS

•48 kidneys from 24 donors. All were DCD donors

•The authors concluded that HMP was superior to SCS, as it reduces the

incidence of DGF. This paired study was not properly randomised and risk of bias was

felt to be unacceptable given the following: one kidney from each pair was randomised

51Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Wang 2017 (Continued)

to SCS and one to HMP but surgeons could switch kidneys between groups if they felt

that aberrant vascular anatomy would interfere with HMP. No data was given on how

many pairs of kidneys were switched between preservation methods, and no intention

to treat analysis was performed. In addition, there was incomplete information on the

SCS group; a mean CIT was not given and the type of solution used was not reported.

A signiﬁcant difference in CIT could have been present. Finally, a non-standard

deﬁnition for DGF was used; requirement for dialysis in the ﬁrst week or SCr greater

than 400µmol/L at day 7 post surgery. No justiﬁcation was given for this deﬁnition.

Only DGF using their deﬁnition was reported as an outcome, and no information was

given as to how many kidneys required dialysis. This raises the possibility of selective

reporting bias

•Funding source: “ This study was supported by the Beijing Municipal

Administration of Hospitals Clinical Medicine Development of Special Funding

Support (ZYLX201408), the National Natural Science Foundation of China (No.

81270837), the Beijing Natural Science Foundation (No. 7132107), and Foundation

Clinical Research of capital Medical University(No. 1140170035)”

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

High risk There was no information on how kidneys

were randomised. Furthermore, surgeons

could swap kidneys from the HMP to the

SCS if they felt the aortic patch was too

small or if the anatomy of the renal ar-

teries was non-standard. No intention to

treat analysis was applied. No indication

was given as to how many kidneys were

swapped between groups

Allocation concealment (selection bias) High risk Allocation concealment was not possible

with the study design, kidneys were moved

between groups without intention to treat

analysis

Blinding of participants and personnel

(performance bias)

All outcomes

High risk No blinding and no reporting of CIT.

Therefore one group may have routinely

been transplanted ﬁrst, adding bias to the

results

Blinding of outcome assessment (detection

bias)

All outcomes

High risk No blinding of DGF data. No informa-

tion is given as to whether the assessors

of “acute rejection” or “time zero biopsies”

were blinded

Incomplete outcome data (attrition bias)

All outcomes

High risk For the outcome “time-zero biopsies” no

data is given for the groups as a whole. Only

H+E stains and electron microscopy from

52Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Wang 2017 (Continued)

a single pair of kidneys are presented

Selective reporting (reporting bias) High risk A non-standard deﬁnition for DGF was

used as the primary outcome of the study.

The number of participants requiring dial-

ysis in the ﬁrst week post-transplant (the

standard deﬁnition for DGF) was not re-

ported. No speciﬁc outcome was associated

with the “time-zero biopsies”. In the results

section some features of H+E stains, and

electron microscopy were reported, leaving

a high risk of selection bias. Furthermore,

only H+E stains and electron microscopy

from a single pair of kidneys are presented

Other bias High risk Although acute rejection is reported as an

outcome, it is not stated whether this is

biopsy proven rejection or clinical rejec-

tion. It is alsonot stated over what time pe-

riod acute rejection data was collected over

Zhong 2017

Methods •Study design: parallel RCT

•Duration of study: July 2010 to July 2015

•Duration of follow-up: 3 years

Participants •Country: China

•Setting: not reported

•Donor characteristics

◦Mean age ± SD: 32.8 ± 12.4 years

◦Number of DCD: 153 (282 kidneys)

◦Sex (M/F): 107/61

◦Inclusion criteria: DCD donors which where Maastricht category III; organ

donors had to be at least 16 years of age

◦Exclusion criteria: not reported.

•Recipient characteristics

◦Inclusion criteria: ﬁrst time kidney transplants

◦Exclusion criteria: received the kidney with another organ

◦Sex (M/F): MP group (79/62); SCS group (73/68)

◦Mean age ± SD (years): MP group (41.4 ± 11.6); SCS group (40.6 ± 9.3)

Interventions Machine perfusion

•LifePort kidney transporter machines (ORS) with a constant pressure of 30

mmHg and temperature of 0°C to 4°C was used for HMP using KPS-1

Static cold storage

•UW solution

Mean CIT

53Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Zhong 2017 (Continued)

•Not signiﬁcantly different between groups: 11.8 (6.3 to 22.5) hours in the SCS

group and 10.3 (5.1 to 24.0) hours in the MP group (P = 0.063)

Outcomes •DGF

•Functional DGF: deﬁned by the absence of a decrease in the SCr level of at least

10% per day for at least three consecutive days within the ﬁrst week after

transplantation

•One and 3-year graft survival

•Median SCr and median urine output each day of the ﬁrst week post-transplant

•Resistance in renal arteries using Doppler ultrasound within 48 hours post-

transplant

Notes •One kidney from each pair assigned to MP and the other to SCS

•282 kidneys from 153 donors. All donors were DCD

•Doppler USS was used to assess arterial resistance in the renal vasculature within

48 hours post -transplant. As arterial resistance was signiﬁcantly lower in the HMP

group, the authors concluded that part of the beneﬁcial effect of HMP is due to

decreased vasospasm

•Funding source: No conﬂict of interest. Funding was from the State Key Program

of National Natural Science of China, No: U1403222; Special Foundation of Basic

Research for the Central Universities, No: 2042014kf0101

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk No speciﬁc information on random se-

quence generation, but all consecutive

donors were assessed for inclusion, and

valid reasons were given for any excluded

donors

Allocation concealment (selection bias) Low risk No speciﬁc information on allocation con-

cealment but all consecutive donors were

assessed for inclusion, and valid reasons

were given for any excluded donors

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Transplanting teams were blinded to the

perfusion parameter readings. Transplant

teams were not blinded to the storage

method used but this is unlikely to affect

the outcome, especially as there was no dif-

ference in CIT between the groups

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk No blinding, but outcome measurements

are unlikely to be affected by the lack of

blinding

54Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Zhong 2017 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Low risk Full follow-up was reported for all partici-

pants

Selective reporting (reporting bias) Low risk Outcomes suitable, with adequate report-

ing

Other bias Low risk No kidneys were swapped between groups.

