Donor Pretreatment and Machine Perfusion: Current Views 

Authors

Stephen O'Neill; Transplant Surgery Registrar1

Gabriel C Oniscu; Consultant Transplant Surgeon and Reader in Transplant Surgery1.2

Institutions

1 Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA

2 Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA

Corresponding author

Gabriel C. Oniscu, Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA

Tel.0044-7849592113

E-mail: gabriel.oniscu@ed.ac.uk

Sources of financial support

None

Type of article for submission

Review article

Conflicts of interest

None

Word count text

2758

Word count abstract

173

Author contribution

Each author has made a substantial contribution to the conception, design, drafting and critical revision of this article for important intellectual content; and has given final approval of the version to be published. Specific roles are summarised below:

SON – writing of manuscript

GO – writing and drafting of manuscript

Abbreviations

SCS – Static Cold Storage

NHSBT - National Health Service Blood and Transplant

HMP – Hypothermic Machine Perfusion

DCD – Donation after Circulatory Death

cDCD – Controlled Donation after Circulatory Death

uDCD – Uncontrolled Donation after Circulatory Death

DBD – Donation after Brain Death

OR - Odds Ratio

RR - Risk Ratio

DGF – Delayed Graft Function

RCT – Randomised Controlled Trial

HRP – Hypothermic Regional Perfusion

NRP – Normothermic Regional Perfusion

ESNP – Ex-situ Normothermic Perfusion

Abstract

Purpose of review: To summarise recently published studies of donor pretreatment and machine perfusion strategies in kidney transplantation.

Recent findings: The sparsity of donor pretreatment trials has resulted in the re-analysis of already existing data, and RCTs are urgently needed to reinvigorate this aspect of donor research. Uncontrolled donation after circulatory death kidney transplantation has the highest risk of delayed graft function and graft failure, and recent studies have reported that normothermic regional perfusion improves graft function and survival in this setting. Hypothermic machine perfusion reduces delayed graft function following deceased donor kidney transplantation across donor types but unanswered questions still remain regarding its use. The use of oxygenated hypothermic machine perfusion appears to improve graft function in controlled donation after circulatory death mediated by a reduction in acute rejection. Ex situ normothermic perfusion is emerging and while technically challenging it may facilitate the delivery of pretreatments.

Summary: RCTs are urgently needed to reinvigorate research into donor pretreatment and to establish the place of specific preservation techniques to in deceased donor kidney transplantation.

Keywords; pretreatment, normothermia, hypothermia, machine perfusion, DCD donation

Introduction

The rising demand for kidneys for transplantation has led to an increased utilisation of grafts from higher risk donors. Since these organs are more susceptible to injury, there is potential for worse outcomes in terms of delayed graft function (DGF) and reduced graft survival. DGF is not definitively associated with reduced graft survival but it is closely linked to an increased length of hospital stay and cost following kidney transplantation (1). Two potential strategies to mitigate organ injury, reduce DGF, improve graft survival and widen acceptance criteria for kidney donation are donor “pretreatments” and “machine perfusion”. This review will highlight articles recently published on these topics and present an interpretation of the findings.

Donor pretreatment

Management of the donor can have a significant impact on recipient outcomes following kidney transplantation. A recent retrospective cohort study of donation after brain death (DBD) donors (n=122) reported that meeting donor management goals at the time of diagnosis of brain death reduced DGF following kidney transplantation (adjusted OR 0.39, 0.16‐0.99, p=0.04). In this study the benefit of meeting donor management goals was independent of the reduction in DGF associated with the use of hypothermic machine perfusion (HMP) (adjusted OR 0.45, 0.22‐0.94, p=0.03) (2).

