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Liver Transplantation: Improving Results under Worsening Conditions
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Liver Transplantation: Improving Results under Worsening Conditions

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 42612

Special Issue Editor

Prof. Dr. Robert Öllinger

E-Mail Website
Guest Editor
Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Surgery, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Interests: oncology; immunology; advanced therapies; transplantation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last century, liver transplantation has advanced to excellent results based on surgical progress, improvements in immunosuppression, and the optimization of organ procurement. One- and five-year patient survival rates of >90% and >75%, respectively, have become clinical routine. However, organ scarcity in general, demographic changes, and a decrease in the number of ideal donors have forced liver transplant centers to push the boundaries in accepting marginal donor livers, maximizing utilization by splitting livers and increasing the number of living donations. MELD-based organ allocation rules have been implemented and subsequently adjusted in order to warrant fair allocation as well as reducing the mortality on the waiting list, and is not always successful. Further, indications for liver transplantation have to steadily be reconsidered, especially for patients with malignomas. Very recently, the COVID-19 pandemic has shuttered liver transplant specialists as well and the consequences thereof are unforseable yet. In 2020, the challenge in liver transplantation has become to maintain or even improve the excellent results from the past under worsening conditions by addressing organ quality, e.g., using machine perfusion, minimizing immunosuppression, optimizing anti-infective regimes, and rethinking organ allocation and recipient selection.

Prof. Dr. Robert Öllinger
Guest Editor

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Keywords

  • organ allocation
  • MELD score
  • outcome
  • split liver transplantation
  • machine perfusion
  • marginal donors
  • waitlist mortality
  • liver transplantation for malignomas
  • acute-on-chronic liver failure
  • COVID-19

Published Papers (17 papers)

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Research

12 pages, 647 KiB  
Article
Over 30 Years of Pediatric Liver Transplantation at the Charité—Universitätsmedizin Berlin
by Simon Moosburner, Leke Wiering, Safak Gül-Klein, Paul Ritschl, Tomasz Dziodzio, Nathanael Raschzok, Christian Witzel, Alexander Gratopp, Stephan Henning, Philip Bufler, Moritz Schmelzle, Georg Lurje, Wenzel Schöning, Johann Pratschke, Brigitta Globke and Robert Öllinger
J. Clin. Med. 2022, 11(4), 900; https://doi.org/10.3390/jcm11040900 - 09 Feb 2022
Cited by 6 | Viewed by 2273
Abstract
Background: Pediatric liver transplantation (LT) is the treatment of choice for children with end-stage liver disease and in certain cases of hepatic malignancies. Due to low case numbers, a technically demanding procedure, the need for highly specialized perioperative intensive care, and immunological, as [...] Read more.
Background: Pediatric liver transplantation (LT) is the treatment of choice for children with end-stage liver disease and in certain cases of hepatic malignancies. Due to low case numbers, a technically demanding procedure, the need for highly specialized perioperative intensive care, and immunological, as well as infectious, challenges, the highest level of interdisciplinary cooperation is required. The aim of our study was to analyze short- and long-term outcomes of pediatric LT in our center. Methods: We conducted a retrospective single-center analysis of all liver transplantations in pediatric patients (≤16 years) performed at the Department of Surgery, Charité – Universitätsmedizin Berlin between 1991 and 2021. Three historic cohorts (1991–2004, 2005–2014 and 2015–2021) were defined. Graft- and patient survival, as well as perioperative parameters were analyzed. The study was approved by the institutional ethics board. Results: Over the course of the 30-year study period, 212 pediatric LTs were performed at our center. The median patient age was 2 years (IQR 11 years). Gender was equally distributed (52% female patients). The main indications for liver transplantation were biliary atresia (34%), acute hepatic necrosis (27%) and metabolic