SRS241 - Machine perfusion for deceased donor kidney transplantation: network meta-analysis of the Cochrane review

The effect on early renal function of various dynamic preservation strategies in a preclinical pig ischemia-reperfusion autotransplant model.

Kidney transplantation is the optimal treatment for end-stage kidney disease. Retrieval, transport and transplant of kidney grafts causes ischaemia reperfusion injury. The current accepted standard is static cold storage (SCS) whereby the kidney is stored on ice after removal from the donor and then removed from the ice box at the time of implantation. However, technology is now available to perfuse or "pump" the kidney during the transport phase or at the recipient centre. This can be done at a variety of temperatures and using different perfusates. The effectiveness of treatment is manifest clinically as delayed graft function (DGF), whereby the kidney fails to produce urine immediately after transplant. To compare hypothermic machine perfusion (HMP) and (sub)normothermic machine perfusion (NMP) with standard SCS. We searched the Cochrane Kidney and Transplant Register of Studies to 18 October 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. All randomised controlled trials (RCTs) and quasi-RCTs comparing HMP/NMP versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD), standard and extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion. The results of the literature search were screened and a standard data extraction form was used to collect data. Both of these steps were performed by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was incidence of DGF. Secondary outcomes included: one-year graft survival, incidence of primary non-function (PNF), DGF duration, long term graft survival, economic implications, graft function, patient survival and incidence of acute rejection. No studies reported on NMP, however one ongoing study was identified.Sixteen studies (2266 participants) comparing HMP with SCS were included; 15 studies could be meta-analysed. Fourteen studies reported on requirement for dialysis in the first week post-transplant (DGF incidence); there is high-certainty evidence that HMP reduces the risk of DGF when compared to SCS (RR 0.77; 95% CI 0.67 to 0.90; P = 0.0006). HMP reduces the risk of DGF in kidneys from DCD donors (7 studies, 772 participants: RR 0.75; 95% CI 0.64 to 0.87; P = 0.0002; high certainty evidence), as well as kidneys from DBD donors (4 studies, 971 participants: RR 0.78, 95% CI 0.65 to 0.93; P = 0.006; high certainty evidence). The number of perfusions required to prevent one episode of DGF (number needed to treat, NNT) was 7.26 and 13.60 in DCD and DBD kidneys respectively. Studies performed in the last decade all used the LifePort machine and confirmed that HMP reduces the incidence of DGF in the modern era (5 studies, 1355 participants: RR 0.77, 95% CI 0.66 to 0.91; P = 0.002; high certainty evidence). Reports of economic analysis suggest that HMP can lead to cost savings in both the North American and European settings.Two studies reported HMP also improves graft survival however we were not able to meta-analyse these results. A reduction in incidence of PNF could not be demonstrated. The effect of HMP on our other outcomes (incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain. HMP is superior to SCS in deceased donor kidney transplantation. This is true for both DBD and DCD kidneys, and remains true in the modern era (studies performed in the last decade). As kidneys from DCD donors have a higher overall DGF rate, fewer perfusions are needed to prevent one episode of DGF (7.26 versus 13.60 in DBD kidneys).Further studies looking solely at the impact of HMP on DGF incidence are not required. Follow-up reports detailing long-term graft survival from participants of the studies already included in this review would be an efficient way to generate further long-term graft survival data.Economic analysis, based on the results of this review, would help cement HMP as the standard preservation method in deceased donor kidney transplantation.RCTs investigating (sub)NMP are required.

