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JCM 09 02311
JCM 09 02311
Clinical Medicine
Article
A Retrospective Propensity Score Matched Analysis
Reveals Superiority of Hypothermic Machine
Perfusion over Static Cold Storage in Deceased Donor
Kidney Transplantation
Silvia Gasteiger 1 , Valeria Berchtold 1 , Claudia Bösmüller 1 , Lucie Dostal 2 , Hanno Ulmer 2 ,
Christina Bogensperger 1 , Thomas Resch 1 , Michael Rudnicki 3 , Hannes Neuwirt 3 ,
Rupert Oberhuber 1 , Benno Cardini 1 , Stefan Scheidl 1 , Gert Mayer 3 , Dietmar Öfner 1 ,
Annemarie Weissenbacher 1, *,† and Stefan Schneeberger 1, *,†
1 Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck,
6020 Innsbruck, Austria; [email protected] (S.G.); [email protected] (V.B.);
[email protected] (C.B.); [email protected] (C.B.);
[email protected] (T.R.); [email protected] (R.O.); [email protected] (B.C.);
[email protected] (S.S.); [email protected] (D.Ö.)
2 Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck,
6020 Innsbruck, Austria; [email protected] (L.D.); [email protected] (H.U.)
3 Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck,
6020 Innsbruck, Austria; [email protected] (M.R.); [email protected] (H.N.);
[email protected] (G.M.)
* Correspondence: [email protected] (A.W.); [email protected] (S.S.)
† They contributed equally to this work.
Received: 23 June 2020; Accepted: 17 July 2020; Published: 21 July 2020
Abstract: Hypothermic machine perfusion (HMP) has been introduced as an alternative to static
cold storage (SCS) in kidney transplantation, but its true benefit in the clinical routine remains
incompletely understood. The aim of this study was to assess the effect of HMP vs. SCS in kidney
transplantation. All kidney transplants performed between 08/2015 and 12/2019 (n = 347) were
propensity score (PS) matched for cold ischemia time (CIT), extended criteria donor (ECD), gender
mismatch, cytomegalovirus (CMV) mismatch, re-transplantation and Eurotransplant (ET) senior
program. A total of 103 HMP and 103 SCS instances fitted the matching criteria. Prior to PS matching,
the CIT was longer in the HMP group (17.5 h vs. 13.3 h; p < 0.001), while the delayed graft function
(DGF) rates were 29.8% and 32.3% in HMP and SCS, respectively. In the PS matched groups, the
DGF rate was 64.1% in SCS vs. 31.1% following HMP: equivalent to a 51.5% reduction of the DGF
rate (OR 0.485, 95% CI 0.318–0.740). DGF was associated with decreased 1- and 3-year graft survival
(100% and 96.3% vs. 90.8% and 86.7%, p = 0.001 and p = 0.008) or a 4.1-fold increased risk of graft
failure (HR = 4.108; 95% CI: 1.336–12.631; p = 0.014). HMP significantly reduces DGF in kidney
transplantation. DGF remains a strong predictor of graft survival.
1. Introduction
Kidney transplantation (KTx) is the therapy of choice for patients with end-stage renal disease
(ESRD). The shortage of donor organs results in an ever-increasing waiting list and accumulating
patient deaths. The donor pool and organ utilization have been expanded in recent years through the
use of an increased number of marginal organs [1]. Extended criteria donor (ECD) organs and organs
recovered from donation after circulatory death (DCD), however, are more vulnerable to ischemia
reperfusion injury. This eventually translates into higher rates of delayed graft function (DGF), primary
non-function (PNF) and inferior graft survival [2–5]. While ECD kidneys have a 1.7 times greater
risk for graft failure [6,7], recipients still gain a significant survival benefit compared to dialysis [8].
Nevertheless, ECD organs with prolonged travel time are discarded at a high rate, since transplant
surgeons and physicians fear the increased risk of DGF and PNF [1]. Considering the benefit of ECD
organ use and further decreasing the discard rate, optimal organ preservation and ex situ organ quality
assessment remain key tools for eventually increasing utilization in kidney transplantation.