Donor pre-treatment has much potential because it allows prevention and treatment of organ insults at the earliest stage. However, few studies have prospectively investigated donor interventions that improve recipient kidney function and graft survival (3). These interventions are termed “pretreatments”, and the limited research activity in this area results from a lack of regulatory guidance, infrastructure to conduct studies, and logistical solutions to encourage randomised controlled trials (RCTs) in the donor (4). The latter issue is exacerbated by the time pressures of kidney transplantation as well as questions surrounding the need for recipient consent for donor interventions (3). Specific options for donor pretreatment can be divided broadly into physical pretreatments (e.g. hypothermia, remote ischemic preconditioning) and pharmacological pretreatments (e.g. dopamine, steroids and volatile anaesthesia).

Physical pretreatment

Hypothermia

Mild therapeutic hypothermia in deceased donors has previously been shown in a landmark RCT to reduce delayed graft function (DGF) following kidney transplantation (5). A retrospective cohort study using data from a separate RCT of donor dopamine pretreatment (ClinicalTrials.gov identifier: NCT000115115) investigated whether spontaneous donor hypothermia was also beneficial. Hypothermia was defined by a core body temperature <36°C 4-20 hours before retrieval (n=54 donors, n=99 recipients) and was compared to normothermia (n=210 donors, n=388 recipients) in terms of initial transplant function and 5-year graft survival. The study reported that donor hypothermia reduced DGF after kidney transplantation (OR 0.56, 0.34-0.91, p=0.02) but did not confer a graft survival advantage (hazard ratio 0.83, 0.54-1.27, p=0.39). The study also reported that donor dopamine infusion time reduced dialysis requirement (OR 0.93, 0.87-0.98, per hour of infusion) independent from hypothermia and was associated with improved long-term graft outcome (hazard ratio 0.95, 0.91-0.99, per hour) (3).

Remote ischemic preconditioning

A small RCT assessing the effects of remote ischemic preconditioning using an upper thigh tourniquet in DBD donors at the time of retrieval, found no differences in the eGFR rate of the kidney transplants compared with kidneys recovered using standard retrieval. However, there were differences in the level of pro-inflammatory cytokines, particularly a significant rise in TNF-α by remote ischemic preconditioning (6). In a RCT of living kidney donors, remote ischemic preconditioning using an upper arm blood pressure cuff (n=85) compared to control (n=85) resulted in significantly lower serum creatinine levels for donors at discharge (mean 1.01 vs. 1.13 mg/dL, p=0.003). Serum creatinine levels and estimated glomerular filtration rate were similar between the donor groups over a one-year follow-up period, but no differences in recipient outcomes were observed (7). A study of the Association of Remote Ischemic Preconditioning in Abdominal Organ Transplantation (RIPCOT, NCT00975702) has closed to recruitment after enrolling 580 deceased donors and the outcomes of recipients of kidney, pancreas and liver transplantation are due to be reported (8).

Pharmacological pretreatment

A RCT of living donor and recipient pairs receiving sevoflurane anaesthesia (n=35) compared to desoflurane anaesthesia (n=35) showed no difference in graft function after transplantation. In terms of renal injury biomarkers, only serum IL-8 levels were significantly higher in recipients who underwent sevoflurane anaesthesia (9).

A RCT of kidney transplantation from DBD donors who received corticosteroids (n=238) or placebo (n=217) at least 3 hours prior to the organ retrieval reported that at 5-year follow-up there was no difference in acute rejection or graft survival (10). A RCT of cyclosporine pretreatment aiming to recruit 648 DBD donors is currently enrolling (11).

Machine perfusion

Static cold storage (SCS) may be suitable for kidneys from so called “standard criteria” donors but it is inadequate for the preservation of kidneys with a higher risk of graft failure, and thus limits acceptance criteria for transplantation (12). Alternative strategies to SCS can be generally divided into techniques that utilise in situ regional perfusion in the donor and ex situ machine perfusion of individual organs. In situ regional perfusion involves the isolation and perfusion of the abdominal organs with continuous flow of blood diluted and cooled to 4-22 °C (hypothermic regional perfusion, HRP) or maintained at 350-370C (normothermic regional perfusion, NRP). Ex situ strategies are used following retrieval of kidneys and prior to transplantation. The options in this setting include HMP, whereby the kidney is connected to a device that pumps preservation solution continuously at 1-10°C, hypothermic oxygenated machine perfusion which follows the same principles with the addition delivery of oxygen and ex-situ normothermic perfusion (ESNP) that involves perfusion of kidneys with a warm, oxygenated erythrocyte‐based plasma‐free solution.

