PDF(Pubmed)
Abstract：
BACKGROUND: 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.
OBJECTIVE: To compare machine perfusion (MP) technologies (hypothermic machine perfusion (HMP) and (sub) normothermic machine perfusion (NMP)) with each other and with standard SCS.
METHODS: 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.
METHODS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Continuous non-oxygenated HMP is superior to SCS in deceased donor kidney transplantation, reducing DGF, improving graft survival and proving cost-effective. This is true for both DBD and DCD kidneys, both short and long CITs, and remains true in the modern era (studies performed after 2008). In DCD donors (> 50 years), the simple addition of oxygen to continuous HMP further improves graft survival, kidney function and acute rejection rate compared to non-oxygenated HMP. Timing of HMP is important, and benefits have not been demonstrated with short periods (median 4.6 hours) of end-ischaemic HMP. End-ischaemic NMP (one hour) does not confer meaningful benefits over SCS alone and is inferior to continuous HMP in an indirect comparison of graft survival. Further studies assessing NMP for viability assessment and therapeutic delivery are warranted and in progress.
OBJECTIVE: To compare machine perfusion (MP) technologies (hypothermic machine perfusion (HMP) and (sub) normothermic machine perfusion (NMP)) with each other and with standard SCS.
METHODS: 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.
METHODS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Continuous non-oxygenated HMP is superior to SCS in deceased donor kidney transplantation, reducing DGF, improving graft survival and proving cost-effective. This is true for both DBD and DCD kidneys, both short and long CITs, and remains true in the modern era (studies performed after 2008). In DCD donors (> 50 years), the simple addition of oxygen to continuous HMP further improves graft survival, kidney function and acute rejection rate compared to non-oxygenated HMP. Timing of HMP is important, and benefits have not been demonstrated with short periods (median 4.6 hours) of end-ischaemic HMP. End-ischaemic NMP (one hour) does not confer meaningful benefits over SCS alone and is inferior to continuous HMP in an indirect comparison of graft survival. Further studies assessing NMP for viability assessment and therapeutic delivery are warranted and in progress.
摘要：
背景：肾移植是肾衰竭的最佳治疗方法。捐赠,移植和移植肾导致严重的缺血再灌注损伤。静态冷库（SCS），从供体中取出后，肾脏储存在冰上，直到植入时，代表最简单的保存方法。然而,现在可以在运输阶段（“连续”）或受体中心（“缺血末期”）灌注或“泵”肾脏。这可以在各种温度下并使用不同的灌注液进行。这些治疗的有效性表现为移植后肾功能的改善。
目的：比较机器灌注（MP）技术（低温机器灌注（HMP）和（亚）常温机器灌注（NMP））彼此之间以及与标准SCS。
方法：我们联系了信息专家，并使用与本评论相关的搜索词搜索了Cochrane肾脏和移植研究注册，直至2024年6月15日。登记册中的研究是通过对CENTRAL的搜索确定的，MEDLINE,和EMBASE,会议记录,国际临床试验注册平台(ICTRP)搜索门户，和ClinicalTrials.gov.