An independent scientiﬁc steering commit-

tee composed of clinicians and scientists

was solely responsible for the design, con-

duct, data analysis, and manuscript prepa-

ration

ATN - acute tubular necrosis; CCD - cardiocirculatory death; CIT - cold ischaemic time; CrCl - creatinine clearance; DBD - donor

after brainstem death; DCD - donor after circulatory death; ECD - extended/expanded criteria donor; ICU - intensive care unit;

MP - machine perfusion; PNF - primary non-function; SCr - serum creatinine; SCS - static cold storage

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alijani 1987 Wrong intervention: compared 2 cold storage solutions

Baatard 1993 Wrong intervention: compared 2 cold storage solutions

Guarrera 2004 Wrong intervention: compared 2 solutions for MP

Guarrera 2004a Wrong intervention: compared 2 solutions for MP

Lodge 1993 Wrong intervention: compared 2 types of reﬂush solutions

Polyak 1998 Wrong intervention: compared the type of additive used in MP

Polyak 2002 Wrong intervention: compared the type of additive used in MP

Tisone 1999 Wrong intervention: compared gravity to high pressure perfusion

Wamser 1990 Wrong intervention: compared 2 cold storage solutions

Wszola 2013 Wrong intervention: compared 2 MP techniques

MP - machine perfusion

55Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Characteristics of studies awaiting assessment [ordered by study ID]

ISRCTN50082383

Methods Multicentre RCT; sequential study design - maximum of 270 recipients

Participants Inclusion criteria

•Patients who receive a kidney transplant from a controlled or uncontrolled cardiac-death deceased donor

•Recipient > 18 years

Exclusion criteria

•Lack of informed consent

•Positive crossmatch

•Previous recipient of non-kidney solid-organ transplant

Interventions One kidney will be placed upon the LifePort pulsatile perfusion machine. The other will be placed in standard cold-

storage ice-box

Outcomes •DGF

•Duration of DGF

•The area under the curve of the daily SCr level at days 1 to 14

•Day 14 calculated eGFR

•The need for dialysis in the ﬁrst 7 days excluding the ﬁrst 24 hours post-transplant

•Median times to last dialysis

•Non-graft function rates, deﬁned as a kidney transplant that fails to provide one month of dialysis free renal

replacement, where loss is not attributable directly to rejection or vascular thrombosis

•Incidence of acute rejection

•Three and 12-month graft survival

•Three and 12-month SCr

•Three and 12-month glomerular ﬁltration rate (MDRD method)

•Incidence of graft loss for technical reasons, e.g. renal artery or vein thrombosis

•One-year patient survival

•Length of hospital stay

Notes The following is listed as an editorial note in the ISRCTN registry (http://www.isrctn.com/ISRCTN50082383): 18/

12/2017: The overall study end date was updated from 01/12/2016 to 31/05/2017

NCT01170910

Methods Multicenter, prospective, open, controlled and randomised trial comparing static incubation and pulsatile machine

perfusion in expanded criteria donors

Participants Inclusion criteria for donors (ECD)

•Donors aged > 60 years

•Donors aged between 50 and 60 years of age with at least one of the following characteristics: history of

diabetes mellitus; history of high blood pressure; SCr > 1.5 mg/dL; death by stroke (haemorrhagic or thrombotic)

Inclusion criteria for recipient

•Registered on the kidney transplant waiting list likely to receive a marginal kidney

•Immunized patients whose anti-HLA antibody speciﬁcities have been determined

Exclusion criteria for recipient

56Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

NCT01170910 (Continued)

•Pregnant or breastfeeding women

•People who have been incarcerated

•Minors

•Adults under guardianship

•People who are not afﬁliated with the French healthcare system

•People with HLA immunization whose HLA antibody speciﬁcities have not been determined

Interventions Static incubation

•Kidneys in this group are conserved in University of Wisconsin (e.g., UW, Belzer® or Viaspan®), IGL-1, or

SCOT solution before being transplanted

Pulsatile perfusion

•Kidneys in this group are placed in the pulsatile perfusion machine (RM 3) within two hours and should be

kept there at least 6 hours and 8 hours if possible, before being transplanted

Outcomes •DGF

•Evaluate improvement in the glomerular ﬁltering rate: 12 months after transplantation

•Evaluate the recourse to dialysis: 3 months following transplantation

•Evaluate the proportion of functional grafts (which allows for renal puriﬁcation without recourse to dialysis):

12 months after transplantation

•Evaluate patient survival: 12 months after transplantation

•Stratify the analysis of regaining function and graft survival using Nyberg’s classiﬁcation in order to determine

which risk groups would most beneﬁt from pulsatile perfusion: 12 months after transplantation

•Identify perfusion proﬁles of the machine, which predict regaining kidney function (absence of dialysis during

the week after transplantation) and graft survival: 12 months after transplantation

•Evaluate the medico-economic impact of each conservation strategy in the management of patients who will

beneﬁt from marginal grafts: 12 months after transplantation

Notes Study marked as complete (www.clinicaltrials.gov/ct2/show/study/NCT01170910) but no results available despite at-

tempted contact with the authors.