Early attempts of dynamic organ preservation in the 1960s [9,10] were not pursued further due to
technical and logistical hurdles. The technology was reintroduced decades later and a prospective
randomized trial by Moers et al indicated that DGF rates could be lowered by hypothermic machine
perfusion (HMP) compared to static cold storage (SCS) [11]. Superior outcomes and/or preferable
effects on kidney allografts and transplant outcomes have been confirmed by others [12–14]. The
positive impact seems to be more pronounced in ECD kidneys and is presumed to result from the
protective effect on the endothelium and the removal of waste products [15]. Since the benefit was not
profound in some trials and not uniformly considered to outweigh the logistics and costs involved,
SCS largely remains the current standard of kidney preservation [16]. The aim of our study was to
investigate the impact of HMP on kidney graft function after deceased donor kidney transplantation
in an HMP cohort propensity score matched with SCS (PS cohort).
valganciclovir was applied for 90 days. Patients with DGF received neither additional treatment (i.e.
additional induction therapy) nor standardized protocol biopsies.
Statistical Analysis
Continuous variables are presented as mean ± standard deviation (SD) in case of a normal
distribution and as median and range otherwise. Categorical data are presented as number of cases
with percentage.
Baseline characteristics between kidney preservation (HMP/SCS) were tested using the
independent-sample Mann–Whitney U test for non-normally distributed continuous variables and
χ2 -test or Fisher’s exact test for categorical variables, as appropriate. Standardized mean differences [21]
for comparing means and prevalence between groups are reported.
A propensity score matching with caliper of 0.05 was performed based on following variables:
donor type (SCD/ECD), CIT, gender and CMV mismatch, number of transplants (first or Re-Tx) and
ET-senior program [22]. The quality of matching was assessed by calculation of the standardized mean
difference (SMD) between selected variables, with a SMD < 0.10 reflecting good matching [21].
The effect of HMP on the incidence of DGF was modelled with the conditional logistic regression
analysis. Patient and graft survival were calculated with Kaplan–Meier survival analysis method.
Kaplan–Meier curves were limited at a number at risk of 10% of patients. The effect of DGF on graft
survival was assessed using Cox regression analysis.
All analyses were performed with SPSS (Statistical Package for the Social Sciences) version 25
(IBM; Armonk, NY, USA). A p-value of less than 0.05 was considered to indicate statistical significance.
3. Results
In total, 347 patients were transplanted between August 2015 and December 2019. HMP was
applied in 124/347 patients (35.7%). In the remaining 223/347 patients (64.3%), kidneys were transplanted
following SCS. DGF occurred in 37/124 patients (29.8%) and 72/223 patients (32.3%) following HMP
and SCS (p = 0.638). Mean CIT was 17.5 ± 5.1 h and 13.3 ± 4.6 h in the HMP and SCS group, respectively
(p < 0.001, Table 1).
To correct for key donor and recipient factors and CIT, propensity score matching was performed
in the ratio of 1:1 (103 HMP kidneys and 103 SCS kidneys). Figure 1 displays the algorithm of
patient selection. Following propensity score matching the CIT was 16.3 ± 4.3 and 16.0 ± 4.4 h in the
HMP-cohort and SCS-cohort, respectively. Baseline characteristics following PS-matching are shown
in Table 2, donor and recipient demographics as well as transplant factors (matched cohort) are shown
in Table 3.
J. Clin. Med. 2020, 9, 2311 4 of 12
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 4 of 12
Figure 1. Flow chart of patient selection. HMP: hypothermic machine perfusion, SCS: static cold storage.
Figure 1. Flow chart of patient selection. HMP: hypothermic machine perfusion, SCS: static cold
storage. Table 2. Baseline characteristics of the propensity-score matched cohort (n = 206).
Figure 2. (A) Delayed graft function rate of hypothermically perfused deceased donor kidneys compared
to kidneys
Figure statically
2. (A) Delayedstored on ice;
graft (B) delayed
function rate ofgraft function rate ofperfused
hypothermically kidneys after hypothermic
deceased donor machine
kidneys
perfusion compared to organs stored on ice stratified for standard and extended
compared to kidneys statically stored on ice; (B) delayed graft function rate of kidneys criteria donors. after
hypothermic machine perfusion compared to organs stored on ice stratified for standard and
3.2. Daytime vs. Nighttime Procedures
extended criteria donors.
