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RS - Máquina de Perfusão Renal
RS - Máquina de Perfusão Renal
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 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.
* 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
2. Methods
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]
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
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
associated with a reduced incidence of delayed graft function [17] Heil JE, Canafax DM, Sutherland DE, et al. A controlled
after kidney transplantation, and therefore may offer a signifi- comparison of kidney preservation by two methods:
cant clinical benefit for recipients of deceased donor kidneys. machine perfusion and cold storage. Transplant Proc 1987;
19:2046.
[18] Jaffers GJ, Banowsky LH. The absence of a deleterious effect
of mechanical kidney preservation in the era of cyclosporine.
references Transplantation 1989;47:734.
[19] Kwiatkowski A, Wszola M, Kosieradzki M, et al. The early
and long term function and survival of kidney allografts
[1] Perico N, Cattaneo D, Sayegh MH, et al. Delayed graft stored before transplantation by hypothermic pulsatile
function in kidney transplantation. Lancet 2004;364:1814. perfusion. A prospective randomized study. Ann Transplant
[2] Yarlagadda SG, Coca SG, Formica RN Jr, et al. Association 2009;14:14.
between delayed graft function and allograft and patient [20] Schold JD, Kaplan B, Howard RJ, et al. Are we frozen in
survival: a systematic review and meta-analysis. Nephrol time? Analysis of the utilization and efficacy of pulsatile
Dial Transplant 2009;24:1039. perfusion in renal transplantation. Am J Transplant 2005;5:
[3] Timsit MO, Tullius SG. Hypothermic kidney preservation: 1681.
a remembrance of the past in the future? Curr Opin Organ [21] Gok MA, Buckley PE, Shenton BK, et al. Long-term renal
Transplant 2011;16:162. function in kidneys from non-heart-beating donors: a single-
[4] Belzer FO, Ashby BS, Dunphy JE. 24-hour and 72-hour center experience. Transplantation 2002;74:664.
preservation of canine kidneys. Lancet 1967;2:536. [22] Keizer KM, de Fijter JW, Haase-Kromwijk BJ, et al. Non-
[5] Yuan X, Theruvath AJ, Ge X, et al. Machine perfusion or cold heart-beating donor kidneys in the Netherlands: allocation
storage in organ transplantation: indication, mechanisms, and outcome of transplantation. Transplantation 2005;79:
and future perspectives. Transpl Int 2010;23:561. 1195.
[6] Clark EA, Terasaki PI, Opelz G, et al. Cadaver-kidney [23] Nicholson ML, Metcalfe MS, White SA, et al. A comparison of
transplant failures at one month. N Engl J Med 1974;291:1099. the results of renal transplantation from non-heart-beating,
[7] van der Vliet JA, Vroemen JP, Cohen B, et al. Preservation of conventional cadaveric, and living donors. Kidney Int 2000;
cadaveric kidneys. Cold storage or machine perfusion? Arch 58:2585.
Surg 1983;118:1166. [24] Shiroki R, Hoshinaga K, Higuchi T, et al. Prolonged warm
[8] Wight JP, Chilcott JB, Holmes MW, et al. Pulsatile machine ischemia affects long-term prognosis of kidney transplant
perfusion vs. cold storage of kidneys for transplantation: allografts from non-heart-beating donors. Transplant Proc
a rapid and systematic review. Clin Transplant 2003;17:293. 1998;30:111.
[9] Moers C, Smits JM, Maathuis MH, et al. Machine perfusion or [25] Moustafellos P, Hadjianastassiou V, Roy D, et al. The
cold storage in deceased-donor kidney transplantation. N influence of pulsatile preservation in kidney transplantation
Engl J Med 2009;360:7. from non-heart-beating donors. Transplant Proc 2007;39:
[10] Watson CJ, Wells AC, Roberts RJ, et al. Cold machine 1323.
perfusion versus static cold storage of kidneys donated after [26] Plata-Munoz JJ, Muthusamy A, Quiroga I, et al. Impact of
cardiac death: a UK multicenter randomized controlled trial. pulsatile perfusion on postoperative outcome of kidneys
Am J Transplant 2010;10:1991. from controlled donors after cardiac death. Transpl Int 2008;
[11] Higgins JP, Green S. Cochrane handbook for systematic 21:899.
reviews of intervention, vol. 5.1.0 [updated March 2011]. In: [27] Jochmans I, Moers C, Smits JM, et al. Machine perfusion
The Cochrane Collaboration, 2011. Available from: http:// versus cold storage for the preservation of kidneys donated
www.cochrane.org/training/cochrane-handbook. after cardiac death: a multicenter, randomized, controlled
[12] DerSimonian R, Laird N. Meta-analysis in clinical trials. trial. Ann Surg 2010;252:756.
Control Clin Trials 1986;7(3):177. [28] Balfoussia D, Yerrakalva D, Hamaoui K, et al. Advances in
[13] Higgins JP, Thompson SG, Deeks JJ, et al. Measuring machine perfusion graft viability assessment in kidney, liver,
inconsistency in meta-analyses. BMJ 2003;327:557. pancreas, lung, and heart transplant. Exp Clin Transplant
[14] Hoogland ER, Snoeijs MG, van Heurn LW. DCD kidney 2012;10:87.
transplantation: results and measures to improve outcome. [29] Bond M, Pitt M, Akoh J, et al. The effectiveness and cost-
Curr Opin Organ Transplant 2010;15:177. effectiveness of methods of storing donated kidneys from
[15] Mozes M, Finch W, Reckard C, et al. comparison of cold deceased donors: a systematic review and economic model.
storage and machine perfusion in the preservation of Health Technol Assess 2009;13. iii, xi, 1.
cadaver kidneys. Transplant Proc 1985;17:1474. [30] Groen H, Moers C, Smits JM, et al. Cost-effectiveness of
[16] Halloran P, Aprile M. A randomized prospective trial of cold hypothermic machine preservation versus static cold
storage versus pulsatile perfusion for cadaver kidney storage in renal transplantation. Am J Transplant 2012;12:
preservation. Transplantation 1987;43:827. 1824.