Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation after brain death liver transplantation

Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury (AKI). This suggests that hepatic ischemia‐reperfusion injury may play a critical role in the pathogenesis of AKI after liver transplantation. The aim of this single‐center study was to determine if hepatic ischemia‐reperfusion injury, estimated by peak peri‐operative serum amino‐transferase (AST), is associated with AKI following donation after brain death (DBD) liver transplantation. A total of 296 patients received 298 DBD liver transplants from January 2007 to June 2011. The incidence of AKI was 35.9%. AKI was a risk factor for chronic kidney disease (P = 0.037) and mortality (P = 0.002). On univariate analysis, peak AST correlated with peak creatinine (P < 0.001) and peak change in creatinine from baseline (P < 0.001). Peak AST was higher in AKI patients (P < 0.001). The incidence of AKI in patients with a peak AST of <1500, 1500–2999 and ≥3000 U/l was 26.1%, 39.8% and 71.2%, respectively (P < 0.001). On multiple logistic regression analysis, peak AST was independently associated with the development of AKI (P < 0.001). In conclusion, hepatic ischemia‐reperfusion injury demonstrates a strong relationship with peri‐operative AKI in DBD liver transplant recipients.     

公民逝世后器官捐献供肾移植临床分析

目的探讨公民逝世后器官捐献供肾移植的近期临床效果。方法公民逝世后器官捐献供肾移植73例,供者43例,其中本院器官获取组织42例,外院器官获取组织分享1例。分析肾移植术后人/肾存活率和并发症的发生情况。结果 73例受者随访9~38个月,术后6个月、1年的人/肾存活率分别为97.3%/94.5%、94.5%/91.8%。10例(13.7%)受者发生移植肾功能恢复延迟,15例(20.5%)受者术后发生急性排斥反应,21例(28.8%)受者发生肺部感染。2例受者移植肾丢失,4例受者移植肾带功死亡。结论公民逝世后器官捐献供肾移植近期疗效较好,是解决供肾来源的有效途径。     

Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury

Donation after cardiac death (DCD) liver transplantation is associated with an increased frequency of hepato-biliary complications. The implications for renal function have not been explored previously. The aims of this single-center study of 88 consecutive DCD liver transplant recipients were (1) to compare renal outcomes with propensity-risk-matched donation after brain death (DBD) patients and (2) in the DCD patients specifically to examine the risk factors for acute kidney injury (AKI; peak creatinine ≥2 times baseline) and chronic kidney disease (CKD; eGFR <60 mL/min/1.73 m(2) ). During the immediate postoperative period DCD liver transplantation was associated with an increased incidence of AKI (DCD, 53.4%; DBD 31.8%, p = 0.004). In DCD patients AKI was a risk factor for CKD (p = 0.035) and mortality (p = 0.017). The cumulative incidence of CKD by 3 years post-transplant was 53.7% and 42.1% for DCD and DBD patients, respectively (p = 0.774). Importantly, increasing peak perioperative aspartate aminotransferase, a surrogate marker of hepatic ischemia reperfusion injury, was the only consistent predictor of renal dysfunction after DCD transplantation (AKI, p < 0.001; CKD, p = 0.032). In conclusion, DCD liver transplantation is associated with an increased frequency of AKI. The findings suggest that hepatic ischemia reperfusion injury may play a critical role in the pathogenesis of post-transplant renal dysfunction.     

Transplanting kidneys from donation after cardiac death donors with acute kidney injury

Donation after cardiac death (DCD) and acute kidney injury (AKI) donors have historically been considered independent risk factors for delayed graft function (DGF), allograft failure, and inferior outcomes. With growing experience, updated analyses have shown good outcomes. There continues to be limited data, however, on outcomes specific to DCD donors who have AKI. Primary outcomes for this study were post–kidney transplant patient and allograft survival comparing two donor groups: DCD AKIN stage 2‐3 and DBD AKIN stage 2‐3. In comparing these groups, there were no short‐ or long‐term differences in patient (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.54‐1.93, P = .83) or allograft survival (HR 1.47, 95% CI 0.64‐2.97, P = .32). In multivariate models, the DCD/DBD status had no significant impact on the estimated GFR (eGFR) at 1 (P = .38), 2 (P = .60), and 3 years (P = .52). DGF (57.9% vs 67.9%, P = .09), rejection (12.1% vs 13.9%, P = .12), and progression of interstitial fibrosis/tubular atrophy (IFTA) on protocol biopsy (P = .16) were similar between the two groups. With careful selection, good outcomes can be achieved utilizing severe AKI DCD kidneys. Historic concerns regarding primary nonfunction, DGF resulting in interstitial fibrosis and rejection, and inferior outcomes were not observed. Given the ongoing organ shortage, increased effort should be undertaken to further utilize these donors.     

CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation

Modulation of nitric oxide activity through blockade of CD47 signaling has been shown to reduce ischemia–reperfusion injury (IRI) in various models of tissue ischemia. Here, we evaluate the potential effect of an antibody‐mediated CD47 blockade in a syngeneic and an allogeneic DCD rat kidney transplant model. The donor organ was subjected to 1 hour of warm ischemia time after circulatory cessation, then flushed with a CD47 monoclonal antibody (CD47mAb) in the treatment group, or an isotype‐matched immunoglobulin in the control group. We found that CD47mAb treatment improved survival rates in both models. Serum markers of renal injury were significantly decreased in the CD47mAb‐treated group compared with the control group. Histologically the CD47mAb‐treated group had significantly reduced scores of acute tubular injury and acute tubular necrosis. The expression of biomarkers related to mitochondrial stress and apoptosis also were significantly lower in the CD47mAb‐treated groups. Overall, the protective effects of CD47 blockade were greater in the syngeneic model. Our data show that CD47mAb blockade decreased the IRI of DCD kidneys in rat transplant models. This therapy has the potential to improve DCD kidney transplant outcomes in the human setting.     

心脏死亡器官捐献肝移植术后并发急性肾损伤危险因素分析

目的探讨心脏死亡器官捐献(DCD)肝移植术后并发急性肾损伤(AKI)的危险因素。 方法回顾性分析2012年1月至2018年11月宁波市医疗中心李惠利医院肝胆胰外科159例DCD肝移植受者临床资料,根据改善全球肾脏病预后组织临床实践指南中AKI诊断标准将159例受者分为AKI组(34例)和对照组(125例)。采用两独立样本t检验比较两组受者年龄和术前血清白蛋白。采用Wilcoxon符号秩和检验比较两组受者术前终末期肝病模型(MELD)评分、术前体质指数(BMI)、供肝冷/热缺血时间、术中输液量、术中出血量、术中输血量、术中尿量、手术时间、术中去甲肾上腺素总用量及总住院天数。采用卡方检验比较两组受者性别、术前乙型肝炎、术中低血压、术后感染、肝移植术式及术后再次手术情况。将单因素分析中有统计学差异的变量纳入Logistic回归进行多因素分析。P<0.05为差异有统计学意义。 结果肝移植术后AKI发生率为21.4%(34/159)。单因素分析结果表明,AKI组与对照组受者术前MELD评分、术前血清白蛋白、术中输液量、术中出血量、术中尿量、手术时间、术中低血压及术后再次手术差异均有统计学意义(Z＝2.763, t＝－2.250, Z＝2.040, Z＝2.092, Z＝－3.303, Z＝－2.170, χ²＝8.227, χ²＝5.294, P均<0.05)。Logistic回归多因素分析结果显示：术前MELD评分、术前血清白蛋白、术中尿量和手术时间是DCD肝移植术后并发AKI的独立危险因素,差异均有统计学意义(P均<0.05)。 结论DCD肝移植术前应改善受者一般情况,提高围手术期营养水平,术中控制液体出入量,合理使用利尿剂和缩短手术时间,以降低受者术后AKI发生率。     

Negative impact of prolonged cold storage time before machine perfusion preservation in donation after circulatory death kidney transplantation

Kidney grafts are often preserved initially in static cold storage (CS) and subsequently on hypothermic machine perfusion (MP). However, the impact of CS/MP time on transplant outcome remains unclear. We evaluated the effect of prolonged CS/MP time in a single‐center retrospective cohort of 59 donation after circulatory death (DCD) and 177 matched donation after brain death (DBD) kidney‐alone transplant recipients. With mean overall CS/MP times of 6.0 h/30.0 h, overall incidence of delayed graft function (DGF) was higher in DCD transplants (30.5%) than DBD transplants (7.3%, P < 0.0001). In logistic regression, DCD recipient (P < 0.0001), longer CS time (P = 0.0002), male recipient (P = 0.02), and longer MP time (P = 0.08) were associated with higher DGF incidence. In evaluating the joint effects of donor type (DBD vs. DCD), CS time (<6 vs. ≥6 h), and MP time (<36 vs. ≥36 h) on DGF incidence, one clearly sees an unfavorable effect of MP time ≥36 h (P = 0.003) across each donor type and CS time stratum, whereas the unfavorable effect of CS time ≥6 h (P = 0.01) is primarily seen among DCD recipients. Prolonged cold ischemia time had no unfavorable effect on renal function or graft survival at 12mo post‐transplant. Long CS/MP time detrimentally affects early DCD/DBD kidney transplant outcome when grafts were mainly preserved by MP; prolonged CS time before MP has a particularly negative impact in DCD kidney transplantation.     

