Background
There remains a lack of consensus on the optimal storage method for deceased donor kidneys. This meta‐analysis compares storage with hypothermic machine perfusion (HMP) vs traditional ...static cold storage (SCS).
Methods
The Cochrane Kidney and Transplant Specialised Register was searched to identify (quasi‐) randomized controlled trials (RCTs) to include in our meta‐analysis. PRISMA guidelines were used to perform and write this review.
Results
There is high‐certainty evidence that HMP reduces the risk of delayed graft function (DGF) when compared to SCS (2138 participants from 14 studies, RR = 0.77; 0.67‐0.90, P = .0006). This benefit is significant in both donation following circulatory death (DCD; 772 patients from seven studies, RR = 0.75; 0.64‐0.87, P = .0002) and donation following brainstem death (DBD) grafts (971 patients from four studies, RR = 0.78; 0.65‐0.93, P = .006). The number of perfusions required to prevent one episode of DGF was 7.26 and 13.60 in DCD and DBD grafts, respectively. There is strong evidence that HMP also improves graft survival in both DBD and DCD grafts, at both 1 and 3 years. Economic analyses suggest HMP is cost‐saving at 1 year compared with SCS.
Conclusion
Hypothermic machine perfusion is superior to SCS in deceased donor renal transplantation. Direct comparisons with normothermic machine perfusion in RCTs are essential to identify optimal preservation methods in kidney transplantation.
Background
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.
Objectives
To compare hypothermic machine perfusion (HMP) and (sub)normothermic machine perfusion (NMP) with standard SCS.
Search methods
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.
Selection criteria
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.
Data collection and analysis
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.
Main results
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.
Authors' conclusions
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.
Abstract Background The prognosis of pancreatic cancer remains desperately poor, with little progress made over the past 30 years despite the development of new combination chemotherapy regimens. ...Stromal activity is especially prominent in the tissue surrounding pancreatic tumours, and has a profound influence in dictating tumour development and dissemination. Pancreatic stellate cells (PaSCs) have a key role in this tumour microenvironment, and have been the subject of much research in the past decade. This review examines the relationship between PaSCs and cancer cells. Methods A comprehensive literature search was performed of multiple databases up to March 2014, including Medline, Pubmed and Google Scholar. Results A complex bidirectional interplay exists between PaSCs and cancer cells, resulting in a perpetuating loop of increased activity and an overriding pro-tumorigenic effect. This involves a number of signalling pathways that also impacts on other stromal components and vasculature, contributing to chemoresistance. The Reverse Warburg Effect is also introduced as a novel concept in tumour stroma. Conclusion This review highlights the pancreatic tumour microenvironment, and in particular PaSCs, as an ideal target for therapeutics. There are a number of cellular processes involving PaSCs which could hold the key to more effectively treating pancreatic cancer. The feasibility of targeting these pathways warrant further in depth investigation, with the aim of reducing the aggressiveness of pancreatic cancer and improving chemodelivery.
The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, ...INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro-tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes.
Kidney transplantation is the optimal treatment for kidney failure. Donation, transport and transplant of kidney grafts leads to significant ischaemia reperfusion injury. Static cold storage (SCS), ...whereby the kidney is stored on ice after removal from the donor until the time of implantation, represents the simplest preservation method. However, technology is now available to perfuse or "pump" the kidney during the transport phase ("continuous") or at the recipient centre ("end-ischaemic"). This can be done at a variety of temperatures and using different perfusates. The effectiveness of these treatments manifests as improved kidney function post-transplant.BACKGROUNDKidney transplantation is the optimal treatment for kidney failure. Donation, transport and transplant of kidney grafts leads to significant ischaemia reperfusion injury. Static cold storage (SCS), whereby the kidney is stored on ice after removal from the donor until the time of implantation, represents the simplest preservation method. However, technology is now available to perfuse or "pump" the kidney during the transport phase ("continuous") or at the recipient centre ("end-ischaemic"). This can be done at a variety of temperatures and using different perfusates. The effectiveness of these treatments manifests as improved kidney function post-transplant.To compare machine perfusion (MP) technologies (hypothermic machine perfusion (HMP) and (sub) normothermic machine perfusion (NMP)) with each other and with standard SCS.OBJECTIVESTo compare machine perfusion (MP) technologies (hypothermic machine perfusion (HMP) and (sub) normothermic machine perfusion (NMP)) with each other and with standard SCS.We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies until 15 June 2024 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 Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.SEARCH METHODSWe contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies until 15 June 2024 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 Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.All randomised controlled trials (RCTs) and quasi-RCTs comparing machine perfusion techniques with each other or versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory death (DCD) and brainstem death (DBD), standard and extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion.SELECTION CRITERIAAll randomised controlled trials (RCTs) and quasi-RCTs comparing machine perfusion techniques with each other or versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory death (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 ratios (RR) with 95% confidence intervals (CI). Survival analyses (time-to-event) were performed with the generic inverse variance meta-analysis of hazard ratios (HR). