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Novel Organ Perfusion and Preservation Strategies in Transplantation – Where Are We Going in the United Kingdom?

O’Neill, Stephen FRCS1,2; Srinivasa, Sanket FRCS1; Callaghan, Chris J. FRCS3; Watson, Christopher J.E. FRCS4; Dark, John H. FRCS5; Fisher, Andrew J. FRCP5; Wilson, Colin H. FRCS5; Friend, Peter J. FRCS6; Johnson, Rachel MSc7; Forsythe, John L. FRCS7; Ploeg, Rutger J. FRCS6; Mirza, Darius F. FRCS8; Wigmore, Stephen J. FRCS1,9; Oniscu, Gabriel C. FRCS1,9

Author Information
doi: 10.1097/TP.0000000000003106

Abstract

INTRODUCTION

Rising demand for organs for transplantation has led to increased utilization of grafts from donors that fall outside standard acceptance criteria, which are perceived as higher-risk donors. Static cold storage (SCS) may be adequate for organs from so-called “standard-criteria” donors but is insufficient for the preservation of organs from older donors and/or those with a higher-risk of graft failure. SCS therefore does not facilitate the expansion of organ acceptance criteria for transplantation and likely compounds ongoing organ shortage.1 There has been an explosion of novel strategies to perfuse, preserve, repair, and resuscitate organs before transplantation.2 Technological advances have supported the development of these strategies with a number of devices entering clinical practice or trials. Broadly speaking, the focus of strategies has been either the donor with in situ regional perfusion or the transport and preimplantation phase with ex situ machine perfusion of isolated organs. Although no universal nomenclature is in use, in the context of deceased organ donation, ex situ is the preferred terminology over ex vivo given that machine perfusion occurs after the organs have been removed from the body of a deceased donor.3 A number of perfusion variables including temperature, oxygen delivery, and perfusate (blood-based, blood analogues or specifically designed media) are currently being investigated.2 The theoretical advantages of these dynamic perfusion and preservation modalities have translated into encouraging results that appear to suggest an increased graft utilization, the ability to undertake assessment of graft viability before transplantation, with a potentially improved outcome for recipients.4 However, the increasing number of devices available combined with the wide range of regimens of perfusion technology make the choice increasingly complex. While current trials focus on demonstrating the clinical benefit of individual strategies, the time has come to establish how best to tailor the techniques to specific donor types and conditions while defining their role for each organ, accounting for donor- and organ-specific risk factors.

This review undertakes a horizon scan of the clinical outcomes reported to date using various novel perfusion strategies applied in organ transplantation. The data (Figure 1; Appendix 1, SDC, http://links.lww.com/TP/B866) were presented to experts at the National Health Service Blood and Transplant (NHSBT) Preservation and Perfusion Future Strategy Summit in London in October 2018. The outcomes of the meeting are discussed later after due consideration of the available evidence.

FIGURE 1.
FIGURE 1.:
Search results. HMP, hypothermic machine perfusion; HOPE, hypothermic oxygenated perfusion; HRP, hypothermic regional perfusion; NMP, normothermic machine perfusion; NRP, normothermic regional perfusion; OPAL, oxygen persufflation as adjunct in liver preservation; RCT, randomized controlled trial.

KIDNEY TRANSPLANTATION

The key performance indicators (KPIs) following kidney transplantation are graft utilization, immediate versus delayed graft function (DGF) versus primary-non-function (PNF), graft survival, patient survival, and 1-year graft function (eGFR/creatinine). The standard technique for kidney preservation is SCS in most centers.

Hypothermic Perfusion Strategies

Standard hypothermic machine perfusion (HMP) involves the kidney being connected to a perfusion device and cold acellular preservation solution is pumped continuously through the renal vasculature at temperatures ranging from 1°C to 10°C.5 Meta-analyses have been published comparing HMP kidney preservation with SCS in kidneys recovered from extended criteria donors (ECD),6 donation after circulatory death (DCD) donors,7,8 and across all donor types.8-13 These meta-analyses have described a significant reduction in the odds ratio (OR) or risk ratio (RR) of DGF (ranging from 0.6 to 0.8) following HMP but none have reported a significant reduction in PNF6-13 (Table 1). Only one meta-analysis of ECD reported improved graft survival in kidneys following HMP compared with SCS at 1-year (OR 1.12, 1.03–1.21, P = 0.005).6 Similarly there is a meta-analysis reporting improved graft survival at 3-years across all donor types (RR 1.06, 1.02–1.11, P = 0.009).13 A Cochrane Review concluded that HMP is superior to SCS in both DBD and DCD kidney transplantation, even when assessing only studies that have been published in the last decade. However, because kidneys from DCD donors have an increased risk of DGF, the number needed to treat to prevent one episode of DGF is less for DCD kidneys (7.26 versus 13.60 in DBD kidneys).12

TABLE 1.
TABLE 1.:
Results of meta-analyses of transplantation of kidneys following HMP compared with SCS