When stratifying transplant procedures by time of surgery, 39.3% (n = 81) of transplants were
3.2. Daytimeduring
performed vs. Nighttime Procedures
nighttime. SCS kidneys were more likely to be transplanted during nighttime (56.8%
vs. 43.2%, p = 0.077) compared to HMP kidneys. Nighttime vs. daytime kidney transplant procedures
When stratifying transplant procedures by time of surgery, 39.3% (n = 81) of transplants were
did not differ in regard to postoperative complication rate (27.2% vs. 27.2%), DGF (49.4% vs. 46.4%)
performed during nighttime. SCS kidneys were more likely to be transplanted during nighttime
and graft loss (9.5% vs. 8.8%).
(56.8% vs. 43.2%, p = 0.077) compared to HMP kidneys. Nighttime vs. daytime kidney transplant
procedures did not differ in regard to postoperative complication rate (27.2% vs. 27.2%), DGF (49.4%
3.3. HMP Parameters
vs. 46.4%) and graft loss (9.5% vs. 8.8%).
Median HMP time was 6.2 hours (1.9–18.8). Preservation time did not differ between patients
withHMP
3.3. immediate graft function and DGF (6.1 vs. 6.7, p = 0.963). The flow increased significantly
Parameters
over the course of HMP (70mL/min (range 6–239) vs. 107mL/min (range 48–240), p < 0.001) and
Median HMP time was 6.2 hours (1.9–18.8). Preservation time did not differ between patients
with immediate graft function and DGF (6.1 vs. 6.7, p = 0.963). The flow increased significantly over
J. Clin. Med. 2020, 9, 2311 6 of 12
the intra-renal-resistance (IRR) index declined over time (0.39 mmHg/mL/min (range 0.6–4.7) vs.
0.22 mmHg/mL/min (range 0.1–0.5), p < 0.001). Flow and IRR index at 15 minutes of HMP were
82 mL/min (range 6–239) and 0.30 mmHg/mL/min (range 0.1–4.66) in patients with an immediate graft
function compared to 55 mL/min (range 18–191) and 0.46 mmHg/mL/min (range 0.1–1.22) in patients
with DGF; p = 0.074 and p = 0.080, respectively. At the end of perfusion, flow and IRR did not differ
among patients with, and without DGF; (95 mL/min vs. 115 mL/min and 0.26 mmHg/mL/min vs.
0.22 mmHg/mL/min, p = 0.172 and p = 0.130).
3.4. Complications
Within the median observational period of 24 months, postoperative complications occurred in
56/206 patients (27.2%) and were comparable in patients receiving kidneys after HMP 27/103 (26.2%)
and SCS 29/103 (28.2%). Most common complications were hematoma (n = 14/6.8%), lymphoceles
(n = 19/9.2%), urological complications (n = 15/7.3%), wound infections (n = 13/6.3%) and vascular
complications (n = 4/1.9%). Wound infections occurred significantly more often following SCS than
after HMP; 10/9.7% vs. 3/2.9%, p = 0.041. The incidence of all other postoperative complications was
comparable between groups as listed in Table 4.
1.0 1.0
0.6 0.6
1.0 1.0
0.4 0.4
0.8 0.8
0.2 0.2
0.6 0.6
0.0 0.0
0.4 0.4
0.2 0.2
Figure 3. (A) Estimated 3-year patient and (B) 3-year graft survival rates after transplantation of HMP Commented [M2]: Please update
and SCS kidneys.
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need change.
Graft survival was superior in patients with immediate graft function compared to patients with
DGF. This difference was statistically significant at both, one and three years post-transplant: in
patients with immediate graft function, 1- and 3-year graft survival reached 100% and 96.3%
compared
Figure to 3.
Figure
3. (A) 90.8% and 86.7%
(A) Estimated
Estimated inpatient
3-year
3-year patients with
patient and
and (B)
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graft 0.001after
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Figure and
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and SCS kidneys.
need change.
Graft survival was superior in patients with immediate graft function compared to patients with
DGF. This difference was statistically significant at both, one and three years post-transplant: in
patients with immediate graft function, 1- and 3-year graft survival reached 100% and 96.3%
1.0 1.0
compared to 90.8% and 86.7% in patients with DGF (log rank, p = 0.001 and p = 0.008, respectively,
0.8
Figure 4). 0.8
0.6 0.6
0.4 0.4
1.0 1.0
0.2 0.2
0.8 0.8
0.0 0.0
0.6 0.6
0.4 0.4
0.2 0.2
Figure 4. (A) Estimated 3-year patient and (B) 3-year graft survival rates of patients stratified for
Commented [M3]: Please update
immediate graft function and delayed graft function.