DGF - delayed graft function; ECD - extended/expanded criteria donors; SCr - serum creatinine

Characteristics of ongoing studies [ordered by study ID]

Hosgood 2017

Trial name or title Improving function of transplanted kidneys

Methods UK-based phase II multicentre RCT; not strictly paired

Participants 400 patients receiving a kidney from a DCD donor (categories III and IV, controlled) in the UK setting

Interventions On arrival at the transplant centre, kidneys will be randomised to receive either normothermic MP (n = 200)

or remain in SCS (n = 200). Kidneys undergoing normothermic MP will be perfused with an oxygenated

packed red cell solution at near body temperature for 60 min prior to transplantation

57Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Hosgood 2017 (Continued)

Outcomes •DGF

•PNF: deﬁned as the permanent lack of allograft function from the time of transplantation, including

graft losses due to irreversible rejection and vascular thrombosis, is recorded along with the cause at the end

of the study (12 months)

•Duration of DGF is measured by recording the number of sessions and days that the recipient requires

dialysis after transplantation in days

•Functional DGF: deﬁned as < 10% fall in SCr for 3 consecutive days, is measured using blood analysis

in the ﬁrst week post-transplant

•CRR 2: creatinine day 1 - creatinine day 2/ creatinine day 1 is measured using blood analysis on day 2

•CRR 5: pre transplant creatinine - creatinine day 5/ pre-transplant creatinine is measured using blood

analysis on day 5

•Length of hospital stay is measured as the number of days the recipient remains in hospital after the

transplant

•Biopsy-proven acute rejection rates are measured through examination of kidney biopsy samples when

acute rejection is suspected

•SCr and eGFR is measured using blood and urine analysis at baseline (pre-transplant), 1, 3, 6 and 12

months

•Patient survival (time from transplant to death) is measured in days

•Allograft survival (time from transplant to graft loss or return to dialysis) is measured in days

Starting date 01/03/2015

Contact information Ms Sarah Hosgood

Addenbrooke’s Hospital

Hills Road

Cambridge

CB2 0QQ

United Kingdom

Notes Estimated completion date 30/01/2021

ISRCTN35082773

Trial name or title A multi-centre, randomised, controlled study of pre-transplant machine perfusion of heart-beating donor

kidneys prior to renal transplantation

Methods Multicentre RCT

Participants 200 patients (aged 18 years and over, either gender) undergoing transplantation of a kidney from a heart-

beating cadaver donor

Interventions MP of the kidney before transplantation versus SCS

Outcomes To determine whether a brief period of MP reduces the incidence of DGF following kidney transplantation

•Incidence of DGF at 7 days

•1. Patient survival

•2. Graft survival

•3. Graft function - eGFR

58Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

ISRCTN35082773 (Continued)

•4. Acute rejection incidence

•5. Acute rejection severity

•6. Incidence of steroid resistant rejection, deﬁned as the need for ATG therapy

Starting date Overall study start date: 28/06/2006

Contact information Mr Christopher Watson

Department of Surgery

Box 202

Addenbrooke’s Hospital

Cambridge

CB2 2QQ

United Kingdom

Notes The following is listed as an editorial note in the ISRCTN registry (http://www.isrctn.com/IS-

RCTN35082773): 10/08/2017: No publications found in PubMed, verifying study status with principal

investigator

ISRCTN63852508

Trial name or title COPE-POMP: ‘in house’ pre-implantation oxygenated hypothermic machine perfusion reconditioning after

cold storage versus cold storage alone in expanded criteria donor (ECD) kidneys from brain dead donors

Methods Prospective parallel group RCT patient-blinded controlled multicentre non-paired superiority study

Participants Kidneys donated after brain death from donors fulﬁlling the United Network for Organ Sharing (UNOS)

ECD criteria. Participants are expected from Germany, Belgium, the Netherlands and UK

Interventions ECD kidneys will be randomised to be preserved using either SCS alone or SCS followed by hypothermic

oxygenated MP

Group 1: the kidney will be retrieved and stored in cold storage solution until back-table preparation and

kidney transplantation are performed

Group 2: the kidney will be placed in cold storage solution until arrival at the recipient’s transplant centre.

Following back-table preparation the kidney will be placed on the Kidney Assist device to be perfused with

cold oxygenated Belzer’s Machine preservation solution until immediately before implantation

Outcomes •Graft survival after 1 year

•Patient and graft survival at day 7, and at 3, 6 and 12 months after transplantation

•eGFR deﬁned by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation at

days 7 and 14 and 3, 6 and 12 months after transplantation

•DGF, deﬁned as the need for dialysis within the ﬁrst 7 days after transplantation and preceding the

return of kidney function

•Slow graft function (SGF) based on functional DGF, deﬁned as the absence of a decrease in the SCr

level of at least 10% per day for at least 3 consecutive days in the ﬁrst 7 days after transplantation

•PNF, deﬁned as the continued need for dialysis at 3 months after transplantation

•Biopsy proven acute rejection incidence

•Quality of life measures (EQ-5D-5L) at time of consent, 3 and 12 months

•Health economic analysis: length of hospital stay, intensive care unit stay, requirement of dialysis

59Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

ISRCTN63852508 (Continued)

•Incidence of hyperkalaemia at 3, 6 and 12 months

•Incidence of calcineurin inhibitor toxicity

Starting date 01/12/2013

Contact information Prof Andreas Paul

Department of General

Visceral and Transplant Surgery

University Hospital Essen

Hufelandstr. 55

Essen

45147

Germany

Notes Study ongoing as of 15/12/2016, expected to ﬁnish 31/12/2018

NCT02525510

Trial name or title A randomized trial of mild hypothermia and machine perfusion in deceased organ donors for protection

against delayed graft function in kidney transplant recipients

Methods Parallel assignment RCT to assess the effect of mild hypothermia in the deceased organ donor before organs

are recovered, with or without subsequent hypothermic MP of the kidney after recovery and prior to trans-

plantation

Participants DBD donors > 18 years in the USA

Interventions Enrolled donors will be divided into two populations based on local organ procurement organization criteria:

pump eligible and not pump eligible. These categories will then be split to result in ﬁve arms:

