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This review describes the role of mitochondria in ischemia-reperfusion-injury (IRI).Mitochondria are the power-house of our cells and play a key role for the success of organ transplantation. With their respiratory chain, mitochondria are the main energy producers, to fuel metabolic processes, control cellular signalling and provide electrochemical integrity. The mitochondrial metabolism is however severely disturbed when ischemia occurs. Cellular energy depletes rapidly and various metabolites, including Succinate accumulate. At reperfusion, reactive oxygen species are immediately released from complex-I and initiate the IRI-cascade of inflammation. Prior to the development of novel therapies, the underlying mechanisms should be explored to target the best possible mitochondrial compound. A clinically relevant treatment should recharge energy and reduce Succinate accumulation before organ implantation. While many interventions focus instead on a specific molecule, which may inhibit downstream IRI-inflammation, mitochondrial protection can be directly achieved through hypothermic oxygenated perfusion (HOPE) before transplantation.Mitochondria are attractive targets for novel molecules to limit IRI-associated inflammation. Although dynamic preservation techniques could serve as delivery tool for new therapeutic interventions, their own inherent mechanism should not only be studied, but considered as key treatment to reduce mitochondrial injury, as seen with the HOPE-approach.

Living donor liver transplantation (LT) has been increasingly recognized as an effective treatment modality with excellent patient survival. Indications for LT have evolved not only for cholestatic liver disease, but also metabolic liver diseases. Living donor selection, particularly for pediatric inherited disease, is essential to prevent morbidity, both in the donor and recipient.Based on 30 years of experience in pediatric living donor LT in Japan, we could identify marginal parental living donors who have potential risks following LT, including heterozygous mothers with ornithine transcarbamylase deficiency, heterozygous protein C deficiency, heterozygous hypercholesterolemia, heterozygous protoporphyria, asymptomatic parental donors with paucity of intrahepatic bile duct, and human leukocyte antigen-homozygous parental donors.Although these situations seem rare due to infrequency of the condition, careful living donor evaluation is required to optimize the outcomes for pediatric recipients. In the setting of an appropriate selection of a living donor, we should avoid any additional hazards, given that the procedure itself has risks for a healthy individual.

This review describes recent developments in the field of liver perfusion techniques.Dynamic preservation techniques are increasingly tested due to the urgent need to improve the overall poor donor utilization. With their exposure to warm ischemia, livers from donors after circulatory death (DCD) transmit additional risk for severe complications after transplantation. Although the superiority of dynamic approaches compared to static-cold-storage is widely accepted, the number of good quality studies remains limited. Most risk factors, particularly donor warm ischemia, and accepted thresholds are inconsistently reported, leading to difficulties to assess the impact of new preservation technologies. Normothermic regional perfusion (NRP) leads to good outcomes after DCD liver transplantation, with however short ischemia times. While randomized controlled trials (RCT) with NRP are lacking, results from the first RCTs with ex-situ perfusion were reported. Hypothermic oxygenated perfusion was shown to protect DCD liver recipients from ischemic cholangiopathy. In contrast, endischemic normothermic perfusion seems to not impact on the development of biliary complications, although this evidence is only available from retrospective studies.Dynamic perfusion strategies impact posttransplant outcomes and are increasingly commissioned in various countries along with more evidence from RCTs. Transparent reporting of risk and utilization with uniform definitions is required to compare the role of different preservation strategies in DCD livers with prolonged ischemia times.

Although the utilization of donation after circulatory death donors (DCDs) for liver transplantation (LT) has increased steadily, much controversy remains, and no common acceptance criteria exist with regard to donor and recipient risk factors and prediction models. A consensus conference was organized by International Liver Transplantation Society on January 31, 2020, in Venice, Italy, to review the current clinical practice worldwide regarding DCD-LT and to develop internationally accepted guidelines. The format of the conference was based on the grade system. International experts in this field were allocated to 6 working groups and prepared evidence-based recommendations to answer-specific questions considering the currently available literature. Working group members and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and recommendations provided by working group 2, covering the entire spectrum of donor and recipient risk factors and prediction models in DCD-LT.