diseases (13%). The rate of living donor LT was 25%. The median cold ischemia time for donation after brain death (DBD) LT was 9 h and 33 min (IQR 3 h and 46 min). The overall donor age was 15 years for DBD donors and 32 years for living donors. Overall, respective 1, 5, 10 and 30-year patient and graft survivals were 86%, 82%, 78% and 65%, and 78%, 74%, 69% and 55%. One-year patient survival was 85%, 84% and 93% in the first, second and third cohort, respectively (p = 0.14). The overall re-transplantation rate was 12% (n = 26), with 5 patients (2%) requiring re-transplantation within the first 30 days. Conclusion: The excellent long-term survival over 30 years showcases the effectiveness of liver transplantation in pediatric patients. Despite a decrease in DBD organ donation, patient survival improved, attributed, besides refinements in surgical technique, mainly to improved interdisciplinary collaboration and management of perioperative complications. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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13 pages, 776 KiB  
Article
Epidemiology and Prognostic Significance of Rapid Response System Activation in Patients Undergoing Liver Transplantation
by Marcus Robertson, Andy K. H. Lim, Ashley Bloom, William Chung, Andrew Tsoi, Elise Cannan, Ben Johnstone, Andrew Huynh, Tessa O’Halloran, Paul Gow, Peter Angus and Daryl Jones
J. Clin. Med. 2021, 10(23), 5680; https://doi.org/10.3390/jcm10235680 - 01 Dec 2021
Cited by 4 | Viewed by 1427
Abstract
Patients undergoing liver transplantation have a high risk of perioperative clinical deterioration. The Rapid Response System is an intensive care unit-based approach for the early recognition and management of hospitalized patients identified as high-risk for clinical deterioration by a medical emergency team (MET). [...] Read more.
Patients undergoing liver transplantation have a high risk of perioperative clinical deterioration. The Rapid Response System is an intensive care unit-based approach for the early recognition and management of hospitalized patients identified as high-risk for clinical deterioration by a medical emergency team (MET). The etiology and prognostic significance of clinical deterioration events is poorly understood in liver transplant patients. We conducted a cohort study of 381 consecutive adult liver transplant recipients from a prospectively collected transplant database (2011–2017). Medical records identified patients who received MET activation pre- and post-transplantation. MET activation was recorded in 131 (34%) patients, with 266 MET activations in total. The commonest triggers for MET activation were tachypnea and hypotension pre-transplantation, and tachycardia post-transplantation. In multivariable analysis, female sex, increasing Model for End-Stage Liver Disease score and hepatorenal syndrome were independently associated with MET activation. The unplanned intensive care unit admission rate following MET activation was 24.1%. Inpatient mortality was 4.2% and did not differ by MET activation status; however, patients requiring MET activation had significantly longer intensive care unit and hospital length of stay and were more likely to require inpatient rehabilitation. In conclusion, liver transplant patients with perioperative complications requiring MET activation represent a high-risk group with increased morbidity and length of stay. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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12 pages, 3657 KiB  
Article
Perioperative Perfusion of Allografts with Anti-Human T-lymphocyte Globulin Does Not Improve Outcome Post Liver Transplantation—A Randomized Placebo-Controlled Trial
by Paul Viktor Ritschl, Julia Günther, Lena Hofhansel, Stefanie Ernst, Susanne Ebner, Arne Sattler, Sascha Weiß, Annemarie Weissenbacher, Rupert Oberhuber, Benno Cardini, Robert Öllinger, Matthias Biebl, Christian Denecke, Christian Margreiter, Thomas Resch, Stefan Schneeberger, Manuel Maglione, Katja Kotsch and Johann Pratschke
J. Clin. Med. 2021, 10(13), 2816; https://doi.org/10.3390/jcm10132816 - 25 Jun 2021
Viewed by 1565
Abstract
Due to the lack of suitable organs transplant surgeons have to accept unfavorable extended criteria donor (ECD) organs. Recently, we demonstrated that the perfusion of kidney organs with anti-human T-lymphocyte globulin (ATLG) prior to transplantation ameliorates ischemia-reperfusion injury (IRI). Here, we report on [...] Read more.