1. Pump eligible: normothermia; pump both kidneys

2. Pump eligible: hypothermia; pump right kidney

3. Pump eligible: hypothermia; pump left kidney

4. Not pump eligible: normothermia

5. Not pump eligible: hypothermia

Outcomes •DGF

•Graft and patient survival at 1 year

Starting date 26/07/2017

Contact information Claus Niemann, MD; Claus.Niemann@ucsf.edu

Darren Malinoski, MD; malinosk@ohsu.edu

Notes Estimated completion date 26/07/2021

60Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

NCT02621281

Trial name or title Clinical impact of hypothermic machine perfusion in renal transplant recipients (CIHMP)

Methods Multicentre prospective, paired, RCT to compare HMP with SCS. Factors during the MP, such as the pressure,

ﬂow rate, and resistance index will also be investigated. This study aims to recruit 200 donors

Participants DCD donors > 16 years in China

Interventions SCS versus HMP with a kidney transporter machine

Outcomes •DGF

•eGFR at 1 week, 3 months, 6 months, 12 months

Starting date December 2015

Contact information Chenguang Ding, PhD; doctor ding@126.com

Wujun Xue, PhD; xwujun@126.com

Notes Estimated completion date January 2019

CRR - creatinine reduction ratio; DCD - donor after circulatory death; DGF - delayed graft function; ECD - extended/expanded

criteria donors; eGFR - estimated glomerular ﬁltration rate; (H)MP - (hypothermic) machine perfusion; PNF - primary non-

function; RCT - randomised controlled trial; SCS - static cold storage

61Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

D A T A A N D A N A L Y S E S

Comparison 1. Hypothermic machine perfusion versus static cold storage

Outcome or subgroup title No. of

studies

No. of

participants Statistical method Effect size

1 Delayed graft function 14 2138 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.67, 0.90]

2 Delayed graft function: type of

donor

14 2138 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.68, 0.89]

2.1 DCD 7 772 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.64, 0.87]

2.2 DBD 4 971 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.65, 0.93]

2.3 Type of donor not

speciﬁed

4 395 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.46, 1.44]

3 Delayed graft function: era of

study

14 2138 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.67, 0.90]

3.1 Modern era 5 1355 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.66, 0.91]

3.2 Pre-2008 9 783 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.61, 0.99]

4 Delayed graft function:

preservation times

14 2138 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.67, 0.90]

4.1 Short mean cold ischaemic

time (< 24 hours)

6 1288 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.70, 1.04]

4.2 Long mean cold ischaemic

time (≥24 hours)

6 725 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.57, 0.83]

4.3 Cold ischaemic time not

reported

2 125 Risk Ratio (M-H, Random, 95% CI) 0.82 [0.31, 2.18]

5 Primary non-function 7 1387 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.58, 1.33]

6 Duration of DGF 4 220 Mean Difference (IV, Random, 95% CI) -1.23 [-5.87, 3.40]

7 One year patient survival 3 920 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.95, 1.03]

8 Treated acute rejection in the

ﬁrst year

2 248 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.37, 1.17]

62Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Analysis 1.1. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 1 Delayed

graft function.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 1 Delayed graft function

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

Veller 1994 6/18 5/18 2.0 % 1.20 [ 0.45, 3.23 ]

Chen 2014c 6/35 13/36 2.6 % 0.47 [ 0.20, 1.11 ]

Alijani 1985 5/29 18/29 2.6 % 0.28 [ 0.12, 0.65 ]

Kwiatkowski 1996 11/34 17/34 4.8 % 0.65 [ 0.36, 1.17 ]

Heil 1987 14/27 11/27 4.9 % 1.27 [ 0.71, 2.28 ]

Merion 1990 21/51 16/51 5.8 % 1.31 [ 0.78, 2.21 ]

Matsuno 1994 8/13 11/13 6.4 % 0.73 [ 0.45, 1.19 ]

van der Vliet 2001 14/35 24/36 6.8 % 0.60 [ 0.38, 0.96 ]

Halloran 1985 24/91 33/90 7.5 % 0.72 [ 0.46, 1.11 ]

Zhong 2017 31/141 47/141 8.7 % 0.66 [ 0.45, 0.97 ]

PPART 2010 26/45 25/45 9.6 % 1.04 [ 0.72, 1.49 ]

Mozes 1985 40/93 51/94 11.8 % 0.79 [ 0.59, 1.07 ]

Tedesco-Silva 2017 36/80 49/80 11.8 % 0.73 [ 0.55, 0.99 ]

Moers 2009 92/376 118/376 14.7 % 0.78 [ 0.62, 0.98 ]

Total (95% CI) 1068 1070 100.0 % 0.77 [ 0.67, 0.90 ]

Total events: 334 (HMP), 438 (SCS)

Heterogeneity: Tau2= 0.02; Chi2= 19.51, df = 13 (P = 0.11); I2=33%

Test for overall effect: Z = 3.45 (P = 0.00056)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

63Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Analysis 1.2. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 2 Delayed

graft function: type of donor.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 2 Delayed graft function: type of donor

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

1 DCD

Chen 2014c 6/35 13/36 2.2 % 0.47 [ 0.20, 1.11 ]

Kwiatkowski 1996 11/34 17/34 4.2 % 0.65 [ 0.36, 1.17 ]

Matsuno 1994 8/13 11/13 5.7 % 0.73 [ 0.45, 1.19 ]

van der Vliet 2001 14/35 24/36 6.1 % 0.60 [ 0.38, 0.96 ]

Zhong 2017 31/141 47/141 8.0 % 0.66 [ 0.45, 0.97 ]

PPART 2010 26/45 25/45 8.8 % 1.04 [ 0.72, 1.49 ]

Moers 2009 44/82 57/82 13.5 % 0.77 [ 0.60, 0.99 ]

Subtotal (95% CI) 385 387 48.4 % 0.75 [ 0.64, 0.87 ]

Total events: 140 (HMP), 194 (SCS)

