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Available online at www.sciencedirect.com

journal homepage: www.JournalofSurgicalResearch.com

Hypothermic machine perfusion in deceased donor kidney


transplantation: a systematic review

Vincent W.T. Lam, MBBS, MS, FRACS,a,b,* Jerome M. Laurence, MBChB, MRCS, FRACS, PhD,a,b
Arthur J. Richardson, MBBS, FRACS,a,b Henry C.C. Pleass, MD, FRCS, FRACS,a,b,c
and Richard D.M. Allen, MBBS, FRACSa,b,c
a
Discipline of Surgery, Sydney Medical School, University of Sydney, New South Wales, Australia
b
Department of Surgery, Westmead Hospital, Sydney, Australia
c
Transplantation Services, Royal Prince Alfred Hospital, Sydney, Australia

article info abstract

Article history: Background: Hypothermic machine perfusion (HMP) of kidneys is intended to mitigate the
Received 30 June 2012 deleterious effects of cold storage on organ quality, particularly when the cold ischemic
Received in revised form time is prolonged or the donor is otherwise marginal. The use of HMP has remained
5 October 2012 controversial; however, a number of randomized controlled trials (RCTs) have recently
Accepted 26 October 2012 been conducted to clarify its benefits.
Available online 15 November 2012 Methods: We undertook a systematic search of the Medline and Embase databases and of
the Cochrane Central Register of Controlled Trials. We included only RCTs in the meta-
Keywords: analysis. Outcomes analyzed were the incidence of delayed graft function (DGF), primary
Kidney transplantation nonfunction (PNF), graft loss, and patient death at 1 y.
Renal transplantation Results: We identified seven RCT trials and subjected them to meta-analysis, including 1353
Deceased donor kidney transplant recipients. Hypothermic machine perfusion significantly reduced the
Machine perfusion incidence of DGF (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.72e0.96). There was no
Hypothermic machine perfusion difference in the incidence of PNF (RR 0.78, 95% CI 0.36e1.68), graft loss at 1 y (RR 0.87, 95%
Delayed graft function CI 0.64e1.19), and patient death at 1 y (RR 0.91, 95% CI 0.60e1.37) between HMP and donor
Systematic review kidneys preserved using cold storage.
Meta-analysis Conclusions: There are few RCT comparing HMP and cold storage of kidneys in deceased
donor kidney transplantation. Although these studies are small and heterogeneous in
design, HMP appeared to be associated with a reduced incidence of DGF. No difference
in the incidence of PNF, graft loss, or patient death at 1 y could be demonstrated.
Crown Copyright ª 2013 Published by Elsevier Inc. All rights reserved.

1. Introduction ischemic injury to the graft before and during organ


procurement, and is further aggravated by the reperfusion
Delayed graft function (DGF) and primary nonfunction (PNF) syndrome [2]. Optimization of graft quality under conditions
are well-known complications after kidney transplantation. of prolonged ischemia thus represents the primary goal of
The frequency of DGF and PNF in deceased donor kidney deceased donor kidney preservation. To date, the predomi-
transplantation ranges from 2% to 50% and 2% to 15%, nant organ preservation method of deceased donor kidneys
respectively [1]. Delayed graft function is usually the result of used by most centers is static cold storage (CS). Cold storage

* Corresponding author. Department of Surgery, Westmead Hospital, PO Box 533, Wentworthville, NSW 2145, Australia. Tel.: þ61 2 9845
7365; fax: þ61 2 9893 7440.
E-mail address: vincent.lam@sydney.edu (V.W.T. Lam).
0022-4804/$ e see front matter Crown Copyright ª 2013 Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jss.2012.10.055
j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 0 ( 2 0 1 3 ) 1 7 6 e1 8 2 177