A randomized controlled trial (RCT) of 336 consecutive deceased donors in the Eurotransplant region that randomized in a paired design 1 kidney from each donor to HMP (LifePort, Organ Recovery Systems, USA) or SCS reported a significant reduction in DGF (adjusted-OR 0.57, 0.36–0.88, P = 0.01) and 1-year graft failure (adjusted-OR 0.52, 0.29–0.93, P = 0.03) with HMP.5 The reduction in DGF with HMP was confirmed in an independently powered extension of this RCT into 82 DCD donors (adjusted-OR 0.43, 0.20–0.89, P = 0.025),14 and another independent study of 91 donation after brain death (DBD) donors that were ECD (adjusted-OR 0.46, 0.21–0.99, P = 0.047).15 The sub-analysis of ECD reported that 1-year death censored graft survival was significantly higher with HMP compared with SCS (92% versus 80%, P = 0.02; adjusted hazard ratio for 1-y graft loss 0.35, 0.15–0.86, P = 0.02).15 In the DCD population, a significant reduction in DGF was observed in the HMP group (54%versus 70%; P = 0.007) but no significant difference was seen for 1-year graft survival between HMP and SCS groups (94% versus 95%).14

In contrast to the DCD study in the Eurotransplant region, a UK RCT comparing HMP (LifePort, Organ Recovery Systems, USA) with SCS in DCD kidneys and analyzed by sequential analysis was stopped due to futility (DGF rate HMP; 58% versus SCS; 56%).16 There are differences between these RCTs, most notably that in the UK trial kidneys were not preserved with HMP from procurement and underwent an initial variable-length period of SCS. In the UK trial, there was also fixed control preservation fluid in the SCS group while in the European RCT both histidine-tryptophan-ketoglutarate (76%) and University of Wisconsin (UW) solution (22%) were used.17 Furthermore, the DGF rate for DCD kidneys subjected to SCS was lower in the UK study than in the European DCD study (UK DGF 56% versus 70% in the European study) but DGF rates after HMP were similar in the UK (58%) and European (54%) trials.16

In recent analysis of the NHSBT database (2007–2015), DGF rates were significantly lower in kidneys preserved with HMP compared with SCS (34% versus 42%, P < 0.001; adjusted-OR 0.65, 0.53–0.80, P < 0.001) with no difference in graft survival (adjusted hazard ratio 0.88, 0.70–1.10, P = 0.263).18 In a single-center retrospective study from West London, preimplantation HMP (RM3, Waters Medical Sytem, USA) following SCS (n = 33) decreased DGF (24% versus 48%, P = 0.04) compared with SCS alone (n = 33).19 A further paired-kidney analysis from Germany reported a reduced rate of DGF (12% versus 21%, P = 0.38; adjusted-OR 0.28, 0.07–0.94, P < 0.04) with preimplantation HMP (LifePort, Organ Recovery Systems, n = 66) compared with SCS (n = 43).20 Currently, there is an ongoing UK trial replicating the EuroTransplant methods (ISRCTN 50082383). Two further RCTs of the Consortium for Organ Preservation in Europe (COPE) have completed recruitment assessing standard HMP versus oxygenated-HMP (Kidney Assist-transport, Organ Assist, Netherlands). One RCT has randomized kidneys from ECD to oxygentated-HMP after SCS versus SCS alone with graft survival at 1-year as a primary endpoint (COPE-POMP, ISRCTN 63852508). The second RCT has randomized kidneys in a paired design from controlled DCD donors >50 years to either oxygenated-HMP (n = 106) or standard HMP (n = 106) with eGFR as its primary endpoint (COPE-COMPARE, ISRCTN 32967929). The results of the COPE-COMPARE study were reported at the American Transplant Congress in May 2019, showing a significant reduction in biopsy-proven acute rejection (14% versus 28%, P = 0.01), reduced graft loss (3% versus 10%, P = 0.021) and on sensitivity analysis a significantly higher eGFR (47.6 versus 42.6 mL/min/1.73 m2, P = 0.035) at 1-year follow-up for kidneys perfused with oxygenated-HMP. No statistically significant difference was seen as regards DGF and PNF (oxygenated-HMP versus standard HMP: DGF: 38% versus 38%; PNF: 3% versus 5%).21

Hypothermic regional perfusion (HRP) involves isolation and perfusion of abdominal organs with continuous flow of diluted blood cooled to 4°C–22°C.22 In the largest reported series of HRP in uncontrolled DCD (uDCD) kidneys (n = 320), there was a 4% rate of PNF, 61% rate of DGF, and an 87% graft survival at 1-year.23 PNF rates of 0%–6%, DGF rates of 21%–85%, and 1-year graft survival rates of 88%–97% have been reported in other single-center studies (n = 8–34).24-27 In a study from St Petersburg, subnomothermic regional perfusion (27°C–32°C) in 44 uDCD kidney donors with prolonged asystole (mean 61 min) led to comparable 1-year graft survival (95% versus 96%) to DBD kidneys (n = 87). A 52% rate of DGF was also observed in this study but no cases of PNF.28

Normothermic Perfusion Strategies

Normothermic regional perfusion (NRP) is performed in a similar manner to HRP but maintaining perfusion temperature close to normothermia (35°C–37°C ).22 A study from France compared NRP (n = 19) with SCS (n = 31) in kidneys from uDCD donors. All kidneys underwent HMP (LifePort, Organ Recovery Systems, USA) for at least 2 hours following NRP. PNF as well as patient and graft survival rates did not differ between the groups. However, the use of NRP was associated with a significantly lower risk of DGF compared with SCS (53% versus 81%, P = 0.036), which persisted in multivariate models (adjusted-OR = 0.17, 0.03–0.87, P = 0.034). Furthermore, the use of NRP was the only significant factor associated with a likelihood of an eGFR > 40 mL/min/1.73 m2 at 1-year post-transplantation (adjusted-OR = 3.68, 1.06–12.8, P = 0.04).29

