烟酰胺单核苷酸通过Sirt3减轻心脏死亡供肝诱导的缺血-再灌注损伤

目的  探讨烟酰胺单核苷酸（NMN）对大鼠心脏死亡供肝诱导的缺血-再灌注损伤（IRI）的作用及机制。方法  通过“磁环+双袖套”法建立大鼠原位肝移植模型。将SD大鼠随机分为假手术组（Sham组）、原位肝移植组（OLT组）、NMN处理+原位肝移植组（NMN组）、NMN+去乙酰化酶-3（Sirt3）抑制剂（3-TYP）+原位肝移植组（NMN+3-TYP组）。观察各组大鼠肝组织病理学改变及肝细胞凋亡情况,检测血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）水平,测定肝组织超氧化物歧化酶（SOD）和丙二醛（MDA）含量,检测肝组织Sirt3、微管相关蛋白1轻链3（LC3）Ⅱ、PTEN诱导假定激酶1（PINK1）、Parkin、线粒体外膜转位酶20（TOMM20）表达水平。分析各组大鼠术后生存情况。结果  与Sham组比较,OLT组ALT、AST水平升高;与OLT组比较,NMN组ALT、AST水平均下降;与NMN组比较,NMN+3-TYP组ALT、AST水平升高（均为P < 0.05）。Sham组大鼠肝组织结构基本正常;OLT组大鼠肝组织可见明显的淤血、空泡变性和肝细胞坏死等病理改变。OLT组Suzuki评分、细胞凋亡率较Sham组升高;NMN组Suzuki评分、细胞凋亡率较OLT组降低;NMN+3-TYP组Suzuki评分、细胞凋亡率较NMN组升高（均为P < 0.05）。与Sham组比较,OLT组SOD含量下降,MDA含量升高;与OLT组比较,NMN组SOD含量升高,MDA含量下降;与NMN组比较,NMN+3-TYP组SOD含量下降,MDA含量升高（均为P < 0.05）。与Sham组比较,OLT组Sirt3、TOMM20蛋白相对表达量下降,PINK1、Parkin、LC3Ⅱ蛋白相对表达量升高;与OLT组比较,NMN组Sirt3、PINK1、Parkin、LC3Ⅱ蛋白相对表达量升高,TOMM20蛋白相对表达量下降;与NMN组比较,NMN+3-TYP组PINK1、Parkin、LC3Ⅱ蛋白相对表达量下降,TOMM20蛋白相对表达量升高（均为P < 0.05）。Sham组、OLT组、NMN组、NMN+3-TYP组大鼠术后7 d生存率分别为100%、50%、75%、58%。结论  NMN可通过上调Sirt3,增强肝脏抗氧化能力及诱导PINK1/Parkin介导的线粒体自噬,减轻肝IRI,从而对心脏死亡供肝发挥保护作用。     

氧化应激反应在边缘供肝肝移植缺血-再灌注损伤中的作用研究进展

常见的边缘供肝主要包括脂肪变性供肝、高龄供肝、小体积供肝、心脏死亡器官捐献（DCD）供肝等。边缘供肝的应用可在一定程度上解决供肝数量严重短缺的问题,但边缘供肝面临着缺血-再灌注损伤（IRI）的难题,且IRI程度相比正常供肝更加严重,是导致移植失败的重要原因,其中氧化应激反应又是引起边缘供肝IRI的重要因素。因此如何减少氧化应激反应及解决边缘供肝IRI的难题成为临床研究的热点问题。活性氧簇（ROS）介导的氧化应激反应贯穿IRI整个过程,本文就氧化应激反应在边缘供肝肝移植IRI中的作用及以ROS为靶点的防治进行综述,以期为临床提供参考。     