preservation is based on the suppression of metabolism by


hypothermia. Blood is removed by flushing the kidney and
replaced with an appropriate cooled preservation solution [3].
The concept of hypothermic machine perfusion (HMP) of
deceased donor kidneys, which had been developed before the
routine use of CS preservation, provides an attractive alter-
native [4]. Hypothermic machine perfusion is based on
a controlled continuous circulation of a perfusate, which,
although not oxygenated or refreshed during storage, has
been hypothesized to protect the deceased donor kidneys
from injuries related to ischemia and reperfusion [5]. This
protection may be particularly important when the cold
ischemic time is prolonged or the donor is otherwise marginal.
Several clinical studies have compared HMP with CS
preservation of deceased donor kidneys. Early reports showed
no significant difference in DGF or graft survival rates when
comparing HMP and CS preservation [6,7]. In 2003, Wight et al
[8] published a systematic review and meta-analysis, and
demonstrated a 20% reduction in DGF when HMP was used.
More recently, two randomized controlled trials (RCTs) using
modern immunosuppression were conducted and showed
contradictory results [9,10].
The primary aim of this study was to assess evidence for the
effect of HMP compared with CS of donor kidneys on delayed
graft function using a systematic review and meta-analysis of
the available RCTs. We assessed the impact of HMP on rates
of primary nonfunction, graft loss, and patient death at 1 y.

2. Methods

2.1. Search methods

We undertook a comprehensive search through October 2011,


including the Cochrane Central Register of Controlled Trials,
MEDLINE, and EMABSE, with additional reports identified
from hand-searching conference proceedings and reference
lists of included studies. Two reviewers (V.L. and J.L.) inde-
pendently performed search strategies. When there was more
than one report from an individual trial, all reports were
examined for any available data. The publication reporting the
most outcome data was designated the index publication, and
is referenced in this report. Figure 1 shows the search strategy.

2.2. Selection criteria and study outcomes

We included all RCTs of parallel design comparing HMP versus


CS of kidneys for deceased donor kidney transplantation,
irrespective of blinding, sample size, publication status (i.e., Fig. 1 e Flowchart showing the process of identifying
whether published as the full text or presented only as an randomized controlled trials for inclusion in systematic
abstract at a conference), and language. We excluded quasi- review. RCT [ randomized controlled trial.
randomized trials and other study designs. Primary
outcomes analyzed were the incidence of DGF and graft loss at
1 y. Secondary outcomes sought were the incidence of PNF paper version to identify eligible trials. Two reviewers
and patient death at 1 y. extracted data independently, using a standardized form.
We assessed methodological quality of trials according to
2.3. Data collection and analysis the method recommended by the Cochrane Collaboration
[11]. We analyzed data using Review Manager (RevMan,
Two reviewers (V.L. and J.L.) independently screened search Version 5.1.4; The Cochrane Collaboration, Copenhagen,
results using titles, abstracts, and, where necessary, the full Denmark).
178 j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 0 ( 2 0 1 3 ) 1 7 6 e1 8 2

Table 1 e Characteristics of trials included in review.


Study Year Donor Preservation HMP model CS perfusate Initial
type method immunosuppression
(BDD/NHBD) (HMP/CP)

Mozes et al [15] 1985 All BDD 93/94 Waters MOX-100 Euro-Collin solution 38 AZA and steroids
120 ALG
29 CYC
Heil et al [17] 1987 All BDD 27/27 Waters MOX-100 Euro-Collin solution NS
Halloran and 1987 All BDD 91/90 Waters MOX-100 Euro-Collin solution CsA and steroids
Aprile [16] AZA and steroids
ALG, AZA  CsA and
steroids
Jaffers and 1989 All BDD 136/66 Waters MOX-100 Euro-Collin solution CsA
Banowsky [18] 10 kidneys with
Gambro machine
Kwiatkowski 2009 All BDD 37/37 Waters MOX-100 NS CsA, AZA, and steroids
et al [19]
Moers et al [9] 2009 588 BDD 336/336 LifePort NS Majority CsA or Tac-based
84 NHBD Kidney therapy
Transporter machines
Watson et al [10] 2010 All NHBD 45/45 LifePort University of Basliximab, Tac, MMF, and
Kidney Wisconsin solution steroids
Transporter machines

AZA ¼ azathioprine; ALG ¼ antilymphocyte globulin; BDD ¼ brain death donor; CsA ¼ cyclosporine; MMF ¼ mycophenolate sodium; NS ¼ not
stated; Tac ¼ tacrolimus.