Three other studies have reported on kidney transplant outcomes following NRP in controlled DCD (cDCD) donors with DGF rates of 18%,30 31%,31 and 40%.32 Three further studies have reported on outcomes following NRP in cDCD kidney transplantation in comparison to DBD control groups.33-35 In a study from the University of Wisconsin, there was no statistically significant difference in DGF (8% versus 24%, P = 0.1) in cDCD kidneys following NRP (n = 24) compared with DBD kidneys (n = 100).34 A second study from Spain showed that there was no statistically significant difference in DGF (27% versus 33%, P = 0.56) or 1-year graft survival (92% versus 97%, P = 0.32) in cDCD kidneys following NRP (n = 37) compared with DBD kidneys (n = 36).33 The largest study to date reports the use of NRP followed by HMP (LifePort, Organ Recovery Systems, USA) according to the National Protocol for kidneys from cDCD donors in France (n = 92) and compares the outcomes to kidneys from DBD donors (n = 5176).35 This study was presented at the American Transplant Congress in 2017 and reported significantly lower levels of DGF in cDCD kidneys following NRP when compared with DBD kidneys (9% versus 19%, P < 0.05).35 In Italy, where declaration of circulatory death is based on absence of electrical activity and requires a minimum no-touch period of at least 20 minutes,36 a series of 10 kidneys from cDCD donors using NRP and oxygenated-HMP reported a DGF rate of 30% and no PNF.37

Ex situ normothermic machine perfusion (ex situ NMP) of kidneys involves perfusion with an oxygenated red cell-based plasma-free perfusate. A study of preimplantation ex situ NMP of ECD kidneys (n = 18) using pediatric cardiopulmonary bypass technology (Medtronic, UK) compared with matched control kidneys preserved with SCS using Soltran solution (n = 47) reported a significant reduction in DGF (6% versus 36%, P = 0.01) with no difference in graft survival at 1-year (100% versus 98%, P = 0.51).38 Ex situ NMP is a technically challenging technique. The Cambridge group reported the assessment by ex situ NMP of 10 declined DCD kidneys, 5 of which were transplanted and 4 had initial graft function.39 Recently, Guy’s and Newcastle reported their initial experience with ex situ NMP performed on 14 kidneys from 12 donors, with 12 kidneys transplanted into 10 recipients (2 dual grafts). There were no cases of PNF, 3 patients (30%) experienced DGF and graft survival was 100% at 1-year. There were 7 donors where 1 kidney received SCS and ex situ NMP, and the other received SCS alone. Although there was a trend towards lower DGF and PNF rates in the ex situ NMP group, this did not reach statistical significance.40 A UK multicenter RCT (ISRCTN 15821205) of preimplantation ex situ NMP for 60 minutes (n = 200) compared with SCS (n = 200) in kidneys from cDCD is currently recruiting and is estimated to complete in 2020.41

LIVER TRANSPLANTATION

KPIs following liver transplantation are graft utilization, immediate versus early allograft dysfunction (EAD) versus PNF, hepatic artery (HA) thrombosis, biliary complications including ischemic cholangiopathy (IC), graft survival, patient survival, and retransplantation. The standard technique for liver preservation is still SCS in the majority of centers.

Hypothermic Perfusion Strategies

Hypothermic liver perfusion can be accomplished either via the portal vein (PV) alone or through the PV and HA (dual-perfusion). In liver transplantation, the feasibility of end-ischemic dual-HMP using a modified bypass device (Medtronic PBS, USA) was demonstrated in a case-matched series of HMP preserved DBD grafts (n = 20) compared with SCS (n = 20).42 There were no cases of PNF in either group but recipients in the HMP arm demonstrated a lower peak AST (1154 versus 3339 IU/ml, P = 0.011), shorter length of stay (11 versus 15-d, P = 0.006), and lower incidence of EAD (5% versus 25%, P = 0.08). A subsequent case-matched series comparing declined livers undergoing HMP (n = 31) to 50 extended criteria liver grafts preserved with SCS (n = 50) showed a lower incidence of biliary complications (including strictures and leaks) within 1-year (13% versus 43%, P = 0.02) and reduced hospital stay (16 versus 20-d, P = 0.001) without any difference in PNF (3% versus 7%, P = 0.61), EAD (19% versus 30%, P = 0.38) or 1-year patient survival (84% versus 80%, P = 0.76).43

Hypothermic oxygenated perfusion (HOPE) seeks to extend HMP by oxygenating standard machine perfusion fluid (UW solution) to restore mitochondrial function with perfusion via the PV alone. In dual flow hypothermic oxygenated perfusion (D-HOPE), cold machine preservation solution is pumped via the PV and the HA and has been postulated to optimize oxygen delivery to the biliary system, although evidence that dual-perfusion is superior is lacking.44 One matched case-series in DCD livers (25 HOPE preserved livers from Zurich versus 50 SCS livers from Rotterdam/Birmingham) reported that patients in the HOPE arm (ECOPS, Organ Assist, Netherlands) had significantly lower peak ALT (1239 versus 2065 U/L, P = 0.02), developed fewer biliary complications (20% versus 46%, P = 0.04), with a reduced incidence of IC (0% versus 22%, P = 0.02) and improved 1-year graft survival (90% versus 69%, P = 0.04) but in the context of shorter cold ischemic times (3 versus 6.5 h, P = 0.01).45 After 5-years of follow-up, graft survival was significantly better in the HOPE group compared with SCS (94% versus 78%, P = 0.024).46