体外膜肺氧合在供者维护中的应用进展

器官移植是治疗终末期疾病的有效手段之一,但供者来源不足桎梏了器官移植的发展。体外膜肺氧合（ECMO）可以改善器官低氧状态及低灌注情况,缩短热缺血时间,在器官紧急获取或血流动力学不稳定等情况下,有效维护供者器官功能,使供者器官得到充分利用,造福更多亟需器官移植的患者。本文总结了ECMO在供者维护中的应用进展,为其在器官移植中的应用提出建议。     

IL-10改善心脏死亡大鼠离体肺灌注后供肺功能的实验研究

目的  探讨白细胞介素(IL)-10对心脏死亡大鼠离体肺灌注(EVLP)后供肺功能的影响。方法  将20只成年雄性SD大鼠随机分成单纯灌注组(A组)和改良灌注组(B组),每组10只。A组采用A灌注液(灌注液未添加IL-10)进行灌注,B组采用B灌注液(灌注液中添加IL-10)进行灌注,建立大鼠心脏死亡供肺EVLP模型。比较两组供肺外观及供肺组织干重/湿重(D/W)比值、供肺功能和代谢状态、供肺形态学表现和供肺炎症标志物水平。结果  灌注结束后,A组供肺全肺明显水肿,顺应性差,气道内涌出大量水肿液,而B组未见明显水肿,顺应性较好。与A组比较,B组肺组织D/W比值较高(P < 0.05)。两组肺静脉血氧分压均在灌注2 h时达到最高,组间比较差异无统计学意义(P > 0.05)。与A组比较,B组肺动脉压升高速度较慢,灌注结束时肺动脉压较低; 且灌注液中乳酸水平下降(均为P < 0.05)。A组肺泡结构大量破坏,细胞数量稀少,B组肺泡结构相对正常,未见明显细胞水肿。A组供肺细胞凋亡较多,B组供肺未见明显细胞凋亡现象。两组灌注4 h后单核细胞趋化蛋白(MCP)-1、IL-6水平均升高,IL-4均降低(均为P < 0.05),肿瘤坏死因子(TNF)-α、IL-1α和诱导型一氧化氮合酶(iNOS)变化无统计学意义(均为P > 0.05)。结论  IL-10可通过减少细胞凋亡改善心脏死亡大鼠EVLP后供肺的功能。     

Heart transplantation

Heart transplantation is the definitive treatment for selected patients with end-stage heart failure refractory to medical, interventional and surgical treatment. However, due to limited number of donor organs, most patients wait a long time for heart transplantation and a significant proportion die or become unsuitable for transplantation while waiting. Although post-transplant survival outcomes continue improving, a fifth of recipients die within 1 year after transplantation. In addition, recipients face constant threats from infection, rejection, malignancy and chronic allograft vasculopathy. Therefore, it is imperative to increase donor heart utilization to reduce waiting list mortality, and maintain allograft quality during transportation and optimize post-transplant care to improve outcomes. This review summarizes the process of heart transplantation from recipient and donor selection and matching to post-transplant management with a focus on the surgical aspects, and highlights the recent advancement, including donation after circulatory death programme, mechanical circulatory support, and ex-vivo heart perfusion.     

Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD)

Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia–reperfusion injury, we hypothesize that 3 reperfusion strategies—mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset—provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all 3 strategies improve oxygen‐consumption–cardiac‐work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator‐activated receptor‐gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial‐based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation.     

Outcomes after simultaneous pancreas–kidney transplantation from donation after circulatory death donors: A UK registry analysis