0.0 0.0
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In a Cox regression
immediate analysis,
graft function recipients
and delayed suffering from DGF had a 4.1-times increased
graft function. risk ofneed change.
graft
failure (HR = 4.108; 95% CI: 1.336–12.631; p = 0.014). One year patient survival was 100% in patients
In a Cox regression analysis, recipients suffering from DGF had a 4.1-times increased risk of
with immediate graft= function
graft failure (HR 4.108; 95%and 99% in patients
CI: 1.336–12.631; withOne
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In patients receiving a kidney after HMP, the glomerular filtration rate (GFR) at last follow-up needp = 0.063). waschange.
44.8 mL/min/1.73 2 2
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(range 11.3–122.4) compared
analysis, recipients to 39.0
suffering frommL/min/1.73m
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graft failure (HR an SCS organ;
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95% CI: 0.177). Serum creatinine
p = 0.014). at last
One year follow-up
patient survivalwas was 1.54
100%mg/dL
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patients HMPimmediate
and 1.61graftmg/dL (range
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99% in patients with DGF after rank,(pp =
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= 0.296).
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Serum at 3 yearsand
creatinine afterGFR
transplantation was superior
at last follow-up were in cases within
inferior immediate
patientsgraftwithfunction
DGF: vs.1.92 DGF,
mg/dL (range
but the difference did not reach statistical significance (99.1% vs. 94.9%; 2 log rank, p = 0.063).
0.9–4.14) vs. 1.44 mg/dL (range 0.5–3.9) and 33.9 mL/min/1.73 m (range 11.3–82.0) vs. 45.9 mL/min/1.73
m2 (range 15.6–122.4); p < 0.001 for both, Figure 5. This difference was also evident in subgroup
analysis (HMP vs. SCS, see Table 5). Serum creatinine and GFR at last follow-up were also inferior
in patients who received an ECD kidney compared to those who received a SCD organ: 1.85 mg/dL
(range 0.5–3.9) vs. 1.37 mg/dL (range 0.7–4.1) and 34.5 mL/min/1.73 m2 (range 15.6–122.4) vs. 51.7
mL/min/1.73 m2 (range 11.3–99.4); p < 0.001 for both.
mg/dL (range 0.5–4.14) after HMP and 1.61 mg/dL (range 0.8–3.80) in patients after SCS (p = 0.260).
Serum creatinine and GFR at last follow-up were inferior in patients with DGF: 1.92 mg/dL
(range 0.9–4.14) vs. 1.44 mg/dL (range 0.5–3.9) and 33.9 mL/min/1.73 m2 (range 11.3–82.0) vs. 45.9
mL/min/1.73 m2 (range 15.6–122.4); p < 0.001 for both, Figure 5. This difference was also evident in
subgroup analysis (HMP vs. SCS, see Table 5). Serum creatinine and GFR at last follow-up were also
inferior in patients who received an ECD kidney compared to those who received a SCD organ: 1.85
J. Clin. Med. 2020, 9, 2311
mg/dL (range 0.5–3.9) vs. 1.37 mg/dL (range 0.7–4.1) and 34.5 mL/min/1.73 m2 (range 15.6–122.4) vs. 8 of 12
51.7 mL/min/1.73 m2 (range 11.3–99.4); p < 0.001 for both. Commented [SG4]: MDPI
1. Please update this figure as you need
Such as 0,2 should be 0.2, all numbers n
2. Subfigure A in this picture lack a “0”
revise.
Figure 5. (A) Median serum creatinine and (B) estimated glomerular filtration rate (MDRD) after need change.
Figure 5. (A) Median serum creatinine and (B) estimated glomerular filtration rate (MDRD) after a
a median follow-up of 24of months
median follow-up forpatients
24 months for patients with immediate
with immediate and delayed and delayed
graft function. graft function. 2.◦Subfigure A in this picture lack a “0”
° statistical
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statistical outliers.