Heterogeneity: Tau2= 0.00; Chi2= 6.03, df = 6 (P = 0.42); I2=1%

Test for overall effect: Z = 3.74 (P = 0.00018)

2 DBD

Veller 1994 6/18 5/18 1.7 % 1.20 [ 0.45, 3.23 ]

Moers 2009 48/294 61/294 9.4 % 0.79 [ 0.56, 1.11 ]

Mozes 1985 40/93 51/94 11.1 % 0.79 [ 0.59, 1.07 ]

Tedesco-Silva 2017 36/80 49/80 11.1 % 0.73 [ 0.55, 0.99 ]

Subtotal (95% CI) 485 486 33.2 % 0.78 [ 0.65, 0.93 ]

Total events: 130 (HMP), 166 (SCS)

Heterogeneity: Tau2= 0.0; Chi2= 0.90, df = 3 (P = 0.83); I2=0.0%

Test for overall effect: Z = 2.75 (P = 0.0060)

3 Type of donor not speciﬁed

Alijani 1985 5/29 18/29 2.2 % 0.28 [ 0.12, 0.65 ]

Heil 1987 14/27 11/27 4.3 % 1.27 [ 0.71, 2.28 ]

Merion 1990 21/51 16/51 5.1 % 1.31 [ 0.78, 2.21 ]

Halloran 1985 24/91 33/90 6.7 % 0.72 [ 0.46, 1.11 ]

Subtotal (95% CI) 198 197 18.4 % 0.81 [ 0.46, 1.44 ]

Total events: 64 (HMP), 78 (SCS)

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

(Continued ...)

64Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

(... Continued)

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

Heterogeneity: Tau2= 0.25; Chi2= 11.96, df = 3 (P = 0.01); I2=75%

Test for overall effect: Z = 0.72 (P = 0.47)

Total (95% CI) 1068 1070 100.0 % 0.78 [ 0.68, 0.89 ]

Total events: 334 (HMP), 438 (SCS)

Heterogeneity: Tau2= 0.02; Chi2= 19.52, df = 14 (P = 0.15); I2=28%

Test for overall effect: Z = 3.77 (P = 0.00016)

Test for subgroup differences: Chi2= 0.17, df = 2 (P = 0.92), I2=0.0%

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

Analysis 1.3. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 3 Delayed

graft function: era of study.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 3 Delayed graft function: era of study

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

1 Modern era

Chen 2014c 6/35 13/36 2.6 % 0.47 [ 0.20, 1.11 ]

Zhong 2017 31/141 47/141 8.7 % 0.66 [ 0.45, 0.97 ]

PPART 2010 26/45 25/45 9.6 % 1.04 [ 0.72, 1.49 ]

Tedesco-Silva 2017 36/80 49/80 11.8 % 0.73 [ 0.55, 0.99 ]

Moers 2009 92/376 118/376 14.7 % 0.78 [ 0.62, 0.98 ]

Subtotal (95% CI) 677 678 47.4 % 0.77 [ 0.66, 0.91 ]

Total events: 191 (HMP), 252 (SCS)

Heterogeneity: Tau2= 0.01; Chi2= 4.69, df = 4 (P = 0.32); I2=15%

Test for overall effect: Z = 3.03 (P = 0.0025)

2 Pre-2008

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

(Continued ...)

65Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

(... Continued)

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

Veller 1994 6/18 5/18 2.0 % 1.20 [ 0.45, 3.23 ]

Alijani 1985 5/29 18/29 2.6 % 0.28 [ 0.12, 0.65 ]

Kwiatkowski 1996 11/34 17/34 4.8 % 0.65 [ 0.36, 1.17 ]

Heil 1987 14/27 11/27 4.9 % 1.27 [ 0.71, 2.28 ]

Merion 1990 21/51 16/51 5.8 % 1.31 [ 0.78, 2.21 ]

Matsuno 1994 8/13 11/13 6.4 % 0.73 [ 0.45, 1.19 ]

van der Vliet 2001 14/35 24/36 6.8 % 0.60 [ 0.38, 0.96 ]

Halloran 1985 24/91 33/90 7.5 % 0.72 [ 0.46, 1.11 ]

Mozes 1985 40/93 51/94 11.8 % 0.79 [ 0.59, 1.07 ]

Subtotal (95% CI) 391 392 52.6 % 0.78 [ 0.61, 0.99 ]

Total events: 143 (HMP), 186 (SCS)

Heterogeneity: Tau2= 0.06; Chi2= 14.81, df = 8 (P = 0.06); I2=46%

Test for overall effect: Z = 2.06 (P = 0.039)

Total (95% CI) 1068 1070 100.0 % 0.77 [ 0.67, 0.90 ]

Total events: 334 (HMP), 438 (SCS)

Heterogeneity: Tau2= 0.02; Chi2= 19.51, df = 13 (P = 0.11); I2=33%

Test for overall effect: Z = 3.45 (P = 0.00056)

Test for subgroup differences: Chi2= 0.00, df = 1 (P = 0.97), I2=0.0%

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

66Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Analysis 1.4. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 4 Delayed

graft function: preservation times.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 4 Delayed graft function: preser vation times

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

1 Short mean cold ischaemic time (< 24 hours)

Veller 1994 6/18 5/18 2.0 % 1.20 [ 0.45, 3.23 ]

Merion 1990 21/51 16/51 5.8 % 1.31 [ 0.78, 2.21 ]

Matsuno 1994 8/13 11/13 6.4 % 0.73 [ 0.45, 1.19 ]

Zhong 2017 31/141 47/141 8.7 % 0.66 [ 0.45, 0.97 ]

PPART 2010 26/45 25/45 9.6 % 1.04 [ 0.72, 1.49 ]

Moers 2009 92/376 118/376 14.7 % 0.78 [ 0.62, 0.98 ]