In situ Perfusion Strategies

In a study of 499 kidney transplantations from the French uncontrolled DCD (uDCD) programme, a sensitivity analysis showed that in situ cooling to 4°C instead of undertaking normothermic regional perfusion (NRP) was associated with a higher risk of primary non-function (OR=4.51, 1.34-15.20, p=0.015), a lower GFR (defined as an eGFR <30 ml/min) and higher risk of graft loss at one-year (OR=2.57, 1.45-4.55, p=0.001) (13).

A study of 517 kidney transplants from 288 uDCD donors in Spain reported a significantly increased the risk of graft loss during the first year after transplantation following in situ cooling of kidneys compared with NRP (OR 5.6, 2.7-11.5, p<0.001) or HRP (OR 4.3, 2.1-8.6, p<0.001). In situ cooling of kidneys was also associated with an increased risk of DGF compared with NRP (OR 2.7, 1.0–7.2, p=0.055). The additional use of HMP in this study did not have an impact on graft survival (14). However, another study from Spain assessing transplant kidneys from uDCD donors recovered using NRP (n=194) reported that the combination of donor age >60 years together with final renal resistance <0.3 mmHg/mL/min on HMP (RM3, Waters Medical System, USA) accurately predicted an eGFR <30 mL/min at 6 months after transplantation (area under ROC curve 0.96, standard error 0.032) (15).

Another Spanish single centre study compared the outcomes of kidney transplant from NRP uDCD donors (n=237) with contemporaneous standard criteria DBD donors (n=237). There was a higher DGF rate in the uDCD kidneys (73.4% vs. 46.4%, p< 0.01) but similar GFR rates and comparable 10‐year death‐censored graft (82.1% vs. 80.4%) and recipient survival (86.2% vs. 87.6%) (16). In another study, the outcomes of kidney transplant recipients from uDCD donors (n=774) recovered using HRP in 96.5% of donors and NRP in the remaining 3.5%, were compared to standard criteria DBD donors (n=366) and ECD donors (n=247). Graft survival was worse in recipients of uDCD kidneys (1-year 85.1%, 5-year 78.1%, and 10-year 72.2%) as compared to standard criteria DBD donors (1-year 91.7%, 5-year 85.7%, and 10-year 80.6%, p=0.004) but superior to that seen in transplants from ECD donors (1-year 86.0%, 5-year 75.8%, and 10-year 61.4% p=0.021) (17).

In Italy, where declaration of death based on circulatory criteria requires a minimum stand off period of 20 minutes (18), a series of 10 kidneys from controlled DCD (cDCD) donors recovered using a combination of NRP followed by oxygenated HMP reported a DGF rate of 30% and no cases of primary non-function (19).

Ex situ Perfusion Strategies

In kidney transplantation for deceased donors, HMP has accumulated high-level evidence to support a reduction in the rate of DGF compared to SCS (20-22). However, HMP is not universally accepted due to conflicting results from key RCTs and a lack of evidence to support a reduction of primary non-function or improved longer-term graft survival (22).

Is HMP clinically effective?

In a French registry study of transplantation of kidneys from ECD, HMP (n=801) from the time of retrieval using either a LifePort (Organ Recovery Systems®, USA) or Waves machine (Waters Medical System, USA) compared to SCS (n=3515) significantly reduced DGF (adjusted OR 0.49, 0.40-0.60, p< 0.001), 1‐year death censored graft failure (adjusted HR 0.71, 0.52-0.97, p=0.03), and 1-year graft failure (adjusted HR 0.77, 0.60-0.99, p=0.045). An analysis of paired kidneys (n=66) reported a similar reduction in DGF (adjusted OR 0.23, 0.04‐0.57, p=0.005) (23).