A further prospective case-control study compared DCD livers receiving D-HOPE (Liver Assist, Organ Assist, Netherlands) (n = 10) with SCS (n = 32).44 This study showed reduced peak ALT (966 versus 1858 U/L, P = 0.006), peak bilirubin (1.0 versus 2.6 mg/dL, P = 0.04) but no statistically significant difference in 1-year graft (100% versus 67%, P = 0.052) or patient survival (100% versus 85%, P = 0.21).

Another alternative for oxygen delivery is persufflation, whereby oxygen is passed directly through vasculature into the organ during SCS.4 Oxygen persufflation has been applied to a small number of marginal grafts (n = 5) with 100% graft and patient survival at 2-years follow-up. This approach is currently being compared with SCS in a single-center RCT (ISRCTN00167887) aiming to recruit 116 patients.47

Normothermic Perfusion Strategies

Two studies from the University of Wisconsin on 5 and 13 cDCD liver transplants performed following NRP reported a 1-year graft survival of 86%, a 2-year graft-survival of 71%, and a 14% PNF and biliary stricture rate.31,34 An initial UK series of 11 patients receiving cDCD liver transplantation following NRP had 1 reported case of PNF, an EAD rate of 36%, and no incidence of IC.32 A subsequent larger UK 2-center study of cDCD liver transplantation following NRP (n = 44) compared with SCS controls (n = 185) reported a significantly lower incidence of EAD (12 versus 32%, P = 0.008) and anastomotic stricture rate (7% versus 27%, P < 0.0001), with no cases of IC in the NRP arm (0% versus 27%, P < 0.0001). A lower rate of 30-day graft loss was reported in the NRP group (2% versus 12%, P = 0.06).48 In a single-center study from Spain, 11 livers from cDCD donors were transplanted following NRP with a 1-year graft survival rate of 90.1% and no cases of IC.33 In a large multicenter report from Spain, the use of NRP (n = 95) compared with SCS (n = 117) in cDCD liver transplantation led to decreased rates of biliary complications (8% versus 31%, P < 0.001), IC (2% versus 13%, P = 0.008), and graft loss (12% versus 24%, P = 0.008) in patients receiving grafts following NRP.49

A series of 20 DCD liver transplants performed in Italy with NRP reported no significant difference in 1-year patient (95% versus 94%, P = 0.94) or graft survival (85% versus 91%, P = 0.20) compared with DBD grafts despite the extended standoff period of 20 minutes following donor asystole. The IC rate was 10% but no recipients underwent retransplantation due to biliary complications.50

NRP was first utilized for uDCD donors. In a report from Spain, 34 NRP recovered grafts were compared with 538 DBD controls. Graft survival was significantly higher for the recipients of DBD versus uDCD livers (87% versus 70%, P = 0.011) but patient survival was not significantly different (90% versus 82%, P = 0.141). Biliary complications occurred in 12% of the livers transplanted from uDCD donors after NRP with an 8% rate of IC.51

A further study from Spain comparing 20 liver transplants from NRP uDCD donors with 40 DBD liver transplants reported a nonsignificant difference in 1-year graft survival (80% versus 88%, P = 0.77) and patient survival (86% versus 88%, P = 0.77). The retransplantation rate in the uDCD group was 15% while PNF was 10% with 5% IC rate.52

The suggested standard abbreviation for ex situ NMP of the liver is normothermic machine perfusion (NMP).3 This technique mandates dual-perfusion to mimic normal liver physiology and meet metabolic demands. NMP can be instituted upon procurement at the donor center or upon the arrival of the liver graft in the recipient center.

A number of pilot studies initially demonstrated the feasibility of NMP in DBD, DCD, and discarded livers.53-55 A phase-1 two-center study demonstrated feasibility, safety and demonstrated potential benefits in individual ECD livers.55 A subgroup analysis of 6 of 20 livers identified more stable postreperfusion hemodynamic parameters with a decrease in inotrope use during reperfusion.56 As part of COPE, a subsequent international multicenter RCT of NMP (OrganOx metra, OrganOx, UK) conducted in DBD and DCD livers from the time of procurement, reported that the NMP group (n = 121) compared with the SCS group (n = 101) had lower peak AST (485 versus 974 U/L, P < 0.0001) and significantly lower rates of EAD (10% versus 49%, P < 0.001). This was achieved despite a lower discard rate (12% versus 24%, P = 0.008) and significantly longer preservation times (714 versus 465 min, P < 0.001). There was no significant difference in IC (DBD; 7.4% versus 5.4%, P = 0.68, DCD; 11.1% versus 26.3%, P = 0.18), anastomotic biliary strictures (DBD; 40.7% versus 41.8%, P = 0.91, DCD; 48.1% versus 57.9%, P = 0.52), 1-year graft survival (95% versus 96%, P = 0.71) or 1-year patient survival (95% versus 96%, P = 0.67).57