Due to the lack of suitable organs transplant surgeons have to accept unfavorable extended criteria donor (ECD) organs. Recently, we demonstrated that the perfusion of kidney organs with anti-human T-lymphocyte globulin (ATLG) prior to transplantation ameliorates ischemia-reperfusion injury (IRI). Here, we report on the results of perioperative ATLG perfusion in a randomized, single-blinded, placebo-controlled, feasibility trial (RCT) involving 30 liver recipients (LTx). Organs were randomly assigned for perfusion with ATLG/Grafalon® (AP) (n = 16) or saline only (control perfusion = CP) (n = 14) prior to implantation. The primary endpoint was defined as graft function reflected by aspartate transaminase (AST) values at day 7 post-transplantation (post-tx). With respect to the primary endpoint, no significant differences in AST levels were shown in the intervention group at day 7 (AP: 53.0 ± 21.3 mg/dL, CP: 59.7 ± 59.2 mg/dL, p = 0.686). Similarly, exploratory analysis of secondary clinical outcomes (e.g., patient survival) and treatment-specific adverse events revealed no differences between the study groups. Among liver transplant recipients, pre-operative organ perfusion with ATLG did not improve short-term outcomes, compared to those who received placebo perfusion. However, ATLG perfusion of liver grafts was proven to be a safe procedure without the occurrence of relevant adverse events. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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9 pages, 1197 KiB  
Article
Long-Term Outcomes of Abdominal Wall Reconstruction with Expanded Polytetrafluoroethylene Mesh in Pediatric Liver Transplantation
by Jiyoung Kim, Jeong-Moo Lee, Nam-Joon Yi, Suk Kyun Hong, YoungRok Choi, Kwangpyo Hong, Eui Soo Han, Kwang-Woong Lee and Kyung-Suk Suh
J. Clin. Med. 2021, 10(7), 1462; https://doi.org/10.3390/jcm10071462 - 02 Apr 2021
Cited by 1 | Viewed by 2304
Abstract
Background: Large-for-size syndrome caused by organ size mismatch increases the risk of abdominal compartment syndrome. Massive transfusion and portal vein clamping during liver transplantation may cause abdominal compartment syndrome (ACS) related to mesenteric congestion. In general pediatric surgery—such as correcting gastroschisis—abdominal wall reconstruction [...] Read more.
Background: Large-for-size syndrome caused by organ size mismatch increases the risk of abdominal compartment syndrome. Massive transfusion and portal vein clamping during liver transplantation may cause abdominal compartment syndrome (ACS) related to mesenteric congestion. In general pediatric surgery—such as correcting gastroschisis—abdominal wall reconstruction for the reparation of defects using expanded polytetrafluoroethylene is an established method. The purpose of this study is to describe the ePTFE-Gore-Tex closure method in patients with or at a high risk of ACS among pediatric liver transplant patients and to investigate the long-term prognosis and outcomes. Methods: From March 1988 to March 2018, 253 pediatric liver transplantation were performed in Seoul National University Hospital. We retrospectively reviewed the cases that underwent abdominal wall reconstruction with ePTFE during liver transplantation. Results: A total of 15 cases underwent abdominal closure with ePTFE-GoreTex graft. We usually used a 2 mm × 10 cm × 15 cm sized Gore-Tex graft for extending the abdominal cavity. The median follow up was 59.5 (17–128.7) months and there were no cases of ACS after transplantation. There were no infectious complications related to ePTFE implantation. The patient and graft survival rate during the study period was 93.3% (14/15). Conclusions: Abdominal wall reconstruction using ePTFE is feasible and could be an alternative option for patients with a high risk of ACS. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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14 pages, 1983 KiB  
Article
Real-World Administration of Once-Daily MeltDose® Prolonged-Release Tacrolimus (LCPT) Allows for Dose Reduction of Tacrolimus and Stabilizes Graft Function Following Liver Transplantation
by Katharina Willuweit, Alexandra Frey, Anne Hörster, Fuat Saner and Kerstin Herzer
J. Clin. Med. 2021, 10(1), 124; https://doi.org/10.3390/jcm10010124 - 31 Dec 2020
Cited by 3 | Viewed by 2086
Abstract
The calcineurin inhibitor tacrolimus is included in most immunosuppressive protocols after liver transplantation. This retrospective, observational 24-month study investigated the tolerability of once-daily MeltDose® prolonged-release tacrolimus (LCPT) after switching from twice-daily immediate-release tacrolimus (IR-Tac) in a real-world cohort of 150 patients with [...] Read more.