A number of recent meta-analyses comparing HMP kidney preservation with SCS in kidneys recovered across all donor types have reported a significant reduction in DGF but none reported a significant decrease in primary non-function (20-22) (Table 1). One of these meta-analyses reported improved graft survival at 3-years across all donor types (RR 1.06, 95% CI 1.02-1.11, p=0.009) (20). A recent Cochrane Review concluded that HMP is superior to SCS in both DBD and DCD kidney transplantation even when analysing the results of studies that have been published in the last decade. DCD donors have an increased risk of DGF, therefore the number needed to treat to prevent one episode of DGF is less for DCD kidneys (7.26) compared to DBD kidneys (13.60) (22).

Is HMP cost effective?

Analysis of a data from a RCT of HMP vs. SCS in 80 paired DBD kidneys in Brazil reported that HMP is a cost-effective strategy with an incremental cost-effectiveness ratio of US$22,117/ per quality-adjusted life-year, which is below an accepted willingness-to- pay threshold level of 3 times the gross domestic product per capita (US$28,574) (24). However, in a comparison of three RCTs, the cost of HMP to prevent one episode of DGF (number needed to treat=18) in one recipient was estimated to be $17,064 in comparison to negligible costs for therapeutic hypothermia and renal-dose dopamine pretreatment in DBD donors (25).

Is oxygenated HMP better than conventional HMP?

Two further RCTs are currently assessing oxygenated HMP. One RCT has randomised kidneys from extended criteria DBD donors to oxygentated HMP after SCS or SCS alone (COPE-POMP, ISRCTN 63852508). The second RCT has randomised kidneys from controlled DCD donors older than 50 years to either oxygenated HMP (n=106) or standard HMP (n=106) (COPE-COMPARE, ISRCTN 32967929). These trials have now finished enrollment and the outcome of the COPE-COMPARE study has been presented at the American Transplant Congress in May 2019 and reported a significant reduction in graft loss (3% vs. 10%, p=0.021) and on sensitivity analysis, a significantly higher eGFR (47.6 vs. 42.6 ml/min/1.73 m2, p=0.035) at 1-year follow up with oxygenated HMP. These effects appear to be mediated through a reduction in the incidence of acute rejection events (26).

Does HMP facilitate longer preservation and daytime operating?

In a single centre prospective observational paired kidney study from cDCD donors recovered using NRP (n=12), a kidney received SCS and was transplanted first (average cold ischemic time 6.1 hours), while the contralateral kidney received immediate HMP (LifePort, Organ Recovery Systems®, USA) and was transplanted the following day with a significantly longer mean cold ischemic time (6.1 vs. 19.9 hours, p=0.0001). No significant differences were observed between groups with respect to the incidence of DGF (SCS; 25% vs. HMP; 33.3%), number of dialysis sessions, and renal function during the first post-transplant year. This study suggests that NRP together with HMP may be able to safely increase the tolerance to longer cold ischemia time without adversely affecting outcomes (27).

A different perspective was provided by a post–hoc subgroup analysis of the Machine Preservation Trial which showed that HMP alone cannot offset long cold ischemia times but appears to provide a beneficial effect particularly for short cold ischemic times. There was a significant effect of HMP on reducing the incidence of DGF in kidneys transplanted with cold ischemic times <10 hours [HMP 6.0% (3 of 50)] as compared with SCS, [28.1% (18 of 64), OR 0.015, 0.001-0.317, p=0.007]. Whilst the effect was not statistical significant different in the other subgroups, the greatest reduction was seen when cold ischemic times exceeded 20 hours (HMP 35.8% vs. SCS 53.1%, OR 0.335, 0.11-1.015, p=0.053). The duration of cold ischemia time was an independent and equally relevant risk factor for DGF irrespective of the preservation method with a comparable effect for each additional hour of preservation with HMP (OR 1.08, 1.04-1.14, p=0.003) or SCS (OR 1.08, 1.03-1.14, p=0.004) (28).

