Prevalence of Steatosis Hepatis in the Eurotransplant Region: Impact on Graft Acceptance Rates

Due to the shortage of liver allografts and the rising prevalence of fatty liver disease in the general population, steatotic liver grafts are considered for transplantation.This condition is an important risk factor for the outcome after transplantation.We here analyze the characteristics of the donor pool offered to the Charité –Universitätsmedizin Berlin from 2010 to 2016 with respect to liver allograft nonacceptance and steatosis hepatis. Of the 2653 organs offered to our center, 19.9% (n=527) were accepted for transplantation, 58.8% (n=1561) were allocated to other centers, and 21.3% (n = 565) were eventually discarded from transplantation. In parallel to an increase of the incidence of steatosis hepatis in the donor pool from 20% in 2010 to 30% in 2016, the acceptance rates for steatotic organs increased in our center from 22.3% to 51.5% in 2016 (p 0.001) having less than 30% macrovesicular steatosis hepatis. However, by 2016, the number of canceled transplantations due to higher grades of steatosis hepatis had significantly increased from 14.7% (n = 15) to 63.6% (42; p < 0.001).The rising prevalence of steatosis hepatis in the donor pool has led to higher acceptance rates of steatotic allografts. Nonetheless, steatosis hepatis remains a predominant phenomenon in discarded organs necessitating future concepts such as organ reconditioning to increase graft utilization

Hepatic artery reconstruction using an operating microscope in pediatric liver transplantation—Is it worth the effort?

Introduction: In pediatric liver transplantation (pLT), hepatic artery thrombosis (HAT) is associated with inferior transplant outcome. Hepatic artery reconstruction (HAR) using an operating microscope (OM) is considered to reduce the incidence of HAT. Methods: HAR using an OM was compared to a historic cohort using surgical loupes (SL) in pLT performed between 2009 and 2020. Primary endpoint was the occurrence of HAT. Secondary endpoints were 1-year patient and graft survival determined by Kaplan-Meier analysis and complications. Multivariate analysis was used to identify independent risk factors for HAT and adverse events. Results: A total of 79 pLTs were performed [30 (38.0%) living donations; 49 (62.0%) postmortem donations] divided into 23 (29.1%) segment 2/3, 32 (40.5%) left lobe, 4 (5.1%) extended right lobe, and 20 (25.3%) full-size grafts. One-year patient and graft survival were both 95.2% in the OM group versus 86.2% and 77.8% in the SL group (p = .276 and p = .077). HAT rate was 0% in the OM group versus 24.1% in the SL group (p = .013). One-year patient and graft survival were 64.3% and 35.7% in patient with HAT, compared to 93.9% and 92.8% in patients with no HAT (both p < .001). Multivariate analysis revealed HAR with SL (p = .022) and deceased donor liver transplantation (DDLT) (p = .014) as independent risk factors for HAT. The occurrence of HAT was independently associated with the need for retransplantation (p < .001) and biliary leakage (p = .045). Conclusion: In pLT, the use of an OM is significantly associated to reduce HAT rate, biliary complications, and graft loss and outweighs the disadvantages of delayed arterial perfusion and prolonged warm ischemia time (WIT)

Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation

Background: Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP). Methods: Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion. Results: Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend. Conclusion: Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP

Etablierung und Evaluierung eines Systems zur ex vivo Maschinenperfusion der Rattenleber unter Berücksichtigung von Steatosis hepatis in der Spenderpopulation