An alternative and logistically less challenging approach is to undertake NMP preimplantation upon the arrival of the graft in the implanting center. A study from Birmingham described successful transplantation of 5 discarded livers after a period of NMP and suggested several criteria for organ viability based on perfusate lactate (<2.5 mmol/L) or bile production in combination with 2 of 3 other criteria; perfusate pH > 7.3, stable arterial flow of >150 mL and portal venous flow >500 mL per minute, and homogenous graft perfusion. All 5 recipients were reported well with normalized liver tests at a median follow-up of 7-months. These viability criteria could therefore identify ECD grafts that can be utilized safely.53 The initial viability criteria have since been modified by the addition of measurement of bile pH while the liver is on NMP with a pH ≤ 7.4 associated with IC.58 However these criteria require validation in larger trials.

In a study from Cambridge, 12 declined livers were transplanted after a period of NMP (Liver Assist, Organ Assist, Netherlands). The first 6 livers were perfused at high oxygen tensions and were complicated by post perfusion syndrome and vasoplegia in the recipient, complications that were not seen when the oxygen tension was lowered to physiological levels.59 Outcomes were compared with a contemporaneous cohort of 24 other SCS livers and were found to be similar in terms of 1-year graft survival (NMP 83% versus 88% SCS), 1-year patient survival (NMP 92% versus 96% SCS), and rate of IC (NMP 27% versus 29% SCS). In a subsequent study from Cambridge, 22 declined or high-risk livers were transplanted after NMP with an IC rate of 18%. While NMP preimplantation was associated with an increased organ utilization and rescue of organs that would otherwise have been discarded, there was no impact on the incidence of IC.58

Controlled oxygenated rewarming (COR) from 10°C–20°C over 90-minutes has been proposed to gradually rewarm the liver and thus be less physiologically stressful. In one study of six DBD liver graft recipients compared with 106 historical DBD controls, COR was associated with lower peak AST (564 versus 1204 U/L, P = 0.02).60 Using a combined resuscitation and viability testing protocol of sequential D-HOPE, COR, and NMP using a new hemoglobin-based oxygen carrier-based perfusion fluid, 5 of 7 livers from declined DCD donors were transplanted with a 3-month graft survival of 100%. In this study, use of a synthetic oxygen carrier for end-ischemic NMP has the potential advantage of being able to perform NMP with gradual rewarming, something not possible if blood is used as a perfusate.61 To date, comparison of biomarkers and bile production in blood perfused versus cell free NMP has only been made in declined livers that have not went on to be transplanted.62,63

PANCREAS TRANSPLANTATION

KPIs following pancreas transplantation are graft utilization, graft thrombosis, graft pancreatitis, early graft failures, graft survival, and patient survival. The standard technique for pancreas preservation is SCS.

The pancreas is a low-flow organ with complex vascular anatomy that makes optimal perfusion parameters difficult to obtain.4 As such, experimental work in terms of pancreas perfusion is still ongoing. One recent study reported successful isolation of functional islets from 2 of 10 discarded pancreases after a period of continuous HMP (Deltastream DPII; MEDOS Medizintechnik AG, Germany) with a dual-perfusion system through the mesenteric/splenic arteries.64 Another study from London placed discarded organs on a normothermic circuit (to mimic transplantation) after a period of HMP (RM3, Waters Medical System, USA) and found 2 of 3 discarded organs were functional in terms of insulin production.65 In a study from France, 7 discarded human pancreases have undergone HMP for 24-hours with reducing resistive index for the first 12-hours followed by stabilization of perfusion pressures without developing edema. Postperfusion biopsy samples revealed normal staining for insulin, glucagon, and somatostatin.66

Pancreas preservation by oxygen persufflation in combination with SCS (n = 13) has been compared with SCS alone (n = 11) and reported improved β-cell function after islet cell isolation.67 In a further study, the feasibility of ex situ NMP (pediatric cardiopulmonary bypass technology, Medtronic, UK) in declined human pancreases (n = 5) using warm oxygenated packed red blood cells for 1–2 hours has been demonstrated by insulin secretion from the majority of perfused organs (n = 4/5).68 Other than successful solid organ pancreas and islet transplantation following NRP,31-33 to date there have been no reports of pancreases transplanted into a recipient following novel preservation strategies.

CARDIAC TRANSPLANTATION

KPIs following cardiac transplantation are graft utilization, PNF, need for mechanical support, graft survival, and patient survival. The standard technique for cardiac preservation is SCS for DBD donors and ex situ NMP for DCD donors.