Subtotal (95% CI) 644 644 47.2 % 0.86 [ 0.70, 1.04 ]

Total events: 184 (HMP), 222 (SCS)

Heterogeneity: Tau2= 0.02; Chi2= 6.90, df = 5 (P = 0.23); I2=28%

Test for overall effect: Z = 1.53 (P = 0.13)

2 Long mean cold ischaemic time (≥24 hour s)

Alijani 1985 5/29 18/29 2.6 % 0.28 [ 0.12, 0.65 ]

Kwiatkowski 1996 11/34 17/34 4.8 % 0.65 [ 0.36, 1.17 ]

van der Vliet 2001 14/35 24/36 6.8 % 0.60 [ 0.38, 0.96 ]

Halloran 1985 24/91 33/90 7.5 % 0.72 [ 0.46, 1.11 ]

Mozes 1985 40/93 51/94 11.8 % 0.79 [ 0.59, 1.07 ]

Tedesco-Silva 2017 36/80 49/80 11.8 % 0.73 [ 0.55, 0.99 ]

Subtotal (95% CI) 362 363 45.3 % 0.69 [ 0.57, 0.83 ]

Total events: 130 (HMP), 192 (SCS)

Heterogeneity: Tau2= 0.01; Chi2= 5.93, df = 5 (P = 0.31); I2=16%

Test for overall effect: Z = 3.94 (P = 0.000083)

3 Cold ischaemic time not repor ted

Chen 2014c 6/35 13/36 2.6 % 0.47 [ 0.20, 1.11 ]

Heil 1987 14/27 11/27 4.9 % 1.27 [ 0.71, 2.28 ]

Subtotal (95% CI) 62 63 7.5 % 0.82 [ 0.31, 2.18 ]

Total events: 20 (HMP), 24 (SCS)

Heterogeneity: Tau2= 0.37; Chi2= 3.68, df = 1 (P = 0.05); I2=73%

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

(Continued ...)

67Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

(... Continued)

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

Test for overall effect: Z = 0.41 (P = 0.68)

Total (95% CI) 1068 1070 100.0 % 0.77 [ 0.67, 0.90 ]

Total events: 334 (HMP), 438 (SCS)

Heterogeneity: Tau2= 0.02; Chi2= 19.51, df = 13 (P = 0.11); I2=33%

Test for overall effect: Z = 3.45 (P = 0.00056)

Test for subgroup differences: Chi2= 2.56, df = 2 (P = 0.28), I2=22%

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

Analysis 1.5. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 5 Primary

non-function.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 5 Primar y non-function

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

PPART 2010 1/45 0/45 1.7 % 3.00 [ 0.13, 71.74 ]

Matsuno 1994 0/13 1/13 1.8 % 0.33 [ 0.01, 7.50 ]

Tedesco-Silva 2017 2/80 0/80 1.9 % 5.00 [ 0.24, 102.53 ]

van der Vliet 2001 6/35 4/36 12.4 % 1.54 [ 0.48, 5.00 ]

Moers 2009 7/336 16/336 22.3 % 0.44 [ 0.18, 1.05 ]

Mozes 1985 9/93 11/94 24.7 % 0.83 [ 0.36, 1.90 ]

Halloran 1985 14/91 13/90 35.3 % 1.07 [ 0.53, 2.14 ]

Total (95% CI) 693 694 100.0 % 0.88 [ 0.58, 1.33 ]

Total events: 39 (HMP), 45 (SCS)

Heterogeneity: Tau2= 0.0; Chi2= 5.85, df = 6 (P = 0.44); I2=0.0%

Test for overall effect: Z = 0.60 (P = 0.55)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Less with HMP Less with SCS

68Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Analysis 1.6. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 6

Duration of DGF.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 6 Duration of DGF

Study or subgroup HMP SCS

Mean

Difference Weight

Mean

Difference

N Mean(SD)[days] N Mean(SD)[days] IV,Random,95% CI IV,Random,95% CI

Tedesco-Silva 2017 36 10 (13) 49 9 (6.7) 22.7 % 1.00 [ -3.64, 5.64 ]

Matsuno 1994 8 8 (4.5) 11 12.4 (4.5) 23.9 % -4.40 [ -8.50, -0.30 ]

Mozes 1985 40 15 (9.6) 51 11 (6.8) 25.1 % 4.00 [ 0.49, 7.51 ]

Heil 1987 14 9.9 (2) 11 14.9 (2.2) 28.3 % -5.00 [ -6.67, -3.33 ]

Total (95% CI) 98 122 100.0 % -1.23 [ -5.87, 3.40 ]

Heterogeneity: Tau2= 19.07; Chi2= 24.06, df = 3 (P = 0.00002); I2=88%

Test for overall effect: Z = 0.52 (P = 0.60)

Test for subgroup differences: Not applicable

-10 -5 0 5 10

Shorter with HMP Shorter with SCS

69Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Analysis 1.7. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 7 One

year patient survival.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 7 One year patient survival

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

Tedesco-Silva 2017 75/80 71/78 14.1 % 1.03 [ 0.94, 1.13 ]

PPART 2010 42/45 45/45 14.5 % 0.93 [ 0.86, 1.02 ]

Moers 2009 325/336 327/336 71.4 % 0.99 [ 0.97, 1.02 ]

Total (95% CI) 461 459 100.0 % 0.99 [ 0.95, 1.03 ]

Total events: 442 (HMP), 443 (SCS)

Heterogeneity: Tau2= 0.00; Chi2= 2.50, df = 2 (P = 0.29); I2=20%

Test for overall effect: Z = 0.55 (P = 0.58)

Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

More with SCS More with HMP

70Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Analysis 1.8. Comparison 1 Hypothermic machine perfusion versus static cold storage, Outcome 8 Treated

acute rejection in the ﬁrst year.