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Table 5. analysis
Table 5. Subgroup Subgroup analysis
of serumof serum creatinineand
creatinine and eGFR
eGFR in in
patients with immediate
patients graft function
with immediate graft function
I was not able to change “,” into “.” in S
and DGF.
and DGF. dropped the decimal places. I hope that’
DGF no DGF p-Value
HMP DGF No DGF p-Value
serum creatinine 2.0 (0.9–4.1) 1.42 (0.5–3.9) 0.001
HMP GFR 32.9 (11.3–76.3) 46.8 (15.6–122.4) 0.004
serum creatinineSCS 2.0 (0.9–4.1) 1.42 (0.5–3.9) 0.001
serum creatinine 1.84 (0.92–3.8) 1.5 (0.8–3.63) 0.009
GFR GFR
32.933.9
(11.3–76.3)
(16.7–82.0)
46.8 (15.6–122.4)
42.2 (19.6–98.8) 0.015
0.004
SCS GFR: glomerular filtration rate; values are median (range).
serum creatinine 1.84 (0.92–3.8) 1.5 (0.8–3.63) 0.009
GFR
4. Discussion 33.9 (16.7–82.0) 42.2 (19.6–98.8) 0.015
GFR:assesses
The present study glomerular filtrationafter
the outcome rate;deceased
values are median
donor kidney(range).
transplantation in organs
undergoing HMP compared to a propensity score matched SCS cohort. Our analysis reveals a
relatively strong clinical benefit of HMP with significant lower DGF rates in both ECD and SCD
kidneys. However, the novel and important finding of our study is the fact that we can operate in a
4. Discussionback-to-base fashion, accepting SCS kidneys and connecting them to HMP as soon as the organs
arrive at our center. To our knowledge, our study describes for the first time that now a similar
The present study
beneficial assesses
result with HMPthe overoutcome
SCS can beafter
achieveddeceased donor
with SCS and kidney
end-HMP transplantation
for 6.2 hours. Boffa et in organs
undergoing HMP compared
al presented to trial
the POMP a propensity
by the COPEscore matched
consortium SCSrecently
[23] fairly cohort. Our
at the analysis
congress of thereveals
British a relatively
Transplant
strong clinical benefitSociety.
of HMPIn theirwith
prospective trial, thelower
significant combination
DGFof rates
SCS andinoxygenated
both ECD end-HMP
and inSCD kidneys.
ECD kidneys did not result in any improvement of outcomes, despite shorter CIT compared to our
However, thecohort
noveland and important
an HMP finding
time of 4.7 hours. of ourthestudy
Given is the
fact that fact in
6.2 hours that
ourwe canseemed
cohort operate in aa back-to-base
to have
fashion, accepting SCS kidneys and connecting them to HMP as soon as the organs arrive at our center.
To our knowledge, our study describes for the first time that now a similar beneficial result with HMP
over SCS can be achieved with SCS and end-HMP for 6.2 hours. Boffa et al presented the POMP trial
by the COPE consortium [23] fairly recently at the congress of the British Transplant Society. In their
prospective trial, the combination of SCS and oxygenated end-HMP in ECD kidneys did not result in
any improvement of outcomes, despite shorter CIT compared to our cohort and an HMP time of 4.7
hours. Given the fact that 6.2 hours in our cohort seemed to have a beneficial effect, it will require
more investigational procedures to detect the mechanism of this very impact and, if possible, to define
a certain time frame of SCS and HMP leading to a favorable outcome.
Delayed graft function is the most significant early complication after deceased donor kidney
transplantation. Further to its immediate effect on patient wellbeing and hospital stay, DGF has a
negative long term impact on graft and patient survival [24]. The incidence of DGF ranges from 20%
to 70% and it differs significantly between regions and kidney transplant programs [25]. In several
randomized controlled trials, HMP has been shown to decrease DGF rates and to boost graft survival,
especially in ECD and DCD kidneys [12,26,27]. In the unmatched comparison of this trial, the DGF
rate was comparable between HMP and SCS (29.8% following HMP and 32.3% in SCS). The CIT was
significantly longer in the HMP group. In this regard, our study suggests that HMP may allow safe
prolongation of CIT. To eliminate heterogeneity between the two cohorts, we performed propensity
score matching based for key donor and recipient factors and CIT. This approach revealed that HMP
was associated with a 51.5% reduction of the DGF rate (p = 0.001) in our cohort. While the protective
J. Clin. Med. 2020, 9, 2311 9 of 12
effect of HMP is presumably more pronounced in ECD kidneys [4,28], we found no difference between
SCD and ECD kidneys. This is in line with previously published data by Moers et al, suggesting
that HMP has a beneficial effect on the short-term outcome in all types of deceased-donor kidney
transplants [11]. Interestingly, the positive effect of HMP persisted despite a long CIT (16 hours). This
is in contrast to data published by Kox et al who stated that organs with the shortest CIT benefitted the
most, whereas the DGF rate in kidneys with over 10 hours of CIT did not differ between HMP and
SCS [29].