Optimal donation of kidney transplants after controlled circulatory death

Controlled donation after circulatory death (cDCD) is used for “extended criteria” donors with poorer kidney transplant outcomes. The French cDCD program started in 2015 and is characterized by normothermic regional perfusion, hypothermic machine perfusion, and short cold ischemia time. We compared the outcomes of kidney transplantation from cDCD and brain-dead (DBD) donors, matching cDCD and DBD kidney transplants by propensity scoring for donor and recipient characteristics. The matching process retained 442 of 499 cDCD and 809 of 6185 DBD transplantations. The DGF rate was 20% in cDCD recipients compared with 28% in DBD recipients (adjusted relative risk [aRR], 1.43; 95% confidence interval [CI] 1.12–1.82). When DBD transplants were ranked by cold ischemia time and machine perfusion use and compared with cDCD transplants, the aRR of DGF was higher for DBD transplants without machine perfusion, regardless of the cold ischemia time (aRR with cold ischemia time <18 h, 1.57; 95% CI 1.20–2.03, vs aRR with cold ischemia time ≥18 h, 1.79; 95% CI 1.31–2.44). The 1-year graft survival rate was similar in both groups. Early outcome was better for kidney transplants from cDCD than from matched DBD transplants with this French protocol.     

Successful kidney transplantation from a donation after cardiac death donor with acute renal failure and bowel infarction using extracorporeal support

As a result of the ever widening disparity between organ supply and demand, a resurgence of interest has occurred in kidney recovery from donation after cardiac death (DCD) donors. New techniques of in situ extracorporeal support offer the potential to reduce warm ischemic injury and optimize donor management prior to organ recovery. In addition, preliminary outcomes using kidneys from selected deceased donors with rising serum creatinine levels have been promising. However, contraindications to successful organ donation and transplantation may include the presence of abdominal compartment syndrome, generalized bowel infarction, refractory shock with profound metabolic and lactic acidosis, and acute anuric renal failure, particularly in the setting of DCD. We report herein the successful recovery and transplantation of kidneys from an unstable donor with the above constellation of conditions in the setting of extracorporeal support after declaration of death by asystole.     

脑-心双死亡供肝与尸体供肝移植安全性比较

目的 探讨脑-心双死亡（donation after brain plus cardiac death,DBCD）供肝肝移植手术安全性及近期疗效。方法 收集本科肝移植相关资料：供肝热缺血时间（warm ischemic time,WIT）、冷缺血时间（cold ischemic time,CIT）、手术时间、受体无肝期时间,术后第1、3、7天肝功能变化（ALT、TBIL）,及术后早期各种并发症发生率等。按供肝来源不同分为DBCD组（观察组）与尸体供肝组（对照组）,比较两组相关资料的差异及与术后肝功能和并发症的关系。冷/热缺血时间和早期肝功能受损程度相关性分析采用Pearson检验。结果 与对照组相比,DBCD组热缺血时间较长[（9.5±2.2）min vs （4.9±1.5）min,t =10.719,P ＜0.001],冷缺血时间较短[（4.7±0.9）h vs （7.2±2.2）h,t =8.008,P ＜0.001]。术后第1、3天肝功能ALT和TBIL,DBCD组较对照组增高明显[（1 294.3±181.7）IU/L vs （641.3±41.0）IU/L,P =0.001;（497.4±56.4）IU/L vs （308.6±15.9）IU/L,P =0.003]。术后第7 天两组肝功能变化差异不大（P ＞0.05）。两组术后早期并发症率和手术死亡率比较无统计学意义差异（P＞0.05）。DBCD组数据显示热缺血时间长短与移植术后1周内ALT峰值呈正相关（r 2=0.826,P ＜0.001）。结论 DBCD组冷缺血时间较尸体供肝组缩短,但热缺血时间较尸体供肝组延长,总体在安全范围内且可控性良好,因此DBCD肝移植是安全的。     

Impact of donation after circulatory death donor allografts on outcomes following liver transplantation for fulminant hepatic failure in the United States