Background: This systematic review and Bayesian network meta-analysis aimed to evaluate and compare the relative efficacy of hypothermic oxygenated machine perfusion (HOPE) and hypothermic machine perfusion (HMP) for kidney preservation in terms of delayed graft function (DGF), acute rejection, and primary non-function (PNF). Methods: The review adhered strictly to the PRISMA 2020, AMSTAR and TITAN guidelines and was registered on PROSPERO. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were comprehensively searched up to February 2025. Randomized controlled trials (RCTs) and quasi-RCTs comparing HOPE, HMP, and static cold storage (SCS) for human donor kidneys were included. Two reviewers independently screened and extracted data, assessed bias using RoB 2, and graded the certainty of evidence with the GRADE approach. Data synthesis involved Bayesian network meta-analysis using R (gemtc package). Results: A total of 18 RCTs involving 3505 patients were analyzed. Compared to SCS, HOPE (RR = 0.67; 95% CI: 0.45–1.00; moderate-certainty) and HMP (RR = 0.65; 95% CI: 0.56–0.76; high-certainty) significantly reduced DGF. However, the network estimate for HOPE vs HMP showed no significant differences for DGF (RR = 1.00; 95% CI: 0.69–1.50; low-certainty) or for acute rejection (RR = 0.84; 95% CI: 0.50–1.40; low-certainty). Both HOPE and HMP were comparably effective in reducing PNF relative to SCS. Conclusions: Based on high-certainty evidence, HMP continues to represent the standard of care for reducing DGF in kidney preservation. However, limited and imprecise head-to-head evidence shows no clear advantage of HOPE over HMP in reducing DGF or acute rejection. Further robust, multicenter RCTs are warranted to clarify these preliminary findings.

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.

Initial Clinical Outcomes of Hypothermic Machine Perfusion in Deceased Donor Kidney Transplantation: A Pilot Comparative Feasibility Study from South Korea.

Static cold storage (SCS) and hypothermic machine perfusion (HMP) are two primary options for renal allograft preservation. Compared with SCS, HMP decreased the incidence of delayed graft function (DGF) and protected graft function. However, more evidence is still needed to prove the advantages of the HMP. In this study, the outcomes of kidney grafts from the two preservation methods were compared by conducting a systematic review and meta-analysis. Randomized controlled trials (RCTs) comparing the effect of hypothermic machine perfusion and static cold storage in deceased donor kidney transplantation were identified through searches of the MEDLINE, EMBASE, and Cochrane databases between January 1, 1980 and December 30, 2017. The primary endpoints were delayed graft function and graft survival. Secondary endpoints included primary non-function (PNF), graft renal function, duration of DGF, acute rejection, postoperative hospital stay and patient survival. Summary effects were calculated as risk ratio (RR) with 95% confidence interval (CI) or mean difference (MD) with 95% confidence intervals (CI). A total of 13 RCTs were included, including 2048 kidney transplant recipients. The results indicated that compared with SCS, HMP decreased the incidence of DGF (RR 0.78, 95% CI 0.69-0.87, P<0.0001), and improved the graft survival at 3 years (RR 1.06, 95% CI 1.02-1.11, P=0.009). There was no significant difference in other endpoints. HMP might be a more desirable method of preservation for kidney grafts. The long-term outcomes of kidney allografts stored by hypothermic machine perfusion still need to be further investigated.

Introduction: There is renewed interest in Hypothermic Machine Perfusion (HMP) of kidneys in recent years with the development of a new generation of pumps. However, it remains controversial which method is most beneficial for the transplant recipient. A systematic review of the level of available evidence comparing HMP with SCS and a statistical analysis of the combined data was performed. Methods: A systematic literature search was performed using MEDLINE (1948 to October 2011), EMBASE (1980 to October 2011), the Cochrane Library, the Transplant Library of RCTs from the Centre for Evidence in Transplantation and the International Clinical Trials Registry Platform. Studies were assessed for methodological quality. Summary effects of meta-analysis are presented as Relative Risks (RR) and 95% Confidence Intervals (95%CI). RCTs alone were used for meta-analysis. Results: Nineteen studies met the full inclusion criteria, including 7 RCTs and 12 Non-RCTS with a total of 2,086 kidneys. The overall risk of Delayed Graft Function (DGF) was lower with HMP than with SCS (fixed effects, RR=0.81, 95%CI=0.70-0.92, p< 0.01). DGF was not significantly reduced when results were split into DBD kidneys (fixed effects, RR=0.84, 95%CI=0.68-1.04, p=0.10) and DCD kidneys (fixed effects, RR=0.80, (95%CI=0.62-1.04, p=0.09). There was no evidence that the effect on DGF comparing these two donor types was significantly different (Test of Interaction, p=0.78). There was no difference in the risk of graft loss within the first 12 months (fixed effects, RR=0.86, 95%CI=0.68-1.09, p=0.22) or the rate of Primary Non-Function (PNF) between HMP and SCS kidneys (random effects, RR=1.16, 95%CI=0.46-2.94, p=0.75). Three studies found a faster fall in serum creatinine for HMP preserved kidneys in the first 14 days; however 3 studies found no significant difference in longer term renal function (30-365 days). Rates of acute rejection were equal in 2 studies, although higher following SCS in 1 study. In the 7 studies that reported patient survival there was no relationship between preservation method and this outcome. Conclusion: Data from the included studies shows that HMP reduces DGF compared to SCS. This effect may be the same in both DBD and DCD kidneys. HMP may lead to a quicker reduction in serum creatinine post-op. There was no difference in graft loss in the first 12 months, PNF, long term renal function, acute rejection or patient survival. Figure: Forest plot to show RR of DGF comparing hypothermic machine perfusion (HMP) to static cold storage (SCS) in randomised controlled trials. N= total patients in study arm, n= number of patients with DGF. Summary RR calculated by fixed effects meta-analysis, < 1 Favours HMP. 95%CI=95% confidence interval.Figure: [Forest plot to show relative risk (RR) of DGF.]