Does an initial period of SCS matter?

Multivariate analysis of prospectively collected data on the outcomes of ECD kidneys that underwent HMP (LifePort, Organ Recovery Systems®, USA) after a period of SCS (n=119) compared to ECD kidneys that underwent HMP immediately after retrieval (n=74) showed no significant difference in DGF (OR 1.20, 0.30-4.66, p=0.79) or 1-year graft survival (Hazard ratio 1.93, 0.54-6.85, p=0.31) (29).

In a recent analysis of the NHSBT database from 2007-2015, DGF rates were significantly lower in kidneys preserved with HMP after SCS compared with SCS alone (34% vs. 42%, p<0.001; adjusted OR 0.65, 95% CI 0.53-0.80, p< 0.001) with no difference in graft survival (adjusted hazard ratio 0.88, 95% CI 0.70-1.10, p=0.263) (30). In a recent single centre retrospective study from the West London Renal Transplant Centre, pre-implantation HMP (RM3, Waters Medical System, USA) following SCS (n=33) also decreased DGF (24% vs. 48%, p=0.04) compared to SCS alone (n=33) (31). These studies reflect that HMP may still be beneficial after a period of SCS.

ESNP

ESNP is a technically challenging technique using paediatric cardiopulmonary bypass technology. A study from Cambridge reported on the assessment of 10 DCD kidneys declined by all centres using ESNP. Five kidneys were transplanted, and four had immediate graft function (32). More recently, an initial clinical experience with ESNP in 14 kidneys, reported that 12 were successfully transplanted (two dual grafts). There were no cases of primary non-function and graft survival was 100% at one-year but three patients (30%) experienced DGF (33). A multi-centre RCT (ISRCTN 15821205) of pre-implantation ESNP for 60 minutes (n=200) compared to SCS (n=200) in kidneys from controlled DCD is currently recruiting in the UK and is estimated to complete in 2020 (34).

Conclusion

The sparsity of donor pretreatment trials has resulted in the re-analysis of already existing data, and RCTs are urgently needed to reinvigorate this aspect of donor management. When considering donor pretreatments it must always be considered that some strategies may be beneficial to one organ but not to others. The ideal pretreatment should have benefits for all organs retrieved in the multi-organ donor setting. Therefore, a potential advantage of in-situ normothermic regional perfusion is the combined benefit for all abdominal organs with increased organ utilisation and a minimisation of ischemic cholangiopathy following liver transplantation (35, 36).

It may also be beneficial to treat the kidneys ex situ with pretreatments delivered during ESNP machine perfusion (37). This approach might avoid any negative systemic consequences or off target effects in the donor or recipient thus addressing one of the primary concerns regarding other systemic pretreatments.

uDCD kidney transplantation has the highest risk of DGF and graft failure, and recent studies have reported that NRP improves DGF and graft survival outcomes in this setting (13, 14, 16). The risk of DGF is also increased in cDCD kidney transplantation (22), and future RCTs are needed in order to establish the optimal preservation techniques (Figure 1). To date the lowest rates of DGF (<10%) following transplantation of cDCD kidneys have been reported by the French National Protocol using a combination of NRP and HMP (38). However, it is unclear whether the low rate of DGF reported with this protocol relates to strict donor and recipient selection criteria, NRP alone, or the combination of NRP with HMP (38). The encouraging effects of oxygenated HMP reported by the COPE Compare study may provide the evidence to support the continued use of cold perfusion as a simple preservation method. However in order to extend the preservation time, it may be required to combine NRP at the time of retrieval with subsequent preservation using oxygenated HMP. This question needs to be addressed in a RCT to determine if there is a cumulative benefit of the two techniques and which kidneys should undergo these interventions alone or in combination.

Key points

· The sparsity of donor pretreatment trials has resulted in the re-analysis of already existing data, and RCTs are urgently needed to reinvigorate this aspect of donor research.

