Machine perfusion or cold storage in organ transplantation: indication,mechanisms, and future perspectives

Most organs are currently preserved by cold storage (CS) prior to transplantation. However, as more so called marginal donor organs are utilized, machine perfusion has regained clinical interest. Recent studies have demonstrated advantages of pulsatile perfusion over CS preservation for kidney transplantation. However, it remains unclear whether there is a significant benefit of one preservation method over the other in general, or, whether the utilization of particular preservation approaches needs to be linked to organ characteristics. Proposed protective mechanisms of pulsatile perfusion remain largely obscure. It can be speculated that pulsatile perfusion may not only provide nutrition and facilitate the elimination of toxins but also trigger protective mechanisms leading to the amelioration of innate immune responses. Those aspects may be of particular relevance when utilizing grafts with suboptimal quality which may have an increased vulnerability to ischemia/reperfusion injury and compromised repair mechanisms. This review aims to enunciate the principles of organ perfusion and preservation as they relate to indication, aspects of organ protection and to highlight future developments.     

Reconditioning by end‐ischemic hypothermic in‐house machine perfusion: A promising strategy to improve outcome in expanded criteria donors kidney transplantation

This clinical study evaluates end‐ischemic hypothermic machine perfusion (eHMP) in expanded criteria donors (ECD) kidneys. eHMP was initiated upon arrival of the kidney in our center and continued until transplantation. Between 11/2011 and 8/2014 eHMP was performed in 66 ECD kidneys for 369 (98‐912) minutes after 863 (364‐1567) minutes of cold storage (CS). In 49 of 66 cases, the contralateral kidney from the same donor was preserved by static CS only and accepted by another Eurotransplant (ET) center. Five (10.2%) of these kidneys were ultimately judged as “not transplantable” by the accepting center and discarded. After exclusion of early unrelated graft losses, 43 kidney pairs from the same donor were eligible for direct comparison of eHMP vs CS only: primary non‐function and delayed graft function (DGF) were 0% vs 9.3% (P=.04) and 11.6% vs 20.9% (P=.24). There was no statistically significant difference in 1‐year graft survival (eHMP vs CS only: 97.7% vs 88.4%, P=.089). In a multivariate analysis, eHMP was an independent factor for prevention of DGF (OR: 0.28, P=.041). Development of DGF was the strongest risk factor for 1‐year graft failure (Renal resistance: 38.2, P<.001). In summary, eHMP is a promising reconditioning technique to improve the quality and acceptance rate of suboptimal grafts.     

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.     

Impact of machine perfusion after long static cold storage on delayed graft function incidence and duration and time to hospital discharge

Delayed graft function (DGF) is very high in our center (70%‐80%), and we usually receive a kidney for transplant after more than 22 hours of static cold ischemia time (CIT). Also, there is an inadequate care of the donors, contributing to a high rate of DGF. We decided to test whether machine perfusion (MP) after a CIT improved the outcome of our transplant patients. We analyzed the incidence of DGF, its duration, and the length of hospital stay (LOS) in patients who received a kidney preserved with MP after a CIT (hybrid perfusion—HP). We included 54 deceased donors kidneys preserved with HP transplanted from Feb/13 to Jul/14, and compared them to 101 kidney transplants preserved by static cold storage (CS) from Nov/08 to May/12. The median pumping time was 11 hours. DGF incidence was 61.1% vs 79.2% (P = .02), median DGF duration was 5 vs 11 days (P < .001), and median LOS was 13 vs 18 days (P < .011), for the HP compared to CS group. The observed reduction of DGF with machine perfusion did not occur in donors over 50 years old. In the multivariate analysis, risk factors for DGF, adjusted for CIT, were donor age (OR, 1.04; P = .005) and the absence of use of MP (OR, 1.54; P = .051). In conclusion, the use of HP contributed to faster recovery of renal function and to a shorter length of hospital stay.     