The calcineurin inhibitor tacrolimus is included in most immunosuppressive protocols after liver transplantation. This retrospective, observational 24-month study investigated the tolerability of once-daily MeltDose® prolonged-release tacrolimus (LCPT) after switching from twice-daily immediate-release tacrolimus (IR-Tac) in a real-world cohort of 150 patients with previous liver transplantation. No graft rejection or new safety signals were observed. Only 7.3% of patients discontinued LCPT due to side effects. In the overall patient population, median liver transaminases, total cholesterol, triglycerides, glucose, and HbA1c remained constant after switching to LCPT. Total cholesterol significantly decreased (p ≤ 0.002) in patients with initially elevated levels (>200 mg/dL). A total of 71.8% of 96 patients maintained a glomerular filtration rate > 60 mL/min/1.73 m2 throughout the study, while 44.7% of patients were classified as fast metabolizers and 55.3% as slow metabolizers. Median daily tacrolimus dose could be reduced by 50% in fast metabolizers and by 30% in slow metabolizers, while trough levels were maintained in the target range (4–6 ng/mL). In conclusion, our observational study confirmed previous evidence of good overall tolerability and a favorable outcome for the patients after switching from IR-Tac to LCPT after liver transplantation. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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17 pages, 3009 KiB  
Article
Treatment of Anti-HLA Donor-Specific Antibodies Results in Increased Infectious Complications and Impairs Survival after Liver Transplantation
by Sinem Ünlü, Nils Lachmann, Maximilian Jara, Paul Viktor Ritschl, Leke Wiering, Dennis Eurich, Christian Denecke, Matthias Biebl, Sascha Chopra, Safak Gül-Klein, Wenzel Schöning, Moritz Schmelzle, Petra Reinke, Frank Tacke, Johann Pratschke, Robert Öllinger and Tomasz Dziodzio
J. Clin. Med. 2020, 9(12), 3986; https://doi.org/10.3390/jcm9123986 - 09 Dec 2020
Cited by 2 | Viewed by 2231
Abstract
Donor-specific anti-human leukocyte antigen antibodies (DSA) are controversially discussed in the context of liver transplantation (LT). We investigated the relationship between the presence of DSA and the outcome after LT. All the LTs performed at our center between 1 January 2008 and 31 [...] Read more.