Limited data exist regarding the impact of donation after circulatory death (DCD) allografts on outcomes following liver transplantation in fulminant hepatic failure (FHF). Utilizing the Scientific Registry of Transplant Recipients (SRTR), we compared outcomes after DCD in FHF to donation after brain death (DBD) in FHF and DCD in non-FHF over a 15-year period. Primary outcome measures were graft and patient survival. A total of 117, 3437, and 4379 recipients underwent DCD-FHF, DBD-FHF and DCD-non-FHF, respectively. One-year graft survival in DCD-FHF was inferior to DBD-FHF (72.9% vs. 83.8%, p = .002), but comparable to DCD-non-FHF (72.9% vs. 82.7%, p = .23). However, 3- and 5-year graft survival in DCD-FHF were comparable to DBD-FHF (67.9 vs. 77.6%, p = .63; 57.8% vs. 73.2%, p = .27) and DCD-non-FHF (67.9% vs. 72.9%, p = .44; 57.8% vs. 66.6%, p = .06). One-, 3-, and 5-year patient survival were also comparable among the three groups. Graft and patient survival in DCD-FHF improved over the study period. Multivariable analysis identified recipient age, male gender, African American ethnicity, donor age, and cold ischemia time as predictors of graft and patient survival in FHF, while DCD status was only predictive of graft survival. Long-term graft survival and patient survival in DCD-FHF are comparable to DBD-FHF and DCD-non-FHF. Consideration of DCD in FHF could help expand the donor pool in this subset of critically ill patients.     

伴急性肾损伤的脑死亡器官捐献供者供肾移植治疗的体会

目的  总结伴急性肾损伤（AKI）的脑死亡器官捐献（DBD）供者供肾移植的治疗效果。方法  选取成功完成DBD供肾移植的59例供者纳入本研究,根据入重症监护室（ICU）时的血清肌酐（Scr）水平,将DBD供者分为AKI组（14例）与正常组（45例）,相应的101例受者根据供者情况分为AKI组（23例）与正常组（78例）。总结59例供者器官捐献情况,比较两组供者获取前的主要指标。比较两组受者术后肾功能、住院情况及临床结局。结果  59例供者中,14例发生AKI（24%）,其中2例在其维护期间行持续性肾脏替代治疗。与正常组供者相比,AKI组供者的急性生理与慢性健康（APACHE）Ⅱ评分明显升高（P＜0.05）,中枢性尿崩症的发生率更高（P＜0.01）,入ICU时和获取前的Scr水平更高（均为P＜0.01）,获取前24 h尿量更少（P＜0.01）。与正常组受者相比,AKI组受者术后2、3 d的Scr水平更高（均为P＜0.05）,住院时间和住院花费亦明显升高（P＜0.01,P＜0.05）。两组受者术后移植肾功能延迟恢复、急性排斥反应、感染、恢复透析的发生率比较,差异无统计学意义（均为P＞0.05）。术后3个月,两组受者均好转出院,移植肾存活率为100%。结论  伴AKI的DBD供者供肾移植,经过积极的器官维护可纠正AKI,达到与非AKI供肾同样的效果,可以作为扩大供肾来源的途径。     

Simultaneous pancreas and kidney transplantation from organ donation after cardiac death

Background: The concept of organ donation after cardiac death (DCD) historically precedes the current practice of organ procurement from heartbeating donors meeting the brainstem death criteria. DCD has not gained widespread interest, however, due partly to initial fears that transplantation of such organs leads to suboptimal outcome. Methods: Available data on long‐term outcomes following simultaneous pancreas and kidney transplant (SPK) from DCD donors were reviewed, and it was found that the long‐term outcome is comparable to SPK from heartbeating donors. Australia’s first SPK from a DCD donor was performed. Results: The patient received a kidney and a pancreas from a young healthy donor after cardiac death, and at the time of writing was well with functioning grafts. Conclusion: SPK from donation after cardiac death is safe and should continue to be available for patients in need.     

