Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy.

Ex situ normothermic machine perfusion (NMP) is rapidly emerging as a novel platform for testing therapeutics in human donor livers. Recently perfusion of explanted patient livers was achieved, raising the possibility of using these diseased organs to increase the fidelity and resolution of drug testing and development. Here, we provide proof-of-principle for the feasibility of this approach in the context of gene therapy.

Normothermic regional and ex situ perfusion reduces postreperfusion syndrome in donation after circulatory death liver transplantation: A retrospective comparative study.

In controlled donation after circulatory death (DCD) liver transplantation, ischemia-reperfusion injury is linked to postreperfusion syndrome (PRS), acute kidney injury (AKI), and early allograft dysfunction. Normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) are techniques that mitigate ischemic injury and associated complications. In this single-center retrospective study, we compared early transplant outcomes of DCD livers undergoing direct procurement (DP) and static cold storage (SCS) (DCD-DP-SCS), NRP procurement with SCS (DCD-NRP-SCS), or DP with NMP (DCD-DP-NMP).

Localized Liver Injury During Normothermic Ex Situ Liver Perfusion Has No Impact on Short-term Liver Transplant Outcomes.

Background: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized.

Methods: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant.

Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy.

Background: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy.

Outcomes of livers from donation after circulatory death donors with extended agonal phase and the adjunct of normothermic regional perfusion.

The liver performs important functions that are essential for life. If the liver fails, patients will die unless they receive a new liver from a donor (transplant). Unfortunately, there are not enough livers for everyone and some patients die while waiting for a suitable organ.

D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy.

Background: Deceased donor livers are prone to biliary complications, which may necessitate retransplantation, and we, and others, have suggested that these complications are because of peribiliary vascular fibrin microthrombi. We sought to determine the prevalence and consequence of occult fibrin within deceased donor livers undergoing normothermic ex situ perfusion (NESLiP) and evaluate a role for fibrinolysis.

Methods: D-dimer concentrations, products of fibrin degradation, were assayed in the perfusate of 163 livers taken after 2 h of NESLiP, including 91 that were transplanted.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2), could represent a new chemoprophylactic approach for COVID-19 that complements vaccination. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems.

Predicting Early Allograft Function After Normothermic Machine Perfusion.

Background: Normothermic ex situ liver perfusion is increasingly used to assess donor livers, but there remains a paucity of evidence regarding criteria upon which to base a viability assessment or criteria predicting early allograft function.

Methods: Perfusate variables from livers undergoing normothermic ex situ liver perfusion were analyzed to see which best predicted the Model for Early Allograft Function score.

Results: One hundred fifty-four of 203 perfused livers were transplanted following our previously defined criteria.

Liver Transplantation Outcomes From Controlled Circulatory Death Donors: SCS vs in situ NRP vs ex situ NMP.

Objective: To compare the outcomes of livers donated after circulatory death (DCD) and undergoing either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion (NMP) with livers undergoing static cold storage (SCS).

Summary Of Background Data: DCD livers are associated with increased risk of primary nonfunction, poor function, and nonanastomotic strictures (NAS), leading to underutilization.

Methods: A single center, retrospective analysis of prospectively collected data on 233 DCD liver transplants performed using SCS, NRP, or NMP between January 2013 and October 2020.

Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture.

Bile Biochemistry Following Liver Reperfusion in the Recipient and Its Association With Cholangiopathy.

Cholangiocytes secrete bicarbonate and absorb glucose, producing bile with alkaline pH and low glucose content. These functions of cholangiocytes have been suggested as a marker of bile duct viability during normothermic ex situ liver perfusion, and they are now monitored routinely after reperfusion in our center. In this study, we reviewed the composition of bile immediately after reperfusion in liver transplant recipients to determine normal posttransplant parameters and the predictive value of bile biochemistry for the later development of cholangiopathy.