While ex situ hypothermic heart perfusion is still under development,69 ex situ NMP has been implemented clinically. PROCEED II (NCT00855712) was a multicenter RCT that compared 67 standard-criteria DBD heart transplants after ex situ NMP (Organ Care System, TransMedics, USA) with SCS (n = 63) and reported similar outcomes in terms of 30-day patient/graft survival rates (94% versus 97%, P = 0.45) and cardiac-related severe adverse events (13% versus 14%, P = 0.90). Five hearts were not transplanted in the ex situ NMP group on the basis of lactate.70 In a single-center study (n = 26) from Harefield, ex situ NMP (Organ Care System, TransMedics, USA) has been reported to facilitate transplantation of hearts not initially considered suitable for transplantation or to be used for higher-risk recipients with only one reported death (3.8%) and preserved allograft function in 92% of patients.71

DCD heart transplantation has been one of the most important developments in recent years with the potential to significantly increase the number of heart transplants undertaken and a significant reduction in waiting-list mortality.72 The first report of successful DCD heart transplantation using ex situ NMP (Organ Care System, TransMedics, USA) was described in 2015,73 and further case series of DCD heart transplantation have followed.74,75 At present, 2 methods for heart recovery are explored: direct procurement and preservation which requires a rapid cooling and procurement of the heart with collection of blood from the donor with which to prime the OCS system, and thoraco-abdominal NRP.

In a study from Papworth, 12 DCD heart transplants recovered with thoraco-abdominal NRP with ex situ NMP (Organ Care System, TransMedics, USA) were compared with 14 hearts recovered with direct procurement and preservation and ex situ NMP (Organ Care System, TransMedics, USA) and DBD heart transplants (n = 26). There were no significant differences in the outcomes between the 2 approaches or in comparison to DBD heart transplantation.76 In a recent review article, the experience with DCD heart transplantation with these techniques was updated to 39 cases with a recipient survival to discharge rate of 93%.77

LUNG TRANSPLANTATION

KPIs following lung transplantation are graft utilization, primary graft function versus primary graft dysfunction (PGD), unplanned extracorporeal membrane oxygenation support (ECMO), graft survival, and patient survival. The standard technique for lung preservation is still SCS in the vast majority of centers.

In lung transplantation, there are 2 main systems that have been used for ex situ NMP. The XVIVO Perfusion System (XVIVO Perfusion, Gothenburg, Sweden) is a static system utilizing either acellular or red-cell supplemented perfusion while the Organ Care System (Organ Care System, TransMedics, USA) is a portable system that uses red cell supplemented perfusion.78 The Steen group (Lund, Sweden) described the first successful lung transplantation after ex situ NMP with 6 out of 9 donor lungs initially rejected for transplantation. The 6 recipients survived the first 3-months and 4 of the 6 were alive at 1-year.79 After modification of Steen’s initial ex situ NMP protocol, a matched-controlled study from Toronto of 20 high-risk lungs preserved with ex situ NMP (XVIVO Perfusion System) compared with conventional-risk SCS lungs (n = 116) reported no statistically significant difference in the primary endpoint of PGD 72-hours posttransplantation (15% versus 30%, P = 0.11); or secondary endpoints of 30-day mortality, bronchial complications, duration of mechanical ventilation, intensive care unit length of stay, or hospital length of stay.80

In a follow-up study, the ex situ NMP group (n = 50) was compared with a SCS group (n = 235) and the incidence of PGD grade-3 at 72-hours was lower (2% versus 9%, P = 0.14) with similar 30-day mortality (4% versus 3.5%, P = 1.0), and 1-year survival (87% versus 86%, P = 1.0).81 In a further study from Toronto, patients transplanted with DCD lungs after ex situ NMP (n = 28) were compared with patients transplanted with DCD lungs after SCS (n = 27) and had similar patient survival (86% versus 92%, P = 0.68) but shorter hospital stay (median 18 versus 23-d, P = 0.047) and a shorter length of mechanical ventilation (2 versus 3-d, P = 0.059).82 In a retrospective study from Harefield, lungs initially deemed unusable for transplantation (n = 13) underwent ex situ NMP (adapting the Toronto protocol) and 46% (n = 6) were transplanted with 100% survival at 3-months.83 The reported conversion rate from ex situ NMP to transplantation is lower in the Harefield experience at 46% compared with the Swedish (67%) and Toronto (87%) experience.83 In a combined analysis of United Kingdom, Sweden, and Toronto experience, only 2 deaths within 90-days were reported in over 65 ex situ NMP lung transplants.84

In a further study from France, ex situ NMP (XVIVO Perfusion System) was performed in lungs initially considered unsuitable for transplantation (n = 32) and compared with SCS controls (n = 81) with similar rates of PGD after 72-hours (9.5% versus 8.5%, P = 1.0), 30-day mortality (3.3% versus 3.7%, P = 0.69), and 1-year survival (93% versus 91%, P = 0.8).85 In a single-center RCT from Vienna, standard-criteria lungs were randomized to ex situ NMP and SCS (XVIVO Perfusion System, n = 39) or SCS (n = 41) with no significant difference in PGD (6% versus 20%, P = 0.10), need for postoperative prolonged ECMO (6% versus 12%, P = 0.44), 30-day survival (97% versus 100%, P = 0.46) or intubation time, intensive care stay and hospital stay. There was also loss of some standard-criteria donor lungs due to technical issues during perfusion making exposure of all donor lungs to ex situ NMP unattractive.86 In the largest multicenter RCT (INSPIRE, NCT01630434) of ex situ NMP (n = 151) (Organ Care System) compared with SCS (n = 169), a composite end-point of a 30-day patient survival (96% versus 100%) and the incidence of PGD grade-3 within 72-hours (18% versus 30%, P = 0·015) was not statistically significantly different between the groups (70% versus 79%, P = 0.068). Patient survival at 1-year posttransplant was also similar (89% versus 88%).87