Graft survival at three years reached 91.8% (95.2% following HMP and 88.4% following SCS). In
our series, the difference in graft survival between HMP and SCS did not reach statistical significance.
With the apparent trend, we believe that this is due to the small sample size and reference properly
powered studies (e.g., the Eurotransplant trial [2]), which reported a graft survival benefit after one
and three years following HMP. In our cohort, DGF was associated with a 4.1-times increased risk for
graft failure, resulting in a graft survival rate of only 86.7% at three years (compared to 96.3% in non
DGF kidneys). Hence, the effect of HMP in kidney transplantation seems significant and puts into
question why HMP has not evolved as the new standard of care with more widely adoption.
Moreover, HMP led to a shift towards more daytime kidney transplant procedures. The impact of
the daytime of surgery on the outcomes after transplantation is contradictory. Fechner et al observed
a higher incidence of complications as well as inferior graft survival following nighttime kidney
transplant procedures [30]. In our cohort, outcomes were comparable between daytime and nighttime
transplants. This is in line with prior published data from our center [19], as well as others [31].
Moving surgical procedures from nighttime to daytime may be particularly beneficial in times of
working hour restrictions and staffing shortage. Further to this, safe prolongation of preservation
times may facilitate hemodynamic stabilization in delayed kidney-liver transplantation and delayed
kidney-heart transplantation or allow for pretreatment of the recipient, e.g., immunoadsorption and
other desensitization strategies.
Most studies performed in the last decade used the LifePort Kidney Transporter® . Further to
the established HMP techniques, oxygenation during HMP has shown beneficial effect in several
preclinical studies [32–34]. First clinical data from a double blinded, randomized, paired phase 3 trial
(COPE trial) are promising, suggesting that oxygenated HMP improves graft function at one year
compared to non-oxygenated HMP [35]. These findings need further confirmation, but it is reasonable
to assume that oxygenated HMP will eventually be implemented and improve the outcome after
kidney transplantation further.
Poor kidney function in the first week is detrimental for both the patients’ perception and the
longevity of the deceased donor kidney. Hypothermic machine perfusion was found to be clearly
beneficial in several randomized clinical trials. We herein provide evidence that the actual benefit of
HMP in the real-world scenario might be more significant and impactful than expected. Hypothermic
machine perfusion impressively halved the DGF rate compared to SCS kidneys after similar periods
of CIT. For the purpose of achieving the most optimal kidney preservation, HMP should be the
preferred technique. Moreover, SCS kidney transportation in the ice box is relatively cheap, but if the
back-to-base approach is used and the recipient center based HMP allows to achieve a beneficial effect,
this could be very attractive and still cost-effective, especially within an international long-distance
exchange organization. Future studies should emphasize on the impact of different durations of CIT
accompanied by short periods of HMP to detect possible “rescue” time frames to consider even short
periods of end ischemic HMP, for example, 2–3 hours only, crucial for optimal outcome after deceased
donor kidney transplantation.
Author Contributions: Conceptualization, G.M., D.Ö., A.W. and S.S. (Stefan Schneeberger); Data curation, S.G.,
V.B., C.B. (Claudia Bösmüller), C.B. (Christina Bogensperger), T.R., M.R., H.N., R.O., B.C. and S.S. (Stefan Scheidl);
Formal analysis, S.G., L.D. and H.U.; Investigation, S.G.; Methodology, L.D., H.U., R.O., B.C. and S.S. (Stefan
Scheidl); Project administration, A.W. and S.S. (Stefan Schneeberger); Software, L.D. and H.U.; Supervision, T.R.,
R.O., B.C. and S.S. (Stefan Scheidl); Validation, A.W. and S.S. (Stefan Schneeberger); Writing—original draft, S.G.;
Writing—review & editing, V.B., C.B. (Claudia Bösmüller), C.B. (Christina Bogensperger), T.R., M.R., H.N., R.O.,
J. Clin. Med. 2020, 9, 2311 10 of 12
B.C., S.S. (Stefan Scheidl), G.M., D.Ö., A.W. and S.S. (Stefan Schneeberger). All authors have read and agreed to
the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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