2.4. Quantitative data synthesis and data analysis 1353 kidney transplant recipients, in the review [9,10,15e19].
Table 1 depicts the characteristics of these trials. Four of
We compared interventions with data synthesis using the the seven trials were published before 1990, whereas the
random effects method of DerSimonian and Laird [12]. We remaining three were published after 2000. Five of the seven
expressed results for dichotomous outcomes as the risk ratio trials included only HBD. The two most recent studies included
(RR) with 95% confidence intervals (CIs), with values <1 12.5% and 100% of NHBD [9,10]. Five trials used the Waters
favoring HMP. MOX-100 Transport Unit (Waters Instruments Inc., Rochester,
We assessed heterogeneity among trials using inspection of NY); the remaining two used the LifePort Kidney Transporter
forest plots and Cochran’s Q test, and calculating the I2 statistic machines (Organ Recovery Systems, Chicago, IL) for HMP. Four
(P < 0.05 and > 50%, respectively, considered evidence of early trials used Euro-Collin solution for CS perfusate, whereas
significant heterogeneity) to measure the proportion of total one used University of Wisconsin solution. Two trials did not
variation resulting from heterogeneity beyond chance [13]. specify the CS perfusate. No specific initial immunosuppres-
We performed subgroup analysis for the primary and sion regimen was used among the seven trials.
secondary outcomes to explore important clinical differences
among trials that might be expected to alter the magnitude of 3.1.2. Quality of included trials
treatment effects. Subgroups, defined a priori, were publica- There was some deficiency of reporting of methods for most
tion year (before 2000 versus after 2000), type of deceased trials. Table 2 depicts the risk of bias summary. Sequence
donor (heart-beating donor [HBD] versus noneheart-beating generation was adequate in two trials and unclear in the
donor [NHBD]) and specific immunosuppression regimen remaining five. Allocation concealment was judged to be
used. We chose these subgroups because older immunosup- adequate to minimize selection bias in two trials, unclear in
pression regimens and NHBD have been shown to be asso- four, and inadequate in one. Blinding was judged to be
ciated with poorer outcomes after kidney transplantation adequate to prevent bias for objective outcomes in two trials,
[1,14]. In addition, we assessed publication bias by using unclear in four, and inadequate in one. Blinding methodology
funnel plots of the log risk ratio. was judged to be adequate to prevent bias for outcomes in two
trials and unclear in five. The quality of outcome data
reporting was adequate in two trials, unclear in two, and
3. Results inadequate in three. There was no selective reporting of
outcomes in two trials; in four trials this was unclear, and in
3.1. Systematic review and meta-analysis one trial selective reporting was evident. Other bias was
categorized as unclear in all seven trials.
3.1.1. Included trials
We included seven randomized controlled trials comparing 3.1.3. Outcomes
HMP with CS of donor kidneys for deceased donor kidney All seven trials reported the incidence of DGF after trans-
transplantation, including a total of 1353 donor kidneys and plantation. Five trials defined DGF as the requirement of
j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 0 ( 2 0 1 3 ) 1 7 6 e1 8 2 179

Table 2 e Risk of bias summary: Review authors’ judgments about each risk of bias item for each included study.
Random Allocation Blinding of Blinding of Incomplete Selective Other
sequence concealment participants outcome outcome data reporting bias
generation (selection and personnel assessment (attrition (reporting
(selection bias) (performance (detection bias) bias)
bias) bias) bias)

Halloran and
Aprile [16]

Heil et al [17]

Jaffers and
Banowsky [18]

Kwiatkowski
et al [19]

Moers et al [9]

Mozes et al [15]

Watson et al [10]

(Color version of Table is available online.)