DEVELOP-UK was a multicenter (n = 5) observational study that assessed ex situ NMP (Vivoline LS1, Vivoline Medical AB, Sweden) in extended criteria lungs (53 assessed and 18 transplanted) in comparison to standard donor lungs (n = 184). The study was terminated early due to higher rate of very early PGD grade-3 (44% versus 18%) and a need for unplanned ECMO (39% versus 3%) at increased cost (~£35,000) in the ex situ NMP group. Survival at 30-days was similar (94% versus 97%) but by 12-months of follow-up the hazard ratio for mortality in the ex situ NMP arm relative to the standard arm was 1.96, 0.83, to 4.67.84 The use of ex situ NMP in ECD lung transplantation is still under evaluation in the EXPAND I (NCT01963780) and II trials (NCT03343535), with preliminary data suggesting good lung utilization.78 Other series of ex situ NMP lung transplantation not discussed but published in the literature are summarized in Table 2.88-102 Overall clinical outcomes of ex situ NMP treated lungs appear equivalent to SCS despite the use of ex situ NMP for lungs not initially considered suitable for transplantation.90,91,96,100,102

TABLE 2.
TABLE 2.:
Results of other studies of transplantation of lungs following Ex situ NMP compared with SCS

DISCUSSION

This review has undertaken a horizon scan across the available literature on novel strategies for the perfusion and preservation of the solid organs currently used in clinical transplantation. The review has identified a range of evidence levels for different techniques spanning from quasi-experimental work in pancreas up to multiple meta-analyses of RCTs in the case of HMP of kidneys (Figure 2).

FIGURE 2.
FIGURE 2.:
Summary of evidence level for each the various different novel perfusion strategies applied in kidney, liver, pancreas, heart, and lung transplantation.

In kidney transplantation, HMP is well established and over time has accumulated evidence to support a reduction in the rate of DGF compared with SCS.6-13 However, HMP is not universally adopted due to conflicting results from major RCTs,5,14,16 and a lack of evidence to support reduced rates of PNF or improved long-term graft survival.12 Another potential reason is that it has not been evaluated how to best introduce a national system providing devices for HMP. In a post-hoc subgroup analysis of the RCT performed in the Eurotransplant region, it has been reported that a significant effect of HMP on reducing the incidence of DGF was most significant in kidneys transplanted with cold ischemic times <10 hours, and was statistically nonsignificant at longer cold ischemic times. This analysis suggests that HMP cannot compensate for cold ischemia, and is still beneficial with short cold ischemic times.103

The risk of DGF is greater in DCD kidney transplantation,12 and the lowest reported rates of DGF (<10%) following transplantation of kidneys from DCD donors are from the French Protocol that uses a combination of NRP and HMP.35 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.35 The results of RCTs assessing ex situ NMP (ISRCTN 15821205)41 and oxygenated-HMP (COPE-POMP, ISRCTN 63852508) are still awaited. There is currently no data to compare HMP and ex situ NMP. The potential of ex situ NMP to extend preservation times also remains untested. Although DGF prolongs hospital stay, increases costs, may mask rejection and prompts graft biopsies, it is not an accurate marker for kidney graft outcome, particularly in the context of DCD kidney transplantation.104 Therefore, use of DGF as an endpoint of many of the studies published is a limitation.

A further limitation is the lack of long-term follow-up for graft survival after HMP. In the recent Cochrane review,12 only 2 trials were identified that assessed long-term graft survival up to 3-years,105,106 and 1 trial assessed 10-year graft survival.107 In the RCT from the Eurotransplant region, 3-year graft survival was better for kidneys in the HMP group compared with SCS (91% versus 87%; adjusted hazard ratio for graft failure, 0.60; P = 0.04).105 In a RCT involving 282 recipients of DCD kidneys, the 3-year graft survival rate in the HMP group was significantly higher than that in the SCS group (93% versus 82%, P = 0.036).106 In the study with 10-year follow-up, the kidneys that received HMP (n = 37) compared with SCS (n = 37) had a statistically nonsignificant improvement in 10-year graft survival (68% versus 43%, P = 0.08).107

In liver transplantation, SCS remains the practice against which emerging strategies have been compared. A RCT has demonstrated that compared with SCS, NMP can increase liver utilization and reduce EAD despite increased preservation time.57 Case series suggest that liver NMP can be applied preimplantation with comparable results with application from procurement. While there is an increased liver utilization in the preimplantation application of NMP, there is no reduction in the incidence of IC, indicating that perhaps the intervention takes place too late. However, it should be appreciated that the multicenter RCT of liver NMP trial was not powered to examine IC, which was identified on magnetic resonance cholangiopancreatography scan performed 6-months after transplantation.57

In the United Kingdom, NRP programmes were introduced in 2 centers in 2011 and 2012 with the aim of improving clinical outcomes in DCD liver transplantation.30,32 Initially NRP was performed in the context of an approved clinical research study that required donor families to consent for NRP treatment of the donor, and for recipients to consent to receiving a NRP treated organ. Following this, a service evaluation of the technique has been performed by NHSBT and the safety of NRP has been confirmed. In the service evaluation phase of the introduction of NRP, recipients have consented to receive an organ from a DCD donor, irrespective of whether the donor procedure has involved NRP or not.48 In large case-controlled studies of DCD liver transplantation, NRP has been reported to limit the incidence of IC and lead to a significant increase in organ utilization.48,49 However, one potential advantage of NMP is the opportunity to perform viability testing on livers before implantation. Following on from case-controlled studies, RCTs of HOPE (NCT01317342, NCT03124641) and D-HOPE (NCT02584283) are awaited.44,45,108,109