Objective The aim of this study was to investigate tumor recurrence after liver transplantation for hepatocellular carcinoma (HCC), with and without hypothermic oxygenated liver perfusion (HOPE) before transplantation. Patients and methods We analyzed all liver recipients with HCC, transplanted between January 2012 and September 2019 with donation after circulatory death (DCD) livers after previous end-ischemic HOPE-treatment (n = 70, Center A). Tumor parameters and key confounders were compared to consecutive recipients with HCC, transplanted during the same observation period with an unperfused DBD liver (n = 70). In a next step, we analyzed unperfused DCD (n = 70) and DBD liver recipients (n = 70), transplanted for HCC at an external center (Center B). Results Tumor parameters were not significantly different between HOPE-treated DCD and unperfused DBD liver recipients at Center A. One-third of patients were outside established tumor thresholds, for example, Milan criteria, in both groups. Despite no difference in tumor load, we found a 4-fold higher tumor recurrence rate in unperfused DBD livers (25.7%, 18/70), compared to only 5.7% (n = 4/70) recipients with tumor recurrence in the HOPE-treated DCD cohort (P = 0.002) in Center A. The tumor recurrence rate was also twice higher in unperfused DCD and DBD recipients at the external Center B, despite significant less cases outside Milan. HOPE-treatment of DCD livers resulted therefore in a 5-year tumor-free survival of 92% in HCC recipients, compared to 73%, 82.7%, and 81.2% in patients receiving unperfused DBD or DCD livers, from both centers. Conclusion We suggest that a simple machine liver perfusion approach appears advantageous to protect from HCC recurrence after liver transplantation, despite extended tumor criteria.

Objective: To compare HOPE and NRP in liver transplantation from cDCD. Summary of Background Data: Liver transplantation after cDCD is associated with higher rates of graft loss. Dynamic preservation strategies such as NRP and HOPE may offer safer use of cDCD grafts. Methods: Retrospective comparative cohort study assessing outcomes after cDCD liver transplantation in 1 Swiss (HOPE) and 6 French (NRP) centers. The primary endpoint was 1-year tumor-death censored graft and patient survival. Results: A total of 132 and 93 liver grafts were transplanted after NRP and HOPE, respectively. NRP grafts were procured from younger donors (50 vs 61 years, P < 0.001), with shorter functional donor warm ischemia (22 vs 31 minutes, P < 0.001) and a lower overall predicted risk for graft loss (UK-DCD-risk score 6 vs 9 points, P < 0.001). One-year tumor-death censored graft and patient survival was 93% versus 86% (P = 0.125) and 95% versus 93% (P = 0.482) after NRP and HOPE, respectively. No differences in non-anastomotic biliary strictures, primary nonfunction and hepatic artery thrombosis were observed in the total cohort and in 32 vs. 32 propensity score-matched recipients Conclusion: NRP and HOPE in cDCD achieved similar post-transplant recipient and graft survival rates exceeding 85% and comparable to the benchmark values observed in standard DBD liver transplantation. Grafts in the HOPE cohort were procured from older donors and had longer warm ischemia times, and consequently achieved higher utilization rates. Therefore, randomized controlled trials with intention-to-treat analysis are needed to further compare both preservation strategies, especially for high-risk donor-recipient combinations.