Lifeport与静态低温保存应用于器官捐献供肾保存效果的Meta分析

目的  系统评价Lifeport与静态低温保存(CS)在器官捐献供肾的保存效果。 方法  计算机检索Medline数据库、Embase数据库、考克兰图书馆(Cochrane library)、中国生物医学文献数据库、中国知网、万方数据库和维普数据库,搜集Lifeport与CS在移植肾保存效果的相关临床研究,检索时限均从建库至2015年12月31日。按照纳入与排除标准选择文献,评价质量并提取资料,并评价纳入研究的偏倚风险后,采用Stata 12软件进行Meta分析。 结果  共纳入16个研究,包括5个随机对照试验(RCT)和11个回顾性队列研究(RCS)。Meta分析结果显示：与CS组比较,(1) 总体捐献供肾(TDD),Lifeport组移植术后移植肾功能延迟恢复(DGF)发生率降低,DGF持续时间减少、平均住院日减少以及术后1年肾存活率增加,两组术后急性排斥反应(AR)发生率与1年人存活率相当;(2) 心脏死亡器官捐献供肾(DCD)：Lifeport组术后DGF发生率降低,术后平均住院日减少,两组术后移植肾原发性无功能(PNF)与AR发生率,术后1年人、肾存活率比较,差异无统计学意义;(3) 扩展标准供肾(ECD)：Lifeport组术后PNF发生率降低并改善术后1年肾存活率,两组术后DGF发生率、AR发生率与术后1年人存活率比较,差异无统计学意义。 结论  Lifeport应用于器官捐献供肾保存具有一定的优势,但受纳入研究数量及质量所限,上述研究结论尚需开展更多高质量研究予以验证。     

Outcomes of kidney paired donation transplants in relation to shipping and cold ischaemia time

To assess the impact of shipping distance and cold ischaemia time (CIT) of shipped organs in a kidney paired donation (KPD) programme, we evaluated the outcomes of the initial 100 kidney transplants performed in the Australian KPD programme. In a 44‐month period, 12 centres were involved in fifteen 2‐way, twenty 3‐way, one 4‐way and one 6‐way exchanges. Sixteen kidneys were transplanted at the same hospital (CIT 2.6 ± 0.6 h) and 84 required transport to the recipient hospital (CIT 6.8 ± 2.8 h). A spontaneous fall in serum creatinine by at least 10% within 24 h was observed in 85% of recipients, with no difference between nonshipped and shipped kidneys. There were two cases of transient delayed graft function requiring dialysis and patient and graft survival at 1 year were 99% and 97%, respectively. There was no difference in recipients of nonshipped compared with shipped kidneys with regard to serum creatinine at 1 month (mean difference (MD) 7.3 μmol/l, 95% CI ?20.2 to 34.8, P = 0.59), 1‐year graft survival (MD 3.9%, 95% CI ?5.4 to 13.2, P = 0.41) or patient survival (MD ?2.4%, 95% CI ?10.0 to 5.2, P = 0.54). Despite prolonged CIT for interstate exchanges, the programme's decision to ship donor kidneys rather than the donor appears to be safe.     

Perioperative administration of high‐dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta‐analysis

Delayed graft function (DGF) due to ischemia–reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta‐analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high‐dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I² = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47–1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25–11.68, P = 0.02). Perioperative, high‐dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.     

High incidence of delayed graft function in HIV‐infected kidney transplant recipients

Kidney transplantation (KT) outcomes in human immunodeficiency virus (HIV)‐infected recipients are under continuous research. High incidence of early post‐transplant complications such as acute rejection has been observed. A multicenter study including HIV‐infected patients who underwent KT in Spain, from 2001 to 2011, was performed. The study population included 108 recipients, 36 HIV‐infected, and 72 matched HIV‐negative KT recipients. HIV‐infected recipients developed more delayed graft function (DGF) (52% vs. 21%, P < 0.001). One‐ and 3‐year graft survival was 91.6% and 86.2% in HIV‐infected patients, and 97.1% and 94.7% in HIV‐negative patients (P = 0.052). In two‐variate Cox analysis, HIV infection was not a predictor of graft loss after adjusting for time on dialysis, acute rejection, and DGF. Multivariate analysis for DGF revealed HIV‐positive status as independent risk factor. We analyzed the evolution of immunosuppressive and antiretroviral therapy (ART). In HIV‐infected patients tacrolimus trough levels were very high in the first week and significantly lower in the second week post‐transplant (P = 0.042). Post‐transplant ART was significantly changed: protease inhibitors use decreased (P = 0.034) and integrase inhibitor use increased (P < 0.001). DGF is another frequent early complication in HIV‐infected recipients that can affect graft survival. Strategies to prevent DGF and antiretroviral regimes with less drug interactions could improve outcomes.     