Hintergrund: Die Lebertransplantation stellt derzeit die einzige kurative Therapieoption für Patient*innen mit terminaler Leberfunktionsstörung dar, wobei die Verfügbarkeit dieses Behandlungskonzepts aufgrund des ausgeprägten Organmangel limitiert ist. Zur Überwindung des bestehenden Organmangels werden zunehmend Lebertransplantate von Spendern mit erweiterten Kriterien akzeptiert, welche mit erhöhten Raten der primären Nichtfunktion und frühen Dysfunktion assoziiert sind. Die ex vivo Leber-Maschineperfusion ist ein Verfahren, welche die Rekonditionierung solcher Organe mit Qualitätseinschränkungen ermöglichen soll, um somit das Outcome nach Lebertransplantation zu verbessern. In dieser Arbeit erfolgte die Etablierung und Evaluation eines Kleintiermodelles zur ex vivo Leber-Maschinenperfusion unter verschiedenen Temperaturbedingungen. Weiterhin wurden klinische Daten zur Akzeptanz von steatotischen Lebertransplantaten am Transplantationszentrum der Charité – Universitätsmedizin Berlin ausgewertet, welche einen bedeutsamen Anteil an der Spenderpopulation mit verminderter Organqualität darstellen und potentiell reversibel sind. Methoden: Im Rahmen des experimentellen Teils erfolgte die Etablierung und Evaluierung eines Systems zur ex vivo Maschinenperfusion der Rattenleber für subnormotherme und normotherme Konditionen. Ein präliminäres System bestehend aus einer Rollerpumpe und einem Oxygenator wurde – unter Hinzunahme von autologen Rattenerythrozyten als Sauerstoffträger und einer Dialyseeinheit – schrittweise optimiert und mit Lebertransplantaten entnommen nach Herztod evaluiert. Im klinischen Anteil erfolgte eine retrospektive Datenanalyse zur Akzeptanz und Ablehnung von Lebertransplantaten zwischen 2010 und 2016 an der Charité – Universitätsmedizin Berlin unter Betrachtung von Steatosis hepatis in der Spenderpopulation. Ergebnisse: Die normotherme Perfusion von Rattenlebern führte im Vergleich zur subnormothermen Perfusion zur erhöhten Freisetzung der Alanin-Aminotransferase in das Perfusat. Über die Perfusionszeit kam es zu ansteigenden Kaliumkonzentrationen im Perfusat, welche durch Erweiterung des Perfusionssystem um einen Dialyseeinheit reduziert werden konnten. Die Miniaturisierung des Perfusionssystem führte zur Reduktion der benötigten Menge an Rattenerythrozyten. Im Modell der Organspende nach Herztod konnte gezeigt werden, dass die Perfusion mit Dialyseeinheit zu einem geringeren Organschaden führt. Zwischen 2010 und 2016 wurden dem Transplantationszentrum 2653 Lebertransplantate angeboten, von denen 527 (19,9%) akzeptiert und transplantiert werden konnten. Während die Anzahl der Angebote zunahm (2010: 208; 2016: 536), sank die Akzeptanz der Transplantate signifikant (2010: 32,9%; 2016: 10,9%; p<0,001). Gleichzeitig stieg die Prävalenz der Steatosis hepatis im angebotenen Kollektiv signifikant an (2013: 24,0%; 2016: 34,7%; p<0,007). Diskussion: Die Steatosis hepatis stellt einen relevanten Faktor für die Verfügbarkeit von Organen für die Lebertransplantation dar. Ein Kleintiermodell zu ex vivo Maschinenperfusion der Leber ist essentiell für die Entwicklung von Strategien zur Rekonditionierung steatotischer Lebertransplantate. Durch die Optimierung der Organqualität mittels Maschinenperfusion könnte künftig das Outcome nach Transplantation steatotischer Lebertransplantate verbessert werden.Liver transplantation is the gold standard treatment of patients with end-stage liver disease. The availability of liver transplantation is limited due to severe organ shortage. To overcome this shortage, organs with impaired quality are accepted, which are associated with increased rates of primary organ non-function or early allograft dysfunction. Ex vivo machine perfusion has been proposed for re-conditioning of organs with reduced quality to improve the outcome after liver transplantation. Object of this study was to establish and evaluate a model for ex vivo rat liver machine perfusion and to analyze clinical data regarding acceptance of liver grafts with impaired quality which were offered to the transplantation center of the Charité – Universitätsmedizin Berlin, with the main focus on steatosis hepatis. Methods: In the experimental part a model of the ex vivo machine perfusion of the rat liver under subnormothermic and normothermic temperature conditions was established. A system consisting of a roller pump and an oxygenator was improved step-by-step by adding autologous erythrocytes and by integrating a dialyzing unit. The system was evaluated using rat liver grafts from donation after cardiac death. In the clinical part a retrospective analysis of liver grafts offered to the Charité – Universitätsmedizin Berlin from 2010 to 2016 was performed regrading steatosis hepatis in the donor pool. Results: Normothermic perfusion of the rat liver unlike subnormothermic conditions led to elevated release of alanine-aminotransferase into the perfusate. Potassium concentrations increased over the perfusion time which was reduced by adding a dialyzing unit to the perfusion system. Miniaturization of the perfusion system led to reduced expenditure of autologous rat erythrocytes. Perfusion with dialysis decreased the damage of the liver grafts in the model of donation after cardiac death. Between 2010 and 2016 out of 2653 liver grafts offered to our transplantation center 527 (19.9%) were transplanted. While the number of offers increased (2010: 208; 2016: 536), the rate of acceptance decreased (2010: 32.9%; 2016: 10.9%; p<0.001). In the same time the prevalence of steatosis hepatis increased in the analyzed group (2013: 24.0%; 2016: 34.7%; p<0.007). Discussion: Steatosis hepatis is a critical issue for the availability of liver transplantation. A small animal model for ex vivo liver machine perfusion is essential to establish for strategies for the re-conditioning of steatotic liver grafts. Through the improvement of the organ quality employing ex vivo liver machine perfusion the outcome of liver transplantation could be optimized in the future