Donor-specific anti-human leukocyte antigen antibodies (DSA) are controversially discussed in the context of liver transplantation (LT). We investigated the relationship between the presence of DSA and the outcome after LT. All the LTs performed at our center between 1 January 2008 and 31 December 2015 were examined. Recipients < 18 years, living donor-, combined, high-urgency-, and re-transplantations were excluded. Out of 510 LTs, 113 DSA-positive cases were propensity score-matched with DSA-negative cases based on the components of the Balance of Risk score. One-, three-, and five-year survival after LT were 74.3% in DSA-positive vs. 84.8% (p = 0.053) in DSA-negative recipients, 71.8% vs. 71.5% (p = 0.821), and 69.3% vs. 64.9% (p = 0.818), respectively. Rejection therapy was more often applied to DSA-positive recipients (n = 77 (68.1%) vs. 37 (32.7%) in the control group, p < 0.001). At one year after LT, 9.7% of DSA-positive patients died due to sepsis compared to 1.8% in the DSA-negative group (p = 0.046). The remaining causes of death were comparable in both groups (cardiovascular 6.2% vs. 8.0%; p = 0.692; hepatic 3.5% vs. 2.7%, p = 0.788; malignancy 3.5% vs. 2.7%, p = 0.788). DSA seem to have an indirect effect on the outcome of adult LTs, impacting decision-making in post-transplant immunosuppression and rejection therapies and ultimately increasing mortality due to infectious complications. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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8 pages, 849 KiB  
Article
New OPTN Simultaneous Liver-Kidney Transplant (SLKT) Policy Improves Racial and Ethnic Disparities
by Daniela Goyes, John Paul Nsubuga, Esli Medina-Morales, Vilas Patwardhan and Alan Bonder
J. Clin. Med. 2020, 9(12), 3901; https://doi.org/10.3390/jcm9123901 - 01 Dec 2020
Cited by 5 | Viewed by 2775
Abstract
(1) Background: On 10 August 2017, the Organ Procurement and Transplantation Network (OPTN) adopted standardized eligibility criteria to properly determine which transplant candidates should undergo Simultaneous Liver-Kidney Transplant (SLKT). Racial and ethnic disparities have not been examined after 2017. Therefore, using the United [...] Read more.
(1) Background: On 10 August 2017, the Organ Procurement and Transplantation Network (OPTN) adopted standardized eligibility criteria to properly determine which transplant candidates should undergo Simultaneous Liver-Kidney Transplant (SLKT). Racial and ethnic disparities have not been examined after 2017. Therefore, using the United Network for Organ Sharing (UNOS), we aim to evaluate post-graft survival outcomes among Caucasians, African Americans, and Hispanics. (2) Methods: Kaplan–Meier curves and Cox regression models are used to compare post-transplant graft survival for Caucasians, African Americans (AAs), and Hispanics. Competing risk analysis is used to evaluate the cumulative incidence of death or re-transplantation with re-transplantation and death as competing risks. (3) Results: On multivariate Cox regression analysis, no differences in graft survival are found in AA (hazard ratio (HR): 1.30; 95% CI: 0.74–2.29 p = 0.354) or Hispanics (HR: 1.18; 95% CI: 0.70–2 p = 0.520) compared to Caucasians after 2017. On competing risk analysis of the risk of death with re-transplantation as a competing risk, no difference is found between ethnic minorities after 2017. There is a similar finding from competing risk analysis of the risk of re-transplantation with death as a competing risk. (4) Conclusion: After introducing standardized eligibility criteria for SLKT allocation, the post-graft survival outcomes remain similar between the different racial and ethnic groups, displaying the benefits of adopting such policy in 2017. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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15 pages, 527 KiB  
Article
Outcomes of Liver Resections after Liver Transplantation at a High-Volume Hepatobiliary Center
by Julian M. O. Pohl, Nathanael Raschzok, Dennis Eurich, Michael Pflüger, Leke Wiering, Assal Daneshgar, Tomasz Dziodzio, Maximilian Jara, Brigitta Globke, Igor M. Sauer, Matthias Biebl, Georg Lurje, Wenzel Schöning, Moritz Schmelzle, Frank Tacke, Johann Pratschke, Paul V. Ritschl and Robert Öllinger
J. Clin. Med. 2020, 9(11), 3685; https://doi.org/10.3390/jcm9113685 - 17 Nov 2020
Cited by 4 | Viewed by 1976
Abstract
Although more than one million liver transplantations have been carried out worldwide, the literature on liver resections in transplanted livers is scarce. We herein report a total number of fourteen patients, who underwent liver resection after liver transplantation (LT) between September 2004 and [...] Read more.