Identifying endpoints to predict the influence of immunosuppression on long‐term kidney graft survival

Identifying a short‐term endpoint for use in clinical trials that accurately reflects the influence of specific immunosuppressive regimens on long‐term kidney graft survival is challenging. The number, timing, type (T‐cell‐mediated or antibody mediated), and severity of biopsy‐proven acute rejection (BPAR) episodes in terms of histological changes and functional impact are highly influential for graft prognosis, and a crude measure of overall acute rejection incidence alone is unlikely to be a robust predictor of graft outcome. A series of studies has shown remarkably consistent results in terms of the cutoff point for one‐yr renal function which predicts poor long‐term graft survival, indicating that a threshold of 50 mL/min/1.73 m² is likely to be appropriate. Estimated glomerular filtration rate at one yr post‐transplant discriminates effectively among immunosuppressive regimens with regard to graft survival, primarily calcineurin inhibitor reduction strategies. Several other factors that can affect graft survival, such as pathological changes in the graft, may be partly influenced by the immunosuppressive regimen, but the contribution of drug therapy is difficult to define. A combined approach in which both treated BPAR and renal function at one yr are used to assess novel immunosuppressive regimens appears to be promising as the emphasis shifts toward sustaining kidney allograft survival over the long term.     

Dynamics of early post‐operative plasma ddcfDNA levels in kidney transplantation: a single‐center pilot study

Donor‐derived cell‐free DNA (ddcfDNA) is reported to be a promising noninvasive biomarker for acute rejection in organ transplant. However, studies on monitoring ddcfDNA dynamics during the early periods after organ transplantation are scarce. Our study assessed the dynamic variation in ddcfDNA in early period with various types and status of kidney transplantation. Target region capture sequencing used identifies ddcfDNA level in 21 kidney transplant recipients. Median ddcfDNA level was 20.69% at the initial time post‐transplant, and decreased to 5.22% on the first day and stayed at the stable level after the second day. The ddcfDNA level in DCD (deceased donors) group (44.99%) was significantly higher than that in LDRT (living donor) group (10.24%) at initial time, P < 0.01. DdcfDNA level in DGF (delayed graft function) recipients was lower (23.96%) than that in non‐DGF (47.74%) at the initial time, P = 0.89 (19.34% in DGF and 4.46% in non‐DGF on the first day, P = 0.17). DdcfDNA level at initial time significantly correlated with serum creatinine (r² = 0.219, P = 0.032) and warm ischemia time (r² = 0.204, P = 0.040). Plasma ddcfDNA level decreased rapidly follow an L‐shaped curve post‐transplant, and level in DGF declined slower than non‐DGF. The rebound of ddcfDNA level may indicate the occurrence of acute rejection.     

Early clinical experience using donor‐derived cell‐free DNA to detect rejection in kidney transplant recipients

Donor‐derived cell‐free DNA (dd‐cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd‐cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor–specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd‐cfDNA was higher among patients with antibody–mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%‐1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%‐1.10%; P < .001) and cell–mediated rejection (CMR; median: 0.27%, IQR: 0.19%‐1.30%; P = .01). The dd‐cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17‐0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71‐0.93) and a dd‐cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd‐cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.     

Reassessment of the clinical impact of preformed donor‐specific anti‐HLA‐Cw antibodies in kidney transplantation

Anti‐denatured HLA‐Cw antibodies are highly prevalent, whereas anti‐native HLA‐Cw antibodies seem to lead to random flow cytometry crossmatch results. We aimed to reassess crossmatch prediction for anti‐HLA‐Cw using 2 types of single antigen flow beads (classical beads and beads with diminished expression of denatured HLA), and to compare the pathogenicity of preformed anti‐denatured and anti‐native HLA‐Cw antibodies in kidney transplantation. We performed 135 crossmatches with sera reacting against donor HLA‐Cw (classical beads fluorescence ≥500); only 20.6% were positive. Forty‐three (31.6%) were anti‐denatured HLA antibodies (beads with diminished expression of denatured HLA fluorescence <300); all were crossmatch negative. The correlation between classical beads fluorescence and the crossmatch ratio was low (ρ = 0.178), and slightly higher with beads with diminished expression of denatured HLA (ρ = 0.289). We studied 52 kidney recipients with preformed anti‐HLA‐Cw donor‐specific antibodies. Those with anti‐native HLA antibodies experienced more acute and chronic antibody‐mediated rejections (P = .006 and .03, respectively), and displayed a lower graft survival (P = .04). Patients with anti‐native HLA‐Cw antibodies more frequently had previous sensitizing events (P < .000001) or plausibility of their antibody profile according to known anti‐native HLA‐Cw eplets (P = .0001). Anti‐native but not anti‐denatured HLA‐Cw antibodies are deleterious, which underscores the need for reagents with diminished expression of denatured HLA.     

