Innovations in Liver Preservation Techniques for Transplants from Donors after Circulatory Death: A Special Focus on Transplant Oncology.

Liver transplantation is the preferred treatment for end-stage liver disease. Emerging evidence suggests a potential role for liver transplantation in treating liver tumors such as colorectal liver metastases and cholangiocarcinoma. However, due to a limited donor pool, the use of marginal grafts from donation after circulatory death (DCD) donors is increasing to meet demand. Machine perfusion is crucial in this context for improving graft acceptance rates and reducing ischemia-reperfusion injury. Few studies have evaluated the role of machine perfusion in the context of transplant oncology. Perfusion machines can be utilized in situ (normothermic regional perfusion-NRP) or ex situ (hypothermic and normothermic machine perfusion), either in combination or as a complement to conventional in situ cold flush and static cold storage. The objective of this analysis is to provide an up-to-date overview of perfusion machines and their function in donation after circulatory death with particular attention to their current and likely potential effects on transplant oncology. A literature review comparing standard cold storage to machine perfusion methods showed that, so far, there is no evidence that these devices can reduce the tumor recurrence rate. However, some evidence suggests that these innovative perfusion techniques can improve graft function, reduce ischemia-reperfusion injury, and, based on this mechanism, may lead to future improvements in cancer recurrence.

Focusing on Ischemic Reperfusion Injury in the New Era of Dynamic Machine Perfusion in Liver Transplantation.

Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between the supply and demand of optimal organs. In this context, the use of extended criteria donor grafts has gained importance, even though these grafts are more susceptible to ischemic reperfusion injury (IRI). Hepatic IRI is an inherent and inevitable consequence of all liver transplants; it involves ischemia-mediated cellular damage exacerbated upon reperfusion and its severity directly affects graft function and post-transplant complications. Strategies for organ preservation have been constantly improving since they first emerged. The current gold standard for preservation is perfusion solutions and static cold storage. However, novel approaches that allow extended preservation times, organ evaluation, and their treatment, which could increase the number of viable organs for transplantation, are currently under investigation. This review discusses the mechanisms associated with IRI, describes existing strategies for liver preservation, and emphasizes novel developments and challenges for effective organ preservation and optimization.

Long-term outcomes of liver transplantation using grafts from donors with active hepatitis B virus replication: a multicenter cohort study.

Purpose: Liver grafts from donors with HBV infection contributed to expanding the donor pool under the hepatitis B immunoglobulin and antiviral agents (nucleos(t)ide analogues) in the HBV-endemic area. We report long-term outcomes of liver transplantations (LTs) using grafts from donors with active or chronic HBV infection. Methods: Overall, 2,260 LTs performed in 3 major hospitals in Seoul from January 2000 to April 2019 were assessed for inclusion. Twenty-six grafts (1.2%) were obtained from HBsAg (+), HBeAb (+), or HBcAb (+) donors, and recipient outcomes were retrospectively reviewed. Donor and recipient demographics and transplantation outcomes were analyzed. Results: Sixteen deceased donor LTs were performed using active HBsAg (+) grafts. Ten other LTs were sourced from 10 living donors. There was no significant difference in survival in patients who received deceased donor LTs compared with that in those who underwent LT with non-hepatitis virus-infected grafts. Fourteen patients who were followed up for >5 years were stable, and no difference in hepatocellular carcinoma recurrence rate was observed 5 years after transplantation between transplants from donors with and those without HBV. Conclusion: Considering long-term outcomes, liver grafts from donors with active HBV replication can be safely used for LT.

Current review of machine perfusion in liver transplantation from the Japanese perspective.

In light of the present evidence, machine perfusion is opening up new horizons in the field of liver transplantation. Although many advances have been made in liver transplantation, organ preservation methods have so far changed very little. Static cold storage is universally used for graft preservation in liver transplantation; however, there is a need for better preservation methods, such as ex vivo machine perfusion, to improve the outcomes by decreasing warm ischemic damage. Based on the findings of basic and clinical trials, hypothermic and normothermic machine perfusion techniques are now commercially available and include the OrganOx metra, Liver Assist, Cleveland NMP device, Organ Care System, and LifePort Liver. Recent clinical trials have provided further evidence for the potential role of normothermic machine perfusion to resuscitate and subsequently improve utilization of marginal or currently discarded livers. Further studies are required to explore the longer-term outcomes, late biliary complications, outcomes in specific high-risk groups, viability biomarkers, optimum and maximum perfusion duration, perfusate composition, and liver-directed therapeutic interventions during normothermic machine perfusion. The use of organs from marginal donors after brain death, such as fatty livers and the livers from elderly donors with multiple comorbidities, may be accepted for machine perfusion in Japan in the near future.

Machine perfusion for liver transplantation in the era of marginal organs-New kids on the block.

In the face of a critical organ shortage in the Western world, various strategies are employed to expand the donor pool for orthotopic liver transplantation (OLT). Among them is the transplantation of organs from extended criteria donors, a valuable source of liver allografts, however, characterized by potential risks for post-OLT complications and inferior outcomes. In recent years, machine perfusion (MP) of the explanted donor liver as well as regional perfusion techniques has witnessed significant advancements. Here, we aim to discuss different modes of dynamic organ preservation in OLT. These include hypothermic and normothermic MP, hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols. Over recent years, multiple feasibility trials have demonstrated the clinical prospects of MP. In the context of OLT using organs from extended criteria donors, MP has numerous advantages compared to conventional cold storage, some of which include the preservation and reconditioning of borderline transplantable organs and the viability assessment of high-risk donor allografts. This review aims to address the topic of liver allograft MP, highlighting particularly the current trends in clinical applications and future perspectives. Furthermore, different approaches of liver storage and reconditioning are reviewed in the context of ongoing research.