In deceased donor kidney transplantation (KT), a prolonged cold ischemia time (CIT) is a negative prognostic factor for KT outcome, and the efficacy of hypothermic machine perfusion (HMP) in prolonging CIT without any additional hazard is highly debated. We conducted a retrospective study on a cohort of 154 single graft deceased donor KTs, in which a delayed HMP, after a preliminary period of static cold storage (SCS), was used to prolong CIT for logistic reasons. Primary outcomes were postoperative complications as well as 1year graft survival and function. 73 cases (47.4%) were managed with HMP and planned KT, while 81 (52.6%) with SCS and urgent KT. The median CIT in HMP group and SCS group was 29hour:57minutes [27-31hour:45minutes] and 11hour:25minutes [9-14hour:30minutes], respectively (P<.001). The period of SCS in the HMP group was significantly shorter than in the SCS group (10 vs. 11hour:25minutes, P=.02) as well as the prevalence of expanded criteria donors was significantly higher (43.8% vs. 18.5%, P<.01). After propensity score matching for these two baseline characteristics, the HMP and SCS groups showed comparable outcomes in terms of delayed graft function, vascular, and urologic complications, infections, and episodes of graft rejection. At 1 year follow-up, serum creatinine levels were comparable between the groups. Therefore, the use of HMP to prolong the CIT and convert KT into a planned procedure seemed to have an adequate safety profile, with outcomes comparable to KT managed as an urgent procedure and a CIT nearly three time shorter.

Background Several novel machine perfusion technologies have been developed which aim to improve kidney transplant outcomes compared with ice-box static cold storage (SCS). These machine perfusion technologies can be applied “continuous” from donor centre, or only at the recipient centre (“end-ischaemic”). We aimed to compare machine perfusion technologies with each other and with SCS. Methods We searched the Cochrane Kidney and Transplant Register of Studies to 20 June 2023. Two independent authors screened articles and extracted data. Pairwise random-effects meta-analysis was performed, with additional indirect comparisons performed. Main results 22 studies (4007 participants) were included. “Continuous” non-oxygenated hypothermic machine perfusion (HMP) versus SCS improves graft-survival (follow-up=1-10 years, HR=0.55, 95% confidence interval=0.40-0.77, P=0.0005, GRADE: high-certainty evidence), reduces delayed graft function (RR 0.78, 0.64-0.96, P=0.02; high-certainty evidence) and is cost-saving. Beneficial effects persist when cold ischaemic times were short, but were only seen when HMP was “continuous”; End-ischaemic oxygenated HMP (median 4.6hours) does not improve outcomes. Addition of oxygen to continuous HMP further improves graft-survival in DCD donors. End-ischaemic normothermic machine perfusion (NMP) does not improve outcomes versus SCS; indirect comparison revealed that continuous non-oxygenated HMP was associated with improved graft survival compared with end-ischaemic NMP (HR=0.31, 0.11-0.92, P=0.03). Conclusions Continuous HMP (initiated in donor hospital) is superior to SCS in deceased-donor kidney transplantation. Timing of HMP is important, and benefits have not been demonstrated with end-ischaemic HMP. Whilst end-ischaemic NMP is inferior to continuous HMP on indirect comparisons, further studies assessing NMP for viability assessment and therapeutic delivery are in progress.