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was the incidence of delayed graft function (DGF). Secondary outcomes included graft survival, incidence of primary non-function (PNF), DGF duration, economic implications, graft function, patient survival and incidence of acute rejection. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.DATA COLLECTION AND ANALYSISThe 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 ratios (RR) with 95% confidence intervals (CI). Survival analyses (time-to-event) were performed with the generic inverse variance meta-analysis of hazard ratios (HR). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was the incidence of delayed graft function (DGF). Secondary outcomes included graft survival, incidence of primary non-function (PNF), DGF duration, economic implications, graft function, patient survival and incidence of acute rejection. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Twenty-two studies (4007 participants) were included. The risk of bias was generally low across all studies and bias domains. The majority of the evidence compared non-oxygenated HMP with standard SCS (19 studies). The use of non-oxygenated HMP reduces the rate of DGF compared to SCS (16 studies, 3078 participants: RR 0.78, 95% CI 0.69 to 0.88; P < 0.0001; I2 = 31%; high certainty evidence). Subgroup analysis revealed that continuous (from donor hospital to implanting centre) HMP reduces DGF (high certainty evidence). In contrast, this benefit over SCS was not seen when non-oxygenated HMP was not performed continuously (low certainty evidence). Non-oxygenated HMP reduces DGF in both DCD and DBD settings in studies performed in the 'modern era' and when cold ischaemia times (CIT) were short. The number of perfusions required to prevent one episode of DGF was 7.69 and 12.5 in DCD and DBD grafts, respectively. Continuous non-oxygenated HMP versus SCS also improves one-year graft survival (3 studies, 1056 participants: HR 0.46, 0.29 to 0.75; P = 0.002; I2 = 0%; high certainty evidence). Assessing graft survival at maximal follow-up confirmed a benefit of continuous non-oxygenated HMP over SCS (4 studies, 1124 participants (follow-up 1 to 10 years): HR 0.55, 95% CI 0.40 to 0.77; P = 0.0005; I2 = 0%; high certainty evidence). This effect was not seen in studies where HMP was not continuous. The effect of non-oxygenated HMP on our other outcomes (PNF, incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain. Studies performing economic analyses suggest that HMP is either cost-saving (USA and European settings) or cost-effective (Brazil). One study investigated continuous oxygenated HMP versus non-oxygenated HMP (low risk of bias in all domains); the simple addition of oxygen during continuous HMP leads to additional benefits over non-oxygenated HMP in DCD donors (> 50 years), including further improvements in graft survival, improved one-year kidney function, and reduced acute rejection. One large, high-quality study investigated end-ischaemic oxygenated HMP versus SCS and found end-ischaemic oxygenated HMP (median machine perfusion time 4.6 hours) demonstrated no benefit compared to SCS. The impact of longer periods of end-ischaemic HMP is unknown. One study investigated NMP versus SCS (low risk of bias in all domains). One hour of end ischaemic NMP did not improve DGF compared with SCS alone. An indirect comparison revealed that continuous non-oxygenated HMP (the most studied intervention) was associated with improved graft survival compared with end-ischaemic NMP (indirect HR 0.31, 95% CI 0.11 to 0.92; P = 0.03). No studies investigated normothermic regional perfusion (NRP) or included any donors undergoing NRP.MAIN RESULTSTwenty-two studies (4007 participants) were included. The risk of bias was generally low across all studies and bias domains. The majority of the evidence compared non-oxygenated HMP with standard SCS (19 studies). The use of non-oxygenated HMP reduces the rate of DGF compared to SCS (16 studies, 3078 participants: RR 0.78, 95% CI 0.69 to 0.88; P < 0.0001; I2 = 31%; high certainty evidence). Subgroup analysis revealed that continuous (from donor hospital to implanting centre) HMP reduces DGF (high certainty evidence). In contrast, this benefit over SCS was not seen when non-oxygenated HMP was not performed continuously (low certainty evidence). Non-oxygenated HMP reduces DGF in both DCD and DBD settings in studies performed in the 'modern era' and when cold ischaemia times (CIT) were short. The number of perfusions required to prevent one episode of DGF was 7.69 and 12.5 in DCD and DBD grafts, respectively. Continuous non-oxygenated HMP versus SCS also improves one-year graft survival (3 studies, 1056 participants: HR 0.46, 0.29 to 0.75; P = 0.002; I2 = 0%; high certainty evidence). Assessing graft survival at maximal follow-up confirmed a benefit of continuous non-oxygenated HMP over SCS (4 studies, 1124 participants (follow-up 1 to 10 years): HR 0.55, 95% CI 0.40 to 0.77; P = 0.0005; I2 = 0%; high certainty evidence). This effect was not seen in studies where HMP was not continuous. The effect of non-oxygenated HMP on our other outcomes (PNF, incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain. Studies performing economic analyses suggest that HMP is either cost-saving (USA and European settings) or cost-effective (Brazil). One study investigated continuous oxygenated HMP versus non-oxygenated HMP (low risk of bias in all domains); the simple addition of oxygen during continuous HMP leads to additional benefits over non-oxygenated HMP in DCD donors (> 50 years), including further improvements in graft survival,
The protocol is out of date and does not meet the current methodological standards of Cochrane. Withdrawn by Cochrane Colorectal group, currently no plans to revise/republish.
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