High Center Volume Does Not Mitigate Risk Associated with Using High Donor Risk Organs in Liver Transplantation.

BACKGROUND: High-risk donor allografts increase access to liver transplant, but potentially reduce patient and graft survival. AIMS: It is unclear whether the risk associated with using marginal donor livers is mitigated by increasing center experience. METHODS: The United Network for Organ Sharing registry was queried for adult first-time liver transplant recipients between 2/2002 and 12/2015. High donor risk was defined as donor risk index >1.9, and 1-year patient and graft survival were compared according to donor risk index in small and large centers. Multivariable Cox regression estimated the hazard ratio (HR) associated with using high-risk donor organs, according to a continuous measure of annual center volume. RESULTS: The analysis included 51,770 patients. In 67 small and 67 large centers, high donor risk index predicted increased mortality (p = 0.001). In multivariable analysis, high-donor risk index allografts predicted greater mortality hazard at centers performing 20 liver transplants per year (HR 1.35; 95% CI 1.22, 1.49; p < 0.001) and, similarly, at centers performing 70 per year (HR 1.35; 95% CI 1.26, 1.43; p < 0.001). The interaction between high donor risk index and center volume was not statistically significant (p = 0.747), confirming that the risk associated with using marginal donor livers was comparable between smaller and larger centers. Results were consistent when examining graft loss. CONCLUSION: At both small and large centers, high-risk donor allografts were associated with reduced patient and graft survival after liver transplant. Specific strategies to mitigate the risk of liver transplant involving high-risk donors are needed, in addition to accumulation of center expertise.

Patients' preferences in transplantation from marginal donors: results of a discrete choice experiment.

To increase the donor pool, the strategy of transplantation from "marginal" donors was developed though patients' preferences about these donors were insufficiently known. The preferences of patients registered on the waiting list or already transplanted in eight transplant teams covering four main organs (i.e., kidney, liver, heart, and lung) were evaluated using the discrete choice experiment method. In each left during 2 days, patients were interviewed on four scenarios. Of 178 eligible patients, 167 were interviewed; 40% accepted marginal graft in their own situation and 89% at least in one of the scenarios. Imagining urgent situations or rare profiles with difficult access to transplantation, respectively, 86% and 71% accepted these grafts. Most (76%) preferred to be informed about these grafts and 43% preferred to be involved in decision. The emergency [OR = 1.24; 95% CI: (1.06-1.45)] and the hazardousness [OR = 0.88; 95% CI: (0.78-0.99)] of the transplantation were factors independently associated with marginal graft acceptance. Most patients preferred to be informed and to be involved in the decision. Marginal grafts could be more accepted by patients in critical medical situations or perceiving their situation as critical. Physicians' practices in transplantation should be reconsidered taking into account individual preferences. This study was performed in a single country and thus reflects the cultural bias and practice thereof.

Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation.

BACKGROUND & AIMS: Liver grafts from hepatitis B surface antigen (HBsAg) positive donors could have potential to increase the donor pool. However, knowledge is extremely limited in this setting because currently available data are mostly from case reports. We aimed to assess the outcomes and experiences of liver transplantation from HBsAg positive donors in a single centre study. METHODS: From January 2010 to February 2013, 42 adult patients underwent liver transplantation from HBsAg positive donors and 327 patients from HBsAg negative ones. The outcomes including complications and survival of two groups were compared and antiviral therapy retrospectively reviewed. RESULTS: HBsAg positive liver grafts were more likely to be allocated to patients with hepatitis B (HBV)-related diseases. Post-transplant evaluation showed similar graft function regaining pace and no differences in complications such as primary non-function, acute rejection and biliary complications. Patient and graft survivals were comparable to that of HBsAg negative grafts. Furthermore, HBsAg persisted after transplant in all patients that received positive grafts. The donor HBV serum status determined the one of the recipient after transplantation. No HBV flare-ups were observed under antiviral therapy of oral nucleotide analogues, regardless of using hepatitis B immunoglobulin combination. CONCLUSIONS: Utilization of HBsAg positive liver grafts seems not to increase postoperative morbidity and mortality. Therefore it is a safe way to expand the donor pool when no suitable donor is available. Our experience also suggests that hepatitis B immunoglobulin should be abandoned in recipients of HBsAg positive liver grafts, in whom HBV prophylaxis could be the only oral antiviral therapy.

Liver transplantation for HBsAg-positive recipients using grafts from HBsAg-positive deceased donors.

This study reports our experience using deceased donor liver grafts from HBsAg-positive donors. We performed eight cases of liver transplantation (LT) using grafts from deceased HBsAg-positive donors between November 2005 and October 2010. The median age of donors was 48 years (range: 26-64). HBV DNA in the serum of donors ranged from 44 to 395 IU/ml, but HBeAg in all donors was negative. Preoperative laboratory and liver biopsy samples revealed the absence of definitive cirrhotic features and hepatitis. All recipients showed HBsAg positive preoperatively except one patient with HBsAg(-) status post previous LT for HBV related liver cirrhosis. The median age was 60 years (range: 46-76) at LT. Post-LT antiviral management consisted of hepatitis B immunoglobulin and antiviral nucleos(t)ide analogues. The median follow-up period was 25.5 months (range: 14-82). Of eight recipients, two recipients experienced serum HBsAg and HBV DNA disappearance postoperatively. Three recipients died of HBV-unrelated causes. The remaining five recipients were stable with normal liver function and no marked pathologic changes on follow-up biopsies. This experience shows that LT using grafts from deceased HBsAg-positive donors is feasible, and may represent a valuable expansion of the pool of organ donors with appropriate antiviral management and monitoring.