· uDCD kidney transplantation has the highest risk of DGF and graft failure, and recent studies have reported that NRP improves DGF and graft survival outcomes in this setting.

· HMP reduces DGF following deceased donor kidney transplantation across all donor types but unanswered questions still remain regarding its use.

· ESNP is emerging as a preservation option. While technically challenging, it may better facilitate the delivery of pretreatments.

· Future RCTs are needed in order to establish the role of specific preservation techniques and to identify an approach tailored to the quality of the individual kidney.

Author

Year

Donors

Kidneys

DGF

PNF

1-year graft loss^

1-year graft survival*

1-year patient death^

1-year patient survival*

3-year patient death^

3-year patient survival*

Martinez Arcos(21)

2018

All

1764

RR 0.79 (0.71-0.88)

RR 0.92 (0.73-1.16)

-

-

-

Peng(20)

2018

All

2048

RR 0.78 (0.69-0.87)

RR 1.08 (0.71-1.65)

RR 1.03 (1.00-1.07)*

-

RR 1.06 (1.02-1.11)*

Tingle(22)

2019

All

2266

RR 0.77 (0.67-0.90)

RR 0.88 (0.58-1.33)

-

RR 0.99 (0.95-1.03)^

-

Table 1 | Results of recent meta-analyses of transplantation of kidneys following HMP compared to SCS

Additional abbreviations: ECD – extended criteria donors, PNF – primary non-function

19

Figure 1 | Potential RCT of novel perfusion strategies for DCD kidney transplantation

References

1.Serrano OK, Vock DM, Chinnakotla S, Dunn TB, Kandaswamy R, Pruett TL, et al. The Relationships Between Cold Ischemia Time, Kidney Transplant Length of Stay, and Transplant-related Costs. Transplantation. 2019;103(2):401-11.

2.Cardinal H, Lamarche F, Grondin S, Marsolais P, Lagace AM, Duca A, et al. Organ donor management and delayed graft function in kidney transplant recipients: A multicenter retrospective cohort study. Am J Transplant. 2019;19(1):277-84.

3.Schnuelle P, Mundt HM, Druschler F, Schmitt WH, Yard BA, Kramer BK, et al. Impact of spontaneous donor hypothermia on graft outcomes after kidney transplantation. Am J Transplant. 2018;18(3):704-14.*

4.Niemann CU, Broglio K, Malinoski D. Comments on "Impact of spontaneous donor hypothermia on graft outcomes after kidney transplantation". Am J Transplant. 2018;18(3):763.

5.Niemann CU, Feiner J, Swain S, Bunting S, Friedman M, Crutchfield M, et al. Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function. N Engl J Med. 2015;373(5):405-14.**

Landmark study suggesting a beneficial effect of donor hypothermia on the kidney transplant outcomes

6.Zapata-Chavira H, Hernandez-Guedea M, Jimenez-Perez JC, Perez-Rodriguez E, Munoz-Espinosa L, Munoz-Maldonado G, et al. Modulation of Remote Ischemic Preconditioning by Proinflammatory Cytokines in Renal Transplant Recipients. J Invest Surg. 2019;32(1):63-71.

7.Bang JY, Kim SG, Oh J, Kim SO, Go YJ, Hwang GS, et al. Impact of Remote Ischemic Preconditioning Conducted in Living Kidney Donors on Renal Function in Donors and Recipients Following Living Donor Kidney Transplantation: A Randomized Clinical Trial. Journal of clinical medicine. 2019;8(5).

8.Cheungpasitporn W, Khoury NJ, Thongprayoon C, Craici IM. Is Remote Ischemic Conditioning of Benefit to Patients Undergoing Kidney Transplantation? J Invest Surg. 2019;32(1):72-4.

9.Savran Karadeniz M, Senturk Ciftci H, Tefik T, Oktar T, Nane I, Turkmen A, et al. Effects of Different Volatile Anesthetics on Cytokine and Chemokine Production After Ischemia-Reperfusion Injury in Patients Undergoing Living-Donor Kidney Transplant. Exp Clin Transplant. 2019;17(Suppl 1):68-74.