dialysis within 1 wk of transplantation. One trial defined DGF Four trials reported the incidence of patient death at 1 y.
as the requirement of dialysis after transplantation with no Although there was a trend favoring the use of HMP, the
specific time period, and one other trial did not provide incidence of patient death at 1 y was not significantly different
a definition of DGF. The incidence of DGF was significantly between HMP and CS groups (RR ¼ 0.64; 95% CI 0.60e1.37; P ¼
reduced in the HMP group compared with the CS group 0.64) (Fig. 2D). There was no evidence of heterogeneity among
(RR ¼ 0.83; 95% CI 0.72e0.96; P ¼ 0.01) (Fig. 2A). There was no the trials (I2 ¼ 0% and P ¼ 0.41). For patient death at 1 y, we did
evidence of heterogeneity (I2 ¼ 0% and P ¼ 0.50). Funnel plots not assess publication bias because of the small number of
were also symmetrical, suggesting the absence of publication trials included for analysis.
bias (Fig. 3A).
Only three trials reported the incidence of PNF after 3.1.4. Subgroup analyses
transplantation. The definition of PNF was different in all W performed subgroup analyses for publication year and type
three studies: namely, “never attaining plasma creatinine of deceased donor, but not for specific immunosuppression
<500 mmol/L and/or always requiring dialysis”; or “perma- regimen used, because there were insufficient data for anal-
nent lack of function of the allograft from the time of ysis of this variable. Two outcomes were reported sufficiently
transplantation”; or “a graft that failed to provide 1-mo frequently to allow investigation: namely, DGF and graft loss
dialysis-free survival excluding losses attributable to rejec- at 1 y. There was no evidence of a difference for DGF and graft
tion or vascular thrombosis.” Although there was a trend loss at 1 y on the basis of publication year or type of deceased
favoring the use of HMP, the incidence of PNF was not donor (Table 3).
significantly different between HMP and CS groups
(RR ¼ 0.76; 95% CI 0.45e1.28; P ¼ 0.30) (Fig. 2B). Heterogeneity
was evident but not statistically significant among the trials 4. Discussion
(I2 ¼ 37% and P ¼ 0.21). For PNF, we did not assess publication
bias because of the small number of trials available for Cold storage is the most widely used preservation method in
analysis. kidney transplantation today. This meta-analysis of seven
Six trials reported the incidence of graft loss at 1 y. randomized controlled trials involving 1353 kidney transplant
The incidence of graft loss at 1 y was not significantly different recipients showed that whereas HMP of deceased donor
between HMP and CS groups (RR ¼ 0.87; 95% CI 0.64e1.19; kidneys significantly reduced the incidence of DGF, it had no
P ¼ 0.39) (Fig. 2C). There was moderate although not statisti- effect on PNF, graft loss at 1 y, and patient death at 1 y for both
cally significant heterogeneity among the trials (I2 ¼ 42% and HBD and NHBD. These results are consistent with a previous
P ¼ 0.12). There was no funnel plot asymmetry suggesting the systematic review in 2003 showing that HMP reduced the
absence of publication bias (Fig. 3B). incidence of DGF but had no difference on 1-y graft survival
180 j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 0 ( 2 0 1 3 ) 1 7 6 e1 8 2

Fig. 2 e Forest plots illustrating the meta-analysis of outcomes in HMP versus CS of donor kidneys for deceased donor
kidney transplantation. The outcomes analyzed were (A) DGF, (B) PNF, (C) graft loss at 1 y, (D) patient death at 1 y. (Color
version of figure is available online.)

[8]. In addition, a US registry database analysis of 85,734 in graft loss at 1 y for recipients of organs preserved using
transplant kidneys also showed a significant reduction in DGF HMP. The lack of improvement in graft survival found in these
rate of 19.6% in the HMP group compared with 27.6% in the CS studies may be a consequence of a relatively short follow-up
group [20]. horizon. However, there is precedence for this finding in
The rationale for using HMP is based on the concept of data showing similar medium-term graft survival for HBD and
improving donor organ quality by both providing organs with NHBD kidneys despite higher rates of DGF in recipients of
nutrients and simultaneously eliminating toxic metabolic NHBD kidneys [21e23].
cellular products through continuous perfusate flow [3]. In To date, because demand far exceeds the supply, NHBD
theory, HMP would protect the donor kidneys from injuries has become an important source of additional donor kidney
related to ischemia or reperfusion, and thus reduce the inci- throughout the world. Organs from NHBD are subjected to
dence of DGF. Reducing the incidence of DGF would be ex- a period of warm ischemia, which affects post-transplant
pected to lead to less use of dialysis postoperatively as well as graft function adversely [24]. Previous studies have sug-
a shorter length of hospital stay [2]. Although DGF has been gested that HMP of NHBD kidneys results in better early
shown to be a risk factor for graft failure after kidney trans- function and improved graft survival compared with kidneys
plantation [2], this meta-analysis did not show improvement preserved by CS [25,26]. However, two recent RCTs showed
j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 0 ( 2 0 1 3 ) 1 7 6 e1 8 2 181