Kidney preservation techniques, such as hypothermic machine perfusion (HMP), improve graft outcomes in deceased-donor kidney transplantation by pausing graft metabolism and ameliorated ischemia-reperfusion injury (IRI) but do not completely eliminate injury. Alkaline phosphatase (ALP) has been postulated to reduce IRI-induced kidney injury through the conversion of extracellular adenosine triphosphate into adenosine. This study aimed to evaluate whether ALP offers protection during deceased-donor kidney storage. Sixteen abattoir porcine kidneys (8 ALP and 8 with placebo) were procured after euthanization and exposed to 30 min of warm ischemia followed by 24 h of HMP or static cold storage (SCS). Reperfusion was partly simulated by 240 min of normothermic machine perfusion (NMP). Throughout NMP, we obtained functional, biochemical, and histological parameters. Significantly lower urine production accompanied by lower perfusate pCO2 and higher pH were observed in the ALP group throughout NMP. At the end of NMP, intracellular ATP reserves and oxygen consumption were significantly higher in the ALP-treated group. Metabolomics analysis with principal component analysis demonstrated significant differences between the ALP and placebo groups in glycolysis and mitochondrial metabolites, along with a significantly attenuated rise in perfusate lactate dehydrogenase levels. ALP supplementation during HMP was associated with lower urine production and energetic stress, with a shift toward less metabolic dysfunction and graft injury by the end of NMP. Our findings suggest an improvement in the early metabolic incompetency that characterizes delayed graft function in humans. Further research should elucidate whether these findings result in enhancement of graft functionality after transplantation.

Randomized evaluation of comparative effects of optimized static cold storage, hypothermic and normothermic machine perfusion, and colchicine pretreatment on ischemia-reperfusion injury in a porcine model.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

A systematic review and network meta-analysis of preservation techniques of donor kidneys.

Introduction: To match the current organ demand with organ availability from the donor pool, there has been a shift towards acceptance of extended criteria donors (ECD), often associated with longer ischemic times. Novel dynamic preservation techniques as hypothermic or normothermic machine perfusion (MP) are increasingly adopted, particularly for organs from ECDs. In this study, we compared the viability and incidence of reperfusion injury in kidneys and livers preserved with MP versus Static Cold Storage (SCS). Methods: Systematic review and meta-analysis with a search performed between February and March 2019. MEDLINE, EMBASE and Transplant Library were searched via OvidSP. The Cochrane Library and The Cochrane Central Register of Controlled Trials (CENTRAL) were also searched. English language filter was applied. Results: the systematic search generated 10,585 studies, finally leading to a total of 30 papers for meta-analysis of kidneys and livers. Hypothermic MP (HMP) statistically significantly lowered the incidence of primary nonfunction (PMN, p = 0.003) and delayed graft function (DGF, p < 0.00001) in kidneys compared to SCS, but not its duration. No difference was also noted for serum creatinine or eGFR post-transplantation, but overall kidneys preserved with HMP had a significantly longer one-year graft survival (OR: 1.61 95% CI: 1.02 to 2.53, p = 0.04). Differently from kidneys where the graft survival was affected, there was no significant difference in primary non function (PNF) for livers stored using SCS for those preserved by HMP and NMP. Machine perfusion demonstrated superior outcomes in early allograft dysfunction and post transplantation AST levels compared to SCS, but however, only HMP was able to significantly decrease serum bilirubin and biliary stricture incidence compared to SCS. Conclusions: MP improves DGF and one-year graft survival in kidney transplantation; it appears to mitigate early allograft dysfunction in livers, but more studies are needed to prove its potential superiority in relation to PNF in livers.

Delayed Graft Function: State of the Art, November 10–11, 2000. Summit Meeting, Scottsdale, Arizona, USA