10.Reindl-Schwaighofer R, Kainz A, Jelencsics K, Heinzel A, Berlakovich G, Remport A, et al. Steroid pretreatment of organ donors does not impact on early rejection and long-term kidney allograft survival: Results from a multicenter randomized, controlled trial. Am J Transplant. 2019;19(6):1770-6.

11.Orban JC, Fontaine E, Cassuto E, Baumstarck K, Leone M, Constantin JM, et al. Effects of cyclosporine A pretreatment of deceased organ donors on kidney graft function (Cis-A-rein): study protocol for a randomized controlled trial. Trials. 2018;19(1):231.

12.Abramowicz D, Oberbauer R, Heemann U, Viklicky O, Peruzzi L, Mariat C, et al. Recent advances in kidney transplantation: a viewpoint from the Descartes advisory board. Nephrol Dial Transplant. 2018;33(10):1699-707.

13.Antoine C, Savoye E, Gaudez F, Cheisson G, Badet L, Videcoq M, et al. Kidney transplant from uncontrolled donation after circulatory death: contribution of normothermic regional perfusion. Transplantation. 2019.*

14.Del Rio F, Andres A, Padilla M, Sanchez-Fructuoso AI, Molina M, Ruiz A, et al. Kidney transplantation from donors after uncontrolled circulatory death: the Spanish experience. Kidney Int. 2019;95(2):420-8.

15.Gelpi R, Paredes D, Rodriguez-Villar C, Roque R, Ruiz A, Adalia R, et al. The development of a predictive model of graft function in uncontrolled donors after circulatory death: validity of a pulsatile renal preservation machine cut-off value for kidney acceptance. Nephrol Dial Transplant. 2019;34(3):531-8.

16.Molina M, Guerrero-Ramos F, Fernandez-Ruiz M, Gonzalez E, Cabrera J, Morales E, et al. Kidney transplant from uncontrolled donation after circulatory death donors maintained by nECMO has long-term outcomes comparable to standard criteria donation after brain death. Am J Transplant. 2019;19(2):434-47.**

17.Sanchez-Fructuoso AI, Perez-Flores I, Del Rio F, Blazquez J, Calvo N, Moreno de la Higuera MA, et al. Uncontrolled donation after circulatory death: A cohort study of data from a long-standing deceased-donor kidney transplantation program. Am J Transplant. 2019;19(6):1693-707.

18.De Carlis L, De Carlis R, Muiesan P. Past, present, and future of donation after circulatory death in Italy. Updates Surg. 2019;71(1):7-9.

19.Ravaioli M, De Pace V, Comai G, Capelli I, Baraldi O, D'Errico A, et al. Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study. Transpl Int. 2018;31(11):1233-44.

20.Peng P, Ding Z, He Y, Zhang J, Wang X, Yang Z. Hypothermic Machine Perfusion Versus Static Cold Storage in Deceased Donor Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Artif Organs. 2018.

21.Martinez Arcos L, Fabuel Alcaniz JJ, Gomez Dos Santos V, Burgos Revilla FJ. Functional Results of Renal Preservation in Hypothermic Pulsatile Machine Perfusion Versus Cold Preservation: Systematic Review and Meta-Analysis of Clinical Trials. Transplant Proc. 2018;50(1):24-32.

22.Tingle SJ, Figueiredo RS, Moir JA, Goodfellow M, Talbot D, Wilson CH. Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation. Cochrane Database Syst Rev. 2019;3:Cd011671.

23.Savoye E, Macher MA, Videcoq M, Gatault P, Hazzan M, Abboud I, et al. Evaluation of outcomes in renal transplantation with hypothermic machine perfusion for the preservation of kidneys from expanded criteria donors. Clin Transplant. 2019;33(5):e13536.

24.Tedesco Silva H, Jr., Evans RW, Gavaghan MB, Vazquez VC. A Cost-Effectiveness Analysis of Organ Preservation Methods for Deceased Donor Kidneys at High Risk for Delayed Graft Function in Brazil. Transplant Proc. 2018;50(10):3121-7.