A number of factors may have confounded the interpre-


tation of this meta-analysis. First, most of the studies
analyzed included a relatively small number of patients, and
the methodological quality was poor or uncertain. Second,
because the studies included span over 25 y, there have been
substantial changes in surgical techniques, perfusate, and
immunosuppression regimens. Even for the two most
recently published RCTs, the timings of the start of HMP were
different. In the trial by Moers et al [9], donor kidneys under-
went an initial period of CS of several hours before starting
HMP in the perfusion laboratory, whereas donor kidneys
underwent immediate perfusion after procurement in the
trial by Watson et al [10]. The results of these two trials were
contradictory, and it was proposed that the benefit of HMP
may require immediate rather than delayed use of HMP in
deceased donor kidneys [28]. Despite this, we observed rela-
tively little evidence of heterogeneity in statistical measures
in this meta-analysis. Patterns of care and practices in kidney
transplantation are so variable that the heterogeneity
observed in clinical trials mimics the conditions under which
HMP would be implemented in the real world. In addition,
there was no difference in DGF on subgroup analyses
according to publication year, which suggests no clear
temporal trend in the risk of this complication. In this study,
we have included only data from RCT. In contrast, an earlier
systematic review and meta-analysis combined the results of
RCT with data from other nonrandomized studies [8]. Because
we included no data from nonrandomized studies, there is
Fig. 3 e Funnel plots of comparison of HMP versus CS of
less potential for bias associated with other types of study
donor kidneys for deceased donor kidney transplantation
design, and the findings are therefore more robust.
for (A) DGF and (B) graft loss at 1 year. SE [ standard
Hypothermic machine perfusion is associated with
error. (Color version of figure is available online.)
increased direct costs to the transplant program, principally
because of the capital costs of the machine and the disposables
required to perfuse each organ. It has been suggested that
contradictory results. Watson et al [10] reported no superiority these costs may be substantially or totally defrayed by reduced
of HMP over CS for NHBD kidneys, whereas Jochmans et al [27] requirement for hospital stay and dialysis associated with
reported that HMP was associated with a reduced incidence of a reduced incidence of DGF and improved graft survival [29].
DGF and better early graft function up to 1 mo after trans- One recent economic evaluationebased data from an interna-
plantation [27]. The perceived different outcome of these two tional RCT showed that HMP reduced the risk of DGF and graft
studies might be related to the differences in study design and failure at lower costs than CS. The cost savings was $86,750
statistical approach. Another important difference between per life-year gained and the incremental cost-utility ratio
studies is the use of antithymocyte globulin, which was was e$496,223 per quality-adjusted life-year gained in favor of
administered to about 15% of recipients in the study by Joch- HMP. The authors concluded that life-years and quality-
mans et al, whereas it was not given to patients in the study by adjusted life-years could be gained while reducing costs when
Watson et al. Nevertheless, this meta-analysis demonstrated HMP of deceased donor kidneys was performed [30].
no benefit of HMP over CS in the incidence of DGF on subgroup The meta-analysis demonstrates that hypothermic
analysis. machine perfusion of deceased donor kidneys may be

Table 3 e Subgroup analysis of publication year and type of deceased donor for outcome of DGF and graft loss at 1 y.
Potential bias Subgroup strata DGF Graft loss at 1 y

Number RR (95% CI) P value* No of trials RR (95% CI) P value*


of trials

Publication year <2000 4 0.82 (0.67e1.00) 0.97 3 0.90 (0.71e1.14) 0.54


2000 3 0.82 (0.66e1.01) 3 0.78 (0.52e1.16)
Type of deceased HBD 6 0.80 (0.67e0.94) 0.40 Insufficient data
donor NHBD 2 0.91 (0.70e1.17)

* P value for test of interaction.


182 j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 0 ( 2 0 1 3 ) 1 7 6 e1 8 2

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