Hypothermic oxygenated perfusion (HOPE) has been shown to protect liver recipients from acute rejection in an allogeneic model of liver transplantation in rats. Here we investigate the impact of HOPE on the T cell-mediated immune response following kidney transplantation.Kidneys from Lewis rats were transplanted into Brown Norway recipients to trigger acute rejection (allogeneic untreated group). Next, Brown Norway recipients were treated either with tacrolimus,= or donor kidneys underwent 1h-HOPE-treatment before implantation without additional immunosuppression in recipients. Syngeneic kidney transplants (Brown Norway to Brown Norway) served as controls. In a second set of experiments, the immune response was assessed in a donation after circulatory death model of kidney transplantation comparing standard cold storage with subsequent HOPE treatment and hypothermic nitrogenated perfusion, where oxygen was replaced during cold perfusion.Allogeneic kidney transplantation led to death in all untreated recipients within 10 days due to severe acute rejection. In contrast, immune activation was prevented by tacrolimus with significantly improved recipient survival. Similarly, HOPE treatment, without any immunosuppression, protected recipients from acute immune response, as measured by less cytokine release, T-cell, and macrophage activation. Additionally, HOPE-treated kidneys showed better function and less early fibrosis leading to a significantly improved recipient survival, compared with untreated allogeneic controls. Similarly, HOPE treatment protected recipients of extended donation after circulatory death kidneys from immune activation. This effect was lost when deoxygenated perfusate was used.In summary, this is the first study demonstrating the beneficial effects of HOPE on the immune response following kidney transplantation in an allogeneic rodent model.

The cava-preserving piggyback (PB) technique requires only partial cava clamping during the anhepatic phase in liver transplantation (LT) and, therefore, maintains venous return and may hemodynamically stabilize the recipient. Hence, it is an ongoing debate whether PB implantation is more protective from acute kidney injury (AKI) after LT when compared with a classic cava replacement (CR) technique. The aim of this study was to assess the rate of AKI and other complications after LT comparing both transplant techniques without the use of venovenous bypass. We retrospectively analyzed the adult donation after brain death LT cohort between 2008 and 2016 at our center. Liver and kidney function and general outcomes including complications were assessed. Overall 378 transplantations were analyzed, of which 177 (46.8%) were performed as PB and 201 (53.2%) as CR technique. AKI occurred equally often in both groups. Transient renal replacement therapy was required in 22.6% and 22.4% comparing the PB and CR techniques (P = 0.81). Further outcome parameters including the complication rate were similar in both cohorts. Five-year graft and patient survival were comparable between the groups with 81% and 85%, respectively (P = 0.48; P = 0.58). In conclusion, both liver implantation techniques are equal in terms of kidney function and overall complications following LT.

Background Advanced donor age has been identified as risk factor, when combined with donor warm ischemia, e.g. in donation after circulatory death (DCD). In several countries DCD livers, older than 60 years are not considered suitable due to concerns related to poor graft function and development of ischaemic cholangiopathy. We evaluate in this study outcome after DCD liver transplantation using grafts from donors older than 60 years. Methodology We analysed outcome after DCD liver transplantation (n=315), comparing donors >60 years (n=93) and donors ≤60 years (n=222) from our centre between 2005 and 2015. Endpoints included graft function and complications, patient and graft survival. Multivariate risk analysis was performed to define further key factors that predicted inferior outcome. Results Donor age at the cut-off 60 years failed to stratify patient and graft survival. The rate of vascular, biliary and overall complications was comparably low in both cohorts and the median CCI was 42,7 points, independent from the donor age. Secondly, donor BMI above a threshold of 25 kg/m2 significantly impacted on graft and patient survival, at any donor age, while donor warm and cold ischemia times were not predictive for graft loss. Conclusion Older DCD donors can be successfully used for liver transplantation with good long-term outcomes, when further risk factors are limited. Additional risk is transmitted by an increased donor BMI, regardless of donor age. This article is protected by copyright. All rights reserved.

We read with great interest the paper by Jassem et al(1), which provides detailed gene expression profiles of human livers during normothermic machine perfusion (NMP), compared to conventional cold storage. Authors should be congratulated to this extensive analysis, which shows for the first time transcriptional changes during any form of reperfusion under normothermic conditions(1). However, we would like to add a few critical comments. This article is protected by copyright. All rights reserved.