Review: Machine perfusion preser vation versus static cold storage for deceased donor kidney transplantation

Comparison: 1 Hypothermic machine perfusion versus static cold storage

Outcome: 8 Treated acute rejection in the ﬁrst year

Study or subgroup HMP SCS Risk Ratio Weight Risk Ratio

n/N n/N

M-

H,Random,95%

M-

H,Random,95%

PPART 2010 4/45 10/45 25.8 % 0.40 [ 0.14, 1.18 ]

Tedesco-Silva 2017 16/80 20/78 74.2 % 0.78 [ 0.44, 1.39 ]

Total (95% CI) 125 123 100.0 % 0.66 [ 0.37, 1.17 ]

Total events: 20 (HMP), 30 (SCS)

Heterogeneity: Tau2= 0.03; Chi2= 1.15, df = 1 (P = 0.28); I2=13%

Test for overall effect: Z = 1.43 (P = 0.15)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Less with HMP Less with SCS

A D D I T I O N A L T A B L E S

Table 1. Comparison of preservation solution composition

Solution

name

Energy

substrate

N+K+M2+ Ca2+ pH Buffer Osm Impermeant

Euro-

Collins

Glucose 10 108 0 0 7.4 Bicarbonate/

phosphate

340 Glucose

UW Adenosine 30 125 5 - 7.4 Phosphate 325 Lactobionate

/rafﬁnose

HTK Ketoglu-

tarate

15 10 4 0.015 7.02 to 7.2 Histidine 310 Mannitol

Belzer’s Adenine 100 25 5 0.5 7.4 HEPES 320 Gluconate

/ribose

PBS140 - 92 0 0 0 7.2 Phosphate 310 Sucrose

Celsion® Glutamate 100 15 13 0.25 7.3 Histidine 320 Lactobionate

/mannitol

71Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Table 1. Comparison of preservation solution composition (Continued)

Marshall’s

hyperos-

molar cit-

rate

Citrate 28 26 41 - 7.1 Citrate 486 Mannitol

HEPES - N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid; HTK - histidine-tryptophan-ketoglutarate; Osm - osmolality; THAM

- trometamol; tris-hydroxymethyl aminomethane; UW - University of Wisconsin

Table 2. Summary of studies reporting one-year graft survival

Study ID Number of participants One year graft survival results Information

Chen 2014c 72 SCS: 91.7%

HMP: 97.2%

(P = 0.307)

No information on how percentages

were calculated. Therefore, likely not

time-to-event analysis, and unknown

whether graft survival was censored for

death. Insufﬁcient information to as-

sess how many patients were followed-

up for a full year

Halloran 1985 181 SCS 69.5%

HMP 74.9%

(“not signiﬁcant”)

Survival % is from cox regression time-

to-event analysis. No P value or fur-

ther information was provided which

may allow inclusion in a meta-analysis.

Death counted as graft failure. Most

patients were not followed up for a full

year but no further information was

given on this

Moers 2009 672 in graft survival analysis SCS 90%

HMP 94%

(P = 0.04)

Cox HR 0.52 (P = 0.03)

Used log-rank and cox proportional

hazards model. Graft survival censored

for death (in those dying with a func-

tioning graft). Graft survival rates are a

result of this time-to-event death cen-

sored analysis

PPART 2010 90 SCS 44/45 (97.8%)

MP 42/45 (93.3%)

(P = 0.3)

They give actual numbers for numbers

of grafts which failed by 1 year. Death

was not counted as graft failure. Time-

to-event analysis not performed

Tedesco-Silva 2017 160 SCS 72/78 (92.3%)

HMP 72/80 (90%)

(P = 1.000)

They give actual numbers for numbers

of grafts which failed by 1 year. Death

was not counted as graft failure. Time-

to-event analysis not performed

72Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Table 2. Summary of studies reporting one-year graft survival (Continued)

van der Vliet 2001 76 SCS 84.2%

HMP 76.3%

No information on how percentages

were calculated. Therefore, likely not

time-to-event analysis, and unknown

whether graft survival was censored for

death. Insufﬁcient information to as-

sess how many patients were followed-

up for a full year. No P value was re-

ported

Veller 1994 36 SCS 82%

HMP 83%

No information on how percentages

were calculated. Therefore, likely not

time-to-event analysis, and unknown

whether graft survival was censored for

death. Insufﬁcient information to as-

sess how many patients were followed-

up for a full year. No P value was re-

ported

Zhong 2017 282 SCS 93%

HMP 98%

(P = 0.026)

Graft survival was analysed using a log-

rank test. Graft survival was censored

for death (in those dying with a func-

tioning graft). Graft survival estimates

are based on time-to-event analysis and

raw data for number of graft losses was

not given. Hazard ratios were not re-

ported

HMP - hypothermic machine perfusion; SCS - static cold storage

A P P E N D I C E S

Appendix 1. Electronic search strategies

Database Search terms

CENTRAL 1. MeSH descriptor: [Kidney Transplantation] this term only

2. MeSH descriptor: [Organ Preservation] this term only

3. MeSH descriptor: [Organ Preservation Solutions] this term only

4. MeSH descriptor: [Perfusion] this term only

5. machine perfusion:ti,ab,kw (Word variations have been searched)

6. “cold storage”:ti,ab,kw (Word variations have been searched)

73Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

(Continued)

7. celsior:ti,ab,kw (Word variations have been searched)

8. “euro collins”:ti,ab,kw (Word variations have been searched)

9. “university of wisconsin”:ti,ab,kw (Word variations have been searched)

10. kyoto:ti,ab,kw (Word variations have been searched)

11. htk:ti,ab,kw (Word variations have been searched)

12. histidine tryptophan:ti,ab,kw (Word variations have been searched)

13. custodiol or marshall’s or hyperosmolar citrate or soltran:ti,ab,kw (Word variations have been searched)

14. {or #2-#13}

15. {and #1, #14}

MEDLINE (OVID) 1. Kidney Transplantation/

2. Organ Preservation Solutions/

3. Organ Preservation/

4. Perfusion/

5. machine perfusion.tw.