No impact of disseminated intravascular coagulation in kidney donors on long‐term kidney transplantation outcome: A multicenter propensity‐matched study

The diagnosis of disseminated intravascular coagulation (DIC) is often considered to be a contraindication to organ donation. The aim of this study was to evaluate the impact of DIC+ donors on kidney recipient (KR) evolution. We identified 169 KRs with DIC+ donation after brain death donors between January 1996 and December 2012 in 6 French transplant centers. Individuals were matched using propensity scores to 338 recipients with DIC? donors according to donor age and sex, whether expanded criteria for the donor existed, graft year, and transplantation center. After kidney transplantation, delayed graft function was observed in 28.1% of DIC+ KRs and in 22.8% of DIC? KRs (NS). Renal allograft survival at 1, 5, and 10 years was 94.5%, 89.3%, and 73.9% and 96.2%, 90.8%, and 81.3% in DIC+ KRs and DIC? KRs, respectively (NS). The median estimated glomerular filtration rate (eGFR) was similar between DIC+ and DIC? KRs at 3 months, 1 year, and 10 years: 45.9 vs 48.1 mL/min, 42.1 vs 43.1 mL/min, and 33.9 vs 38.1 mL/min, respectively. Delayed calcineurin inhibitor introduction or induction had no impact on delayed graft function rate or eGFR evolution at 10 years after transplantation in DIC+ KRs. Donor DIC did not seem to affect initial outcome, long‐term graft function, or allograft survival.     

Kidney transplantation in children: impact of young recipient age on graft survival.

BACKGROUND: It has been suggested that recipient age may have an effect on renal graft survival due to its potential influence on the competence of the immune system. A comparison of graft survival between children and elderly adults, however, has never been performed. METHODS: Forty patients /=65 years using a case-control analysis. Apart from age, matching criteria were the number of HLA mismatches and the date of transplantation. RESULTS: The mean age differed by 57 years between study and control group (10 +/- 5 vs 67 +/- 2, P < 0.001). There was no difference in the number of initially non-functioning grafts, sex distribution, immunosuppression, number of HLA mismatches on the HLA-DR, -B and -A locus, cold ischaemia time and the number of patients with panel-reactive antibodies. The only difference was a lower donor age in the study group (17 +/- 14 vs 35 +/- 16, P < 0.001) compared with the control group. During the follow-up of 109 +/- 54 and 79 +/- 49 months, respectively, acute rejections were more frequent in the study group (25 vs 12, P < 0.01). There was no significant difference in graft survival between both groups when death with functioning graft was excluded. CONCLUSIONS: This study which compares two groups of patients with a mean age difference of 57 years could not demonstrate an effect of young recipient age on graft survival, though the incidence of acute rejections appeared to be significantly higher in the paediatric population. Thus paediatric renal transplanted patients do not seem to have a disadvantage regarding graft survival due to their young recipient age.     

肾脏常温机械灌注与无缺血肾移植

为了增加扩大标准供者(ECD)肾脏的利用率,肾脏保存方法近年来在不断发展。常温机械灌注(NMP)的使用,促进了离体供肾保存、评估和修复,以及肾移植手术方式革新。中山大学附属第一医院器官移植中心首创的无缺血肾移植(IFKT)手术,利用肾脏NMP机器在供肾获取、保存、移植全过程中,保持供肾血流和供氧不中断,从根本上避免了供肾缺血-再灌注损伤(IRI),降低了术后移植物功能延迟恢复(DGF)和急性排斥反应发生的风险。本文着重总结肾脏NMP的新进展,以及IFKT手术方式和近期疗效,旨在为提高ECD供肾利用率、解决器官短缺的问题提供参考。     

Efficacy of the natural oxygen transporter HEMO2life® in cold preservation in a preclinical porcine model of donation after cardiac death

The growing use of marginal organs for transplantation pushes current preservation methods toward their limits, and the need for improvement is pressing. We previously demonstrated the benefits of M101, a natural extracellular oxygen carrier compatible with hypothermia, for the preservation of healthy renal grafts in a porcine model of autotransplantation. Herein, we use a variant of this preclinical model to evaluate M101 potential benefits both in static cold storage (CS) and in machine perfusion (MP) preservation in the transplantation outcomes for marginal kidneys. In the CS arm, despite the absence of obvious benefits within the first 2 weeks of follow‐up, M101 dose‐dependently improved long‐term function, normalizing creatininemia after 1 and 3 months. In the MP arm, M101 improved short‐ and long‐term functional outcomes as well as tissue integrity. Importantly, we provide evidence for the additivity of MP and M101 functional effects, showing that the addition of the compound further improves organ preservation, by reducing short‐term function loss, with no loss of function or tissue integrity recorded throughout the follow‐up. Extending previous observations with healthy kidneys, the present results point at the M101 oxygen carrier as a viable strategy to improve current organ preservation methods in marginal organ transplantation.