方法：所有随机对照试验（RCT）和准RCT比较机器灌注技术彼此或与SCS对死亡供体肾移植的影响均可纳入。包括所有供体类型（循环系统死亡（DCD）和脑干死亡（DBD）后供体，标准和扩展/扩展标准捐助者)。配对和非配对研究均符合纳入条件。
方法：对文献检索结果进行筛选,并使用标准数据提取表收集数据。这两个步骤都由两个独立的作者进行。二分结果结果表示为风险比（RR）和95％置信区间（CI）。使用风险比（HR）的一般逆方差荟萃分析进行生存分析（事件发生时间）。测量的连续标度表示为平均差(MD)。随机效应模型用于数据分析。主要结果是移植物功能延迟（DGF）的发生率。次要结果包括移植物存活，原发性无功能（PNF）的发生率，DGF持续时间,经济影响，移植物功能，患者生存率和急性排斥反应的发生率。对证据的信心是使用建议分级评估来评估的，开发和评估(等级)方法。
结果：包括22项研究（4007名参与者）。所有研究和偏倚领域的偏倚风险普遍较低。大多数证据将非氧合HMP与标准SCS进行了比较（19项研究）。与SCS相比，使用非氧合HMP可降低DGF的发生率（16项研究，3078名参与者：RR0.78，95％CI0.69至0.88；P<0.0001；I2=31％；高确定性证据）。亚组分析显示，连续（从供体医院到植入中心）HMP降低DGF（高确定性证据）。相比之下,当不连续进行非氧合HMP时,未观察到这种优于SCS的获益(低确定性证据).在“现代”和冷缺血时间（CIT）较短时进行的研究中，非氧合HMP可降低DCD和DBD设置中的DGF。DCD和DBD移植物中预防一次DGF发作所需的灌注次数为7.69和12.5，分别。持续的非氧合HMP与SCS也提高了一年的移植物存活率（3项研究，1056名参与者：HR0.46，0.29至0.75；P=0.002；I2=0％；高确定性证据）。最大随访时评估移植物存活率证实了持续非氧合HMP相对于SCS的益处（4项研究，1124名参与者（随访1至10年）：HR0.55，95％CI0.40至0.77；P=0.0005；I2=0％；高确定性证据）。在HMP不连续的研究中没有观察到这种效果。非氧合HMP对我们其他结果的影响(PNF，急性排斥反应的发生率，患者生存,住院,长期移植物功能，DGF的持续时间)仍然不确定。进行经济分析的研究表明，HMP可以节省成本（美国和欧洲环境）或具有成本效益（巴西）。一项研究调查了连续充氧HMP与非充氧HMP（所有领域的偏倚风险较低）;在DCD供体（>50年）中，在连续HMP期间简单添加氧气比非充氧HMP具有额外的益处。包括进一步改善移植物的存活率，改善一年的肾功能，减少急性排斥反应。一个大的,高质量研究调查了末端缺血性氧合HMP与SCS的比较,发现与SCS相比,末端缺血性氧合HMP(中位机器灌注时间4.6小时)无获益.后期缺血性HMP的影响尚不清楚。一项研究调查了NMP与SCS（所有领域的低偏倚风险）。与单独使用SCS相比，一小时的最终局部缺血NMP并未改善DGF。间接比较显示，与终末期缺血性NMP相比，持续的非氧合HMP（研究最多的干预措施）与改善的移植物存活率相关（间接HR0.31，95％CI0.11至0.92；P=0.03）。没有研究调查正常体温区域灌注（NRP）或包括任何接受NRP的供体。
结论：在死亡供体肾移植中，持续非氧合HMP优于SCS，减少DGF，提高移植物存活率并证明具有成本效益。DBD和DCD肾脏都是如此，短CI和长CITS，并且在现代仍然如此（2008年之后进行的研究）。在DCD捐赠者（>50岁）中，向连续HMP中简单添加氧气进一步提高了移植物的存活率，与非氧合HMP相比，肾功能和急性排斥率。HMP的时机很重要,并且在短期(中位4.6小时)缺血终末期HMP的治疗中没有发现益处.缺血性终末期NMP（一小时）不能比单独的SCS带来有意义的益处，并且在移植物存活率的间接比较中不如连续的HMP。评估用于生存力评估和治疗性递送的NMP的进一步研究是有必要的并且正在进行中。
目的：比较机器灌注（MP）技术（低温机器灌注（HMP）和（亚）常温机器灌注（NMP））彼此之间以及与标准SCS。
方法：我们联系了信息专家，并使用与本评论相关的搜索词搜索了Cochrane肾脏和移植研究注册，直至2024年6月15日。登记册中的研究是通过对CENTRAL的搜索确定的，MEDLINE,和EMBASE,会议记录,国际临床试验注册平台(ICTRP)搜索门户，和ClinicalTrials.gov.