It is possible that the discussed techniques may be best used in concert, in an individualized manner based on the specific requirements of the donor/recipient combination or the set-up available in the transplant unit accepting the organ. Currently, NRP is followed by a period of SCS,32 but it could be combined with NMP as a transport strategy or as a preimplantation strategy to allow further assessment of grafts that are slow to recover during the NRP. Although techniques like oxygen persufflation47 and COR60 are being tested, clinical implementation may be challenging and restricted by current perfusate developments. Therefore, to date, the most developed preimplantation strategies to consider are HMP45 and NMP.56 NMP,57 which has RCT level evidence to support its use, has the potential advantage of facilitating longer preservation times.57 It can also be used to assess higher-risk grafts.53,59 In contrast, viability assessment during HMP is challenging as there is decreased metabolic activity in the liver.110 However, unlike HMP, any technical problems in NMP could lead to graft loss if not recognized promptly, as the default position of SCS does not apply. Previous studies have reported device-related technical complications such as twisting of the PV or hypoperfusion of the HA but overall these appear rare.57,111 In steatotic liver grafts, which are expected to increase in the donor pool due to the obesity pandemic, it is anticipated that novel perfusion strategies will be key to increasing acceptance and improving outcomes after liver transplantation.112

Novel perfusion strategies are having an impact on the transplantation of cardiothoracic organs. With the assistance of novel perfusion strategies, DCD heart transplantation has become established and results are comparable to DBD heart transplantation.77 Ex situ NMP of lungs has accumulated evidence to support improved short- and long-term clinical outcomes as well as increasing organ utilization. However, the main issue in interpretation of the clinical studies is that all use different definitions of ECD lungs. The definitions differ in terms of donor age, smoking history, and use of lungs from DCD donors, which are included in the standard arm of some studies but in the ex situ NMP arm of other studies making direct comparison of results challenging. It has been suggested that a RCT or a registry analysis may be required to compare static ex situ NMP (XVIVO Perfusion System) to portable ex situ NMP (Organ Care System) to help decide the optimal approach.78 Such studies could guide decision-making around integration of ex situ NMP into recovery of lungs, or whether organ-reconditioning hubs or specific centers with their own ex situ NMP technology are required.

From a clinical perspective, we are at cross roads in terms of selecting the optimal strategy from the vast array of options currently at our disposal. It is essential that any clinical studies report similar data to enable post hoc comparisons and to assist the design of future trials. There is also an imperative need for a universally agreed terminology in this field.3 While the results of studies are encouraging, we must caution against over interpretation of benefit and careful consideration of current data before wide-scale implementation without additional evidence.

With these goals in mind for the United Kingdom, NHSBT convened a Preservation and Perfusion Future Strategy Summit in London in October 2018. The findings of this review were considered as the basis for discussion. After considering the available clinical evidence and reports from Industry representatives, the delegates representing abdominal/cardiothoracic organ transplantation units were asked to discuss the clinical use of the various novel technologies/methods alone or in combination to enhance organ utilization. Discussions in the cardiothoracic group centered on the development of organ reconditioning hubs for high-risk organs as a strategy that allows a rapid development of expertise leading to capabilities for novel organ therapy before transplantation. The abdominal transplant group acknowledged the challenges with DCD donation in the United Kingdom and identified this group as the main target for future RCTs (Figure 3). Future trials should move away from the traditional comparison versus SCS and allow for a more innovative modeling of single or combined use of various perfusion approaches to define their benefit for specific donor-recipient combinations. Future trials should also involve collaborations that ensure appropriate sample sizes are achieved to detect statistically significant differences between groups. This will avoid over-interpretation of results or under-appreciation of potentially important clinical differences, which was a risk when analyzing the numerous small studies identified by this review.

FIGURE 3.
FIGURE 3.:
Potential RCT of novel perfusion strategies for controlled DCD donor liver and kidney transplantation. DCD, donation after circulatory death; HMP, hypothermic machine perfusion; NMP, normothermic machine perfusion; NRP, normothermic regional perfusion; RCT, randomized controlled trial; SCS, static cold storage.

A final consideration is the logistical advantages of the available technology to increase the capacity solid organ transplantation by allowing extended periods of preservation and reduced time pressures. This would reduce the stress of organ recovery and could facilitate the performance of complex implant procedures during daytime hours. Taking the time pressure off the movement of transplantable organs is another potential benefit of transportable devices as it could lead to a minimization of urgently arranged and high cost flights to transport organs.

CONCLUSION

A clinical evidence base is rapidly emerging for novel perfusion and preservation strategies in organ transplantation. In the United Kingdom, improving clinical outcomes following DCD transplantation of abdominal organs is a high priority area, and should be the main focus for future RCTs modeling single and combined use of different perfusion and preservation strategies. In cardiothoracic transplantation the development of organ reconditioning hubs for high-risk organs will allow for rapid development of expertise and enable clinical application of available techniques.

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