Host immune response to viral vectors, persistence of nonintegrating vectors, and sustained transgene expression are among the major challenges in gene therapy. To overcome these hurdles, we successfully used minicircle (MC) naked-DNA vectors devoid of any viral or bacterial sequences for the long-term treatment of murine phenylketonuria, a model for a genetic liver defect. MC-DNA vectors expressed the murine phenylalanine hydroxylase (Pah) complementary DNA (cDNA) from a liver-specific promoter coupled to a de novo designed hepatocyte-specific regulatory element, designated P3, which is a cluster of evolutionary conserved transcription factor binding sites. MC-DNA vectors were subsequently delivered to the liver by a single hydrodynamic tail vein (HTV) injection. The MC-DNA vector normalized blood phenylalanine concomitant with reversion of hypopigmentation in a dose-dependent manner for more than 1 year, whereas the corresponding parental plasmid did not result in any phenylalanine clearance. MC vectors persisted in an episomal state in the liver consistent with sustained transgene expression and hepatic PAH enzyme activity without any apparent adverse effects. Moreover, 14–20% of all hepatocytes expressed transgenic PAH, and the expression was observed exclusively in the liver and predominately around pericentral areas of the hepatic lobule, while there was no transgene expression in periportal areas. Conclusion This study demonstrates that MC technology offers an improved safety profile and has the potential for the genetic treatment of liver diseases.

Platelets play a critical role in liver injury and regeneration. Thrombocytopenia is associated with increases in postoperative complications after partial hepatectomy, but it is unknown whether platelet counts could also predict outcomes after transplantation, a procedure that is often performed in thrombocytopenic patients. Therefore, the aim of this study was to evaluate whether platelet counts could be indicators of short- and long-term outcomes after liver transplantation (LT). Two hundred fifty-seven consecutive LT recipients (January 2003-December 2011) from our prospective database were analyzed. Preoperative and daily postoperative platelet counts were recorded until postoperative day 7 (POD7). Univariate and multivariate analyses were performed to assess whether low perioperative platelet counts were a risk factor for postoperative complications and graft and patient survival. The median pretransplant platelet count was 88 × 109/L [interquartile range (IQR) = 58-127 × 109/L]. The lowest platelet counts occurred on POD3: the median was 56 × 109/L (IQR = 41-86 × 109/L). Patients with low platelet counts on POD5 had higher rates of severe (grade IIIb/IV) complications [39% versus 29%, odds ratio (OR) = 1.09 (95% CI = 1.1-3.3), P = 0.02] and 90-day mortality [16% versus 8%, OR = 2.25 (95% CI = 1.0-5.0), P = 0.05]. In the multivariate analysis, POD5 platelet counts

Objective Posttherapeutic changes in the breast after tumorectomy (TE) and radiation therapy (RT) may mimic or obscure recurrent or new malignancies and thus interfere with conventional diagnostic studies. We investigated the enhancement of tissue during variable time intervals after therapy with contrast-enhanced MRI in 62 patients. Materials and Methods We report the results of 77 studies in 62 patients undergoing TE and RT. We include only those studies with at least 24 months of clinical and mammographic follow-up (n = 60) or histopathologic results (n = 17). Results Up to 9 months after therapy, differentiation between posttherapeutic changes and recurrence was frequently impossible because of the strong enhancement. Ten to 18 months after therapy, this posttherapeutic enhancement subsided slowly with some interindividual variations. After 18 months posttherapy, no significant enhancement was encountered in 30 of 32 cases. Diffuse or focal enhancement was present in all recurrent tumors and all recurrences were correctly diagnosed. Furthermore, 4 of 11 recurrences and 10 of 18 single recurrent foci were detected by MR alone, based on focal enhancement. Conclusion Accordingly, contrast-enhanced MR is not recommended during the first 9 months after therapy. Nine to 18 months after therapy, it may be helpful in those two-thirds of cases where the scar does not enhance. If enhancement takes place (one-third of cases), it may represent either scar or tumor, and in such circumstances, enhanced MR is of no value. After 18 months, enhanced MRI has proven a valuable additional tool. By correctly detecting or excluding recurrent tumor, it can significantly improve diagnostic accuracy.