方法：所有随机对照试验（RCT）和准RCT比较机器灌注技术彼此或与SCS对死亡供体肾移植的影响均可纳入。包括所有供体类型（循环系统死亡（DCD）和脑干死亡（DBD）后供体，标准和扩展/扩展标准捐助者)。配对和非配对研究均符合纳入条件。
方法：对文献检索结果进行筛选,并使用标准数据提取表收集数据。这两个步骤都由两个独立的作者进行。二分结果结果表示为风险比（RR）和95％置信区间（CI）。使用风险比（HR）的一般逆方差荟萃分析进行生存分析（事件发生时间）。测量的连续标度表示为平均差(MD)。随机效应模型用于数据分析。主要结果是移植物功能延迟（DGF）的发生率。次要结果包括移植物存活，原发性无功能（PNF）的发生率，DGF持续时间,经济影响，移植物功能，患者生存率和急性排斥反应的发生率。对证据的信心是使用建议分级评估来评估的，开发和评估(等级)方法。
结果：包括22项研究（4007名参与者）。所有研究和偏倚领域的偏倚风险普遍较低。大多数证据将非氧合HMP与标准SCS进行了比较（19项研究）。与SCS相比，使用非氧合HMP可降低DGF的发生率（16项研究，3078名参与者：RR0.78，95％CI0.69至0.88；P<0.0001；I2=31％；高确定性证据）。亚组分析显示，连续（从供体医院到植入中心）HMP降低DGF（高确定性证据）。相比之下,当不连续进行非氧合HMP时,未观察到这种优于SCS的获益(低确定性证据).在“现代”和冷缺血时间（CIT）较短时进行的研究中，非氧合HMP可降低DCD和DBD设置中的DGF。DCD和DBD移植物中预防一次DGF发作所需的灌注次数为7.69和12.5，分别。持续的非氧合HMP与SCS也提高了一年的移植物存活率（3项研究，1056名参与者：HR0.46，0.29至0.75；P=0.002；I2=0％；高确定性证据）。最大随访时评估移植物存活率证实了持续非氧合HMP相对于SCS的益处（4项研究，1124名参与者（随访1至10年）：HR0.55，95％CI0.40至0.77；P=0.0005；I2=0％；高确定性证据）。在HMP不连续的研究中没有观察到这种效果。非氧合HMP对我们其他结果的影响(PNF，急性排斥反应的发生率，患者生存,住院,长期移植物功能，DGF的持续时间)仍然不确定。进行经济分析的研究表明，HMP可以节省成本（美国和欧洲环境）或具有成本效益（巴西）。一项研究调查了连续充氧HMP与非充氧HMP（所有领域的偏倚风险较低）;在DCD供体（>50年）中，在连续HMP期间简单添加氧气比非充氧HMP具有额外的益处。包括进一步改善移植物的存活率，改善一年的肾功能，减少急性排斥反应。一个大的,高质量研究调查了末端缺血性氧合HMP与SCS的比较,发现与SCS相比,末端缺血性氧合HMP(中位机器灌注时间4.6小时)无获益.后期缺血性HMP的影响尚不清楚。一项研究调查了NMP与SCS（所有领域的低偏倚风险）。与单独使用SCS相比，一小时的最终局部缺血NMP并未改善DGF。间接比较显示，与终末期缺血性NMP相比，持续的非氧合HMP（研究最多的干预措施）与改善的移植物存活率相关（间接HR0.31，95％CI0.11至0.92；P=0.03）。没有研究调查正常体温区域灌注（NRP）或包括任何接受NRP的供体。
结论：在死亡供体肾移植中，持续非氧合HMP优于SCS，减少DGF，提高移植物存活率并证明具有成本效益。DBD和DCD肾脏都是如此，短CI和长CITS，并且在现代仍然如此（2008年之后进行的研究）。在DCD捐赠者（>50岁）中，向连续HMP中简单添加氧气进一步提高了移植物的存活率，与非氧合HMP相比，肾功能和急性排斥率。HMP的时机很重要,并且在短期(中位4.6小时)缺血终末期HMP的治疗中没有发现益处.缺血性终末期NMP（一小时）不能比单独的SCS带来有意义的益处，并且在移植物存活率的间接比较中不如连续的HMP。评估用于生存力评估和治疗性递送的NMP的进一步研究是有必要的并且正在进行中。