There are concerns that simultaneous pancreas–kidney (SPK) transplants from donation after circulatory death (DCD) donors have a higher risk of graft failure than those from donation after brain death (DBD) donors. A UK registry analysis of SPK transplants between 2005 and 2018 was performed. Pancreas survivals of those receiving organs from DCD or DBD donors were compared. Multivariable analyses were used to adjust for baseline differences between the two groups and to identify factors associated with pancreas graft loss. A total of 2228 SPK transplants were implanted; 403 (18.1%) were from DCD donors. DCD donors were generally younger, slimmer, less likely to have stroke as a cause of death, with lower terminal creatinines and shorter pancreas cold ischemic times than DBD donors. Median (IQR) follow-up was 4.2 (1.6–8.1) years. On univariable analysis, there were no statistically significant differences in 5-year death-censored pancreas graft survival between the two donor types (79.5% versus 80.4%; p = .86). Multivariable analysis showed no statistically significant differences in 5-year pancreas graft loss between transplants from DCD (n = 343) and DBD (n = 1492) donors (hazard ratio 1.26, 95% CI 0.76–1.23; p = .12). The findings from this study support the increased use of SPK transplants from DCD donors.     

Survival benefit of accepting kidneys from older donation after cardiac death donors

Kidneys from older (age ≥50 years) donation after cardiac death (DCD50) donors are less likely to be transplanted due to inferior posttransplant outcomes. However, candidates who decline a DCD50 offer must wait for an uncertain future offer. To characterize the survival benefit of accepting DCD50 kidneys, we used 2010-2018 Scientific Registry for Transplant Recipients (SRTR) data to identify 92 081 adult kidney transplantation candidates who were offered a DCD50 kidney that was eventually accepted for transplantation. DCD50 kidneys offered to candidates increased from 590 in 2010 to 1441 in 2018. However, 34.6% of DCD50 kidneys were discarded. Candidates who accepted DCD50 offers had 49% decreased mortality risk (adjusted hazard ratio [aHR] _0.460.51_0.55, cumulative mortality at 6-year 23.3% vs 34.0%, P < .001) compared with those who declined the same offer (decliners). Six years after their initial DCD50 offer decline, 43.0% of decliners received a deceased donor kidney transplant (DDKT), 6.3% received living donor kidney transplant (LDKT), 22.6% died, 22.0% were removed for other reasons, and 6.0% were still on the waitlist. Comparable survival benefit was observed even with DCD donors age ≥60 (aHR: _0.420.52_0.65, P < .001). Accepting DCD50 kidneys was associated with a substantial survival benefit; providers and patients should consider these benefits when evaluating offers.     

Successfully sharing the sandbox: A perspective on combined DCD liver and heart donor procurement

Donation after circulatory death (DCD) heart transplantation is currently being performed in the United States as part of a clinical trial. As with all donor procurements, effective coordination between all involved teams is vital for successful organ recovery and maximal utilization of donor organs. The current discussion relays a viewpoint on combined DCD liver and heart donor procurement. Key issues highlighted include the vital importance of donor warm ischemia time (DWIT) on outcome for both recipients as well as issues pertaining to DWIT that may arise when performing combined DCD liver and heart donor procurement.     

Spanish experience with heart transplants from controlled donation after the circulatory determination of death using thoraco-abdominal normothermic regional perfusion and cold storage

Heart transplantation from controlled donation after the circulatory determination of death (cDCDD) may help to increase the availability of hearts for transplantation. During 2020, four heart transplants were performed at three different Spanish hospitals based on the use of thoraco-abdominal normothermic regional perfusion (TA-NRP) followed by cold storage (CS). All donors were young adults <45 years. The functional warms ischemic time ranged from 8 to 16 minutes. In all cases, the heart recovered sinus rhythm within 1 minute of TA-NRP. TA-NRP was weaned off or decreased <1L within 25 minutes. No recipient required mechanical support after transplantation and all were immediately extubated and discharged home (median hospital stay: 21 days) with an excellent outcome. Four livers, eight kidneys, and two pancreata were also recovered and transplanted. All abdominal grafts recipients experienced an excellent outcome. The use of TA-NRP makes heart transplantation feasible and allows assessing heart function before organ procurement without any negative impact on the preservation of abdominal organs. The use of TA-NRP in cDCDD heart donors in conjunction with cold storage following retrieval can eliminate the need to use ex situ machine perfusion devices, making cDCDD heart transplantation economically possible in other countries.