Serum liver‐type fatty acid‐binding protein predicts recovery of graft function after kidney transplantation from donors after cardiac death

Kidneys procured by donation after cardiac death (DCD) may increase the donor pool but are associated with high incidence of delayed graft function (DGF). Urinary liver‐type fatty acid‐binding protein (L‐FABP) level is an early biomarker of renal injury after kidney transplantation (KTx); however, its utility is limited in DGF cases owing to urine sample unavailability. We examined whether serum L‐FABP level predicts functional recovery of transplanted DCD kidneys. Consecutive patients undergoing KTx from living related donors (LD), brain‐dead donors (BD), or DCD were retrospectively enrolled. Serum L‐FABP levels were measured from samples collected before and after KTx. Serum L‐FABP decreased rapidly in patients with immediate function, slowly in DGF patients, and somewhat increased in DGF patients requiring hemodialysis (HD) for >1 wk. Receiver‐operating characteristic curve analysis demonstrated that DGF was predicted with 84% sensitivity (SE) and 86% specificity (SP) at cutoff of 9.0 ng/mL on post‐operative day (POD) 1 and 68% SE and 90% SP at 6.0 on POD 2. DGF >7 d was predicted with 83% SE and 78% SP at 11.0 on POD 1 and 67% SE and 78% SP at 6.5 on POD 2. Serum L‐FABP levels may predict graft recovery and need for HD after DCD KTx.     

供体红细胞输血在DCD肝移植中应用的技术改进和效果

目的探讨公民逝世后捐献(DCD)供体血液采集的改进方法和效果。方法回顾性收集2020年5月至2021年1月期间四川大学华西医院移植团队对供体血液采集及处理方法改进前即Ⅰ期临床试验以及2021年9月至2021年11月期间血液采集及处理方法改进后的供体的临床病理资料。结果与Ⅰ期临床试验数据比较,改进技术之后,血液采集量和经过自体回收机过滤、离心、洗涤之后获得浓缩红细胞悬液量以及获得红细胞悬液量/kg体质量更多(P<0.05)。此外,与库存红细胞悬液的成分比较,经过改进技术后获得的红细胞悬液的p H值、钠离子和氯离子浓度均更高(P<0.05)且钾离子浓度均<1 mmol/L,无一例乳酸浓度>15 mmol/L。结论经过改进技术后能增加供体红细胞血液的采集量,其生化、电解质等指标较库存血更加符合生理要求。     

利奈唑胺用于肝移植术后抗结核治疗一例临床分析

利奈唑胺是一种嗯唑烷酮类抗生素,在轻至中度肝肾功能不全时应用该药是安全的,且利奈唑胺与经细胞色素P450代谢的药物之间不存在相互作用,而移植受者使用的免疫抑制剂基本上均经过该酶代谢,故利奈唑胺在移植术后尤其是肝、肾移植术后有着一定的临床应用价值。既往临床经验及药物说明书中,均无移植受者应用利奈唑胺抗结核疗效的描述,但笔者在临床工作中发现,利奈唑胺对于肝移植术后受者抗结核治疗效果较好,现将相关病例及经验报道如下。     

Safe use of segmental liver grafts from donors after cardiac death (DCD) in children with acute liver failure

Emergency liver transplantation is a life-saving procedure in selected subset of children with acute liver failure (ALF), when most recipients receive a segmental graft from a living or heart-beating deceased donor. The increased use of full-liver grafts from donors after cardiac death (DCD) has had a beneficial impact on elective liver transplantation in adults. These grafts however are more susceptible to poor initial function, and most centres are reluctant to consider their use as segmental grafts, let alone in the situation of ALF where good initial function is imperative. In this short article, we describe the use and successful outcome in two children aged 6 weeks and 6 years with acute liver failure who received reduced-size DCD liver grafts.     

Model for early allograft function is predictive of early graft loss in donation after circulatory death liver transplantation

Donation after circulatory death (DCD) liver transplantation is associated with higher rates of graft loss. In this paper, we explored whether the Model for Early Allograft Function (MEAF) predicted outcome in DCD liver transplantation. We performed a retrospective analysis of prospectively collected data from all adult DCD (Maastricht 3) livers transplanted in Cambridge and Edinburgh between 1 January 2011 and 30 June 2017, excluding those undergoing any form of machine perfusion. 187 DCD liver transplants were performed during the study period. DCD liver transplants with a lower MEAF score had a significantly better survival compared to those with a high MEAF score (Mantel-Cox P < .0001); this was largely due to early graft loss. Beyond 28 days post-transplant, there were no significant long-term graft or patient survival differences irrespective of the grade of MEAF (Mantel-Cox P = .64 and P = .43, respectively). The MEAF score correlated with the length of ICU (P = .0011) and hospital stay (P = .0007), but did not predict the requirement for retransplantation for ischemic cholangiopathy (P = .37) or readmission (P = .74). In this study, a high MEAF score predicted early graft loss, but not the subsequent need for re-transplantation or late graft failure as a result of intrahepatic ischemic bile duct pathology.