25.Schnuelle P, Druschler K, Schmitt WH, Benck U, Zeier M, Kramer BK, et al. Donor organ intervention before kidney transplantation: Head-to-head comparison of therapeutic hypothermia, machine perfusion, and donor dopamine pretreatment. What is the evidence? Am J Transplant. 2019;19(4):975-83.

26.Jochmans I, Hofker H, Davies L, Knight S, Pirenne J, Ploeg ROHMPoKDaCDAIRCT. Oxygenated Hypothermic Machine Perfusion of Kidneys Donated after Circulatory Death: An International Randomised Controlled Trial. Am J Transplant. 2019;19(suppl 3).**

Study reporting on the beneficial effect of oxygenated HMP in improving the graft function mediated by the reduction in acute rejection rates.

27.Arlaban M, Barreda P, Ballesteros MA, Rodrigo E, Suberviola B, Valero R, et al. Static Cold Storage vs Ex Vivo Machine Perfusion: Results From a Comparative Study on Renal Transplant Outcome in a Controlled Donation After Circulatory Death Program. Transplant Proc. 2019;51(2):311-3.

28.Kox J, Moers C, Monbaliu D, Strelniece A, Treckmann J, Jochmans I, et al. The Benefits of Hypothermic Machine Preservation and Short Cold Ischemia Times in Deceased Donor Kidneys. Transplantation. 2018;102(8):1344-50.

29.Ruiz-Hernandez M, Gomez-Dos Santos V, Diaz-Perez D, Fernandez-Alcalde A, Hevia-Palacios V, Alvarez-Rodriguez S, et al. Experience With Hypothermic Machine Perfusion in Expanded Criteria Donors: Functional Outcomes. Transplant Proc. 2019;51(2):303-6.

30.Patel K, Nath J, Hodson J, Inston N, Ready A. Outcomes of donation after circulatory death kidneys undergoing hypothermic machine perfusion following static cold storage: A UK population-based cohort study. Am J Transplant. 2018;18(6):1408-14.

31.Bellini MI, Charalampidis S, Herbert PE, Bonatsos V, Crane J, Muthusamy A, et al. Cold Pulsatile Machine Perfusion versus Static Cold Storage in Kidney Transplantation: A Single Centre Experience. BioMed research international. 2019;2019:7435248.

32.Hosgood SA, Thompson E, Moore T, Wilson CH, Nicholson ML. Normothermic machine perfusion for the assessment and transplantation of declined human kidneys from donation after circulatory death donors. Br J Surg. 2018;105(4):388-94.

33.Chandak P, Phillips BL, Uwechue R, Thompson E, Bates L, Ibrahim I, et al. Dissemination of a novel organ perfusion technique: ex vivo normothermic perfusion of deceased donor kidneys. Artif Organs. 2019.

34.Hosgood SA, Saeb-Parsy K, Wilson C, Callaghan C, Collett D, Nicholson ML. Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation. BMJ open. 2017;7(1):e012237.

35.Watson CJE, Hunt F, Messer S, Currie I, Large S, Sutherland A, et al. In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival. Am J Transplant. 2018.

36.Hessheimer AJ, Coll E, Torres F, Ruiz P, Gastaca M, Rivas JI, et al. Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation. J Hepatol. 2019;70(4):658-65.

37.DiRito JR, Hosgood SA, Tietjen GT, Nicholson ML. The future of marginal kidney repair in the context of normothermic machine perfusion. Am J Transplant. 2018;18(10):2400-8.

38.Antoine C, Videcoq M, Riou B, Dorez D, Cheisson G, Martin-Lefèvre L, et al. Controlled Donation After Circulatory Death (cDCD) Donors May Become Similar to Brain Death Donors (DBD). Am J Transplant. 2017;17(suppl 3).**

Study reporting the beneficial efffect of NRP on the outcomes of cDCD kidneys