6. cold storage.tw.

7. celsior.tw.

8. “euro collins”.tw.

9. “university of wisconsin”.tw.

10. “kyoto et”.tw.

11. htk.tw.

12. histidine tryptophan.tw.

13. custodiol.tw

14. marshall$.tw

15. hyperosmolar citrate.tw

16. soltran.tw

17. or/2-16

18. and/1,17

EMBASE (OVID) 1. exp preservation solution/

2. organ preservation/

3. “preservation and storage”/

4. kidney preservation/

5. organ perfusion/ or perfusion/ or kidney perfusion/

6. machine perfusion.tw.

7. cold storage.tw.

8. celsior.tw.

9. “euro collins”.tw.

10. “university of wisconsin”.tw.

11. “kyoto et”.tw.

12. htk.tw.

13. histidine tryptophan.tw.

14. (custodiol or marshall$ or hyperosmolar citrate or soltran).tw

15. or/2-14

16. and/1,15

74Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inade-

quate generation of a randomised sequence

Low risk of bias: Random number table; computer random num-

ber generator; coin tossing; shufﬂing cards or envelopes; throwing

dice; drawing of lots; minimization (minimization may be imple-

mented without a random element, and this is considered to be

equivalent to being random)

High risk of bias: Sequence generated by odd or even date of birth;

date (or day) of admission; sequence generated by hospital or

clinic record number; allocation by judgement of the clinician; by

preference of the participant; based on the results of a laboratory

test or a series of tests; by availability of the intervention

Unclear: Insufﬁcient information about the sequence generation

process to permit judgement

Allocation concealment

Selection bias (biased allocation to interventions) due to inade-

quate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not

allow investigator/participant to know or inﬂuence intervention

group before eligible participant entered in the study (e.g. central

allocation, including telephone, web-based, and pharmacy-con-

trolled, randomisation; sequentially numbered drug containers of

identical appearance; sequentially numbered, opaque, sealed en-

velopes)

High risk of bias: Using an open random allocation schedule (e.g. a

list of random numbers); assignment envelopes were used without

appropriate safeguards (e.g. if envelopes were unsealed or non-

opaque or not sequentially numbered); alternation or rotation;

date of birth; case record number; any other explicitly unconcealed

procedure

Unclear: Randomisation stated but no information on method

used is available

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions

by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the re-

view authors judge that the outcome is not likely to be inﬂuenced

by lack of blinding; blinding of participants and key study per-

sonnel ensured, and unlikely that the blinding could have been

broken

High risk of bias: No blinding or incomplete blinding, and the

outcome is likely to be inﬂuenced by lack of blinding; blinding

of key study participants and personnel attempted, but likely that

the blinding could have been broken, and the outcome is likely

to be inﬂuenced by lack of blinding

Unclear: Insufﬁcient information to permit judgement

75Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

(Continued)

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by

outcome assessors

Low risk of bias: No blinding of outcomeassessment, but the review

authors judge that the outcome measurement is not likely to be

inﬂuenced by lack of blinding; blinding of outcome assessment

ensured, and unlikely that the blinding could have been broken

High risk of bias: No blinding of outcome assessment, and the

outcome measurement is likely to be inﬂuenced by lack of blind-

ing; blinding of outcome assessment, but likely that the blinding

could have been broken, and the outcome measurement is likely

to be inﬂuenced by lack of blinding

Unclear: Insufﬁcient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete

outcome data

Low risk of bias: No missing outcome data; reasons for missing

outcome data unlikely to be related to true outcome (for survival

data, censoring unlikely to be introducing bias); missing outcome

data balanced in numbers across intervention groups, with similar

reasons for missing data across groups; for dichotomous outcome

data, the proportion of missing outcomes compared with observed

event risk not enough to have a clinically relevant impact on the

intervention effect estimate; for continuous outcome data, plau-

sible effect size (difference in means or standardized difference in

means) among missing outcomes not enough to have a clinically

relevant impact on observed effect size; missing data have been

imputed using appropriate methods

High risk of bias: Reason for missing outcome data likely to be

related to true outcome, with either imbalance in numbers or rea-

sons for missing data across intervention groups; for dichotomous

outcome data, the proportion of missing outcomes compared with

observed event risk enough to induce clinically relevant bias in

intervention effect estimate; for continuous outcome data, plau-

sible effect size (difference in means or standardized difference in

means) among missing outcomes enough to induce clinically rel-

evant bias in observed effect size; ‘as-treated’ analysis done with

substantial departure of the intervention received from that as-

signed at randomisation; potentially inappropriate application of

simple imputation

Unclear: Insufﬁcient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the

study’s pre-speciﬁed (primary and secondary) outcomes that are of

interest in the review have been reported in the pre-speciﬁed way;

the study protocol is not available but it is clear that the published

reports include all expected outcomes, including those that were

pre-speciﬁed (convincing text of this nature may be uncommon)

76Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation (Review)

(Continued)

High risk of bias: Not all of the study’s pre-speciﬁed primary out-

comes have been reported; one or more primary outcomes is re-

ported using measurements, analysis methods or subsets of the

data (e.g. subscales) that were not pre-speciﬁed; one or more re-

ported primary outcomes were not pre-speciﬁed (unless clear jus-

tiﬁcation for their reporting is provided, such as an unexpected

adverse effect); one or more outcomes of interest in the review are

reported incompletely so that they cannot be entered in a meta-

analysis; the study report fails to include results for a key outcome

that would be expected to have been reported for such a study

Unclear: Insufﬁcient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of

bias.

High risk of bias: Had a potential source of bias related to the spe-

ciﬁc study design used; stopped early due to some data-dependent

process (including a formal-stopping rule); had extreme baseline

imbalance; has been claimed to have been fraudulent; had some

Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation

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