Although more than one million liver transplantations have been carried out worldwide, the literature on liver resections in transplanted livers is scarce. We herein report a total number of fourteen patients, who underwent liver resection after liver transplantation (LT) between September 2004 and 2017. Hepatocellular carcinomas and biliary tree pathologies were the predominant indications for liver resection (n = 5 each); other indications were abscesses (n = 2), post-transplant lymphoproliferative disease (n = 1) and one benign tumor. Liver resection was performed at a median of 120 months (interquartile range (IQR): 56.5–199.25) after LT with a preoperative Model for End-Stage Liver Disease (MELD) score of 11 (IQR: 6.75–21). Severe complications greater than Clavien–Dindo Grade III occurred in 5 out of 14 patients (36%). We compared liver resection patients, who had a treatment option of retransplantation (ReLT), with actual ReLTs (excluding early graft failure or rejection, n = 44). Bearing in mind that late ReLT was carried out at a median of 117 months after first transplantation and a median of MELD of 32 (IQR: 17.5–37); three-year survival following liver resection after LT was similar to late ReLT (50.0% vs. 59.1%; p = 0.733). Compared to ReLT, liver resection after LT is a rare surgical procedure with significantly shorter hospital (mean 25, IQR: 8.75–49; p = 0.034) and ICU stays (mean 2, IQR: 1–8; p < 0.001), acceptable complications and survival rates. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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13 pages, 1538 KiB  
Article
Is Routine Prophylaxis Against Pneumocystis jirovecii Needed in Liver Transplantation? A Retrospective Single-Centre Experience and Current Prophylaxis Strategies in Spain
by José Ignacio Fortea, Antonio Cuadrado, Ángela Puente, Paloma Álvarez Fernández, Patricia Huelin, Carmen Álvarez Tato, Inés García Carrera, Marina Cobreros, María Luisa Cagigal Cobo, Jorge Calvo Montes, Carlos Ruiz de Alegría Puig, Juan Carlos Rodríguez SanJuán, Federico José Castillo Suescun, Roberto Fernández Santiago, Juan Andrés Echeverri Cifuentes, Fernando Casafont, Javier Crespo and Emilio Fábrega
J. Clin. Med. 2020, 9(11), 3573; https://doi.org/10.3390/jcm9113573 - 06 Nov 2020
Cited by 8 | Viewed by 2360
Abstract
In liver transplant (LT) recipients, Pneumocystis jirovecii pneumonia (PJP) is most frequently reported before 1992 when immunosuppressive regimens were more intense. It is uncertain whether universal PJP prophylaxis is still applicable in the contemporary LT setting. We aimed to examine the incidence of [...] Read more.
In liver transplant (LT) recipients, Pneumocystis jirovecii pneumonia (PJP) is most frequently reported before 1992 when immunosuppressive regimens were more intense. It is uncertain whether universal PJP prophylaxis is still applicable in the contemporary LT setting. We aimed to examine the incidence of PJP in LT recipients followed at our institution where routine prophylaxis has never been practiced and to define the prophylaxis strategies currently employed among LT units in Spain. All LT performed from 1990 to October 2019 were retrospectively reviewed and Spanish LT units were queried via email to specify their current prophylaxis strategy. During the study period, 662 LT procedures were carried out on 610 patients. Five cases of PJP were identified, with only one occurring within the first 6 months. The cumulative incidence and incidence rate were 0.82% and 0.99 cases per 1000 person transplant years. All LT units responded, the majority of which provide prophylaxis (80%). Duration of prophylaxis, however, varied significantly. The low incidence of PJP in our unprophylaxed cohort, with most cases occurring beyond the usual recommended period of prophylaxis, questions a one-size-fits-all approach to PJP prophylaxis. A significant heterogeneity in prophylaxis strategies exists among Spanish LT centres. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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23 pages, 8671 KiB  
Article
Current Challenges in the Post-Transplant Care of Liver Transplant Recipients in Germany
by Kerstin Herzer, Martina Sterneck, Martin-Walter Welker, Silvio Nadalin, Gabriele Kirchner, Felix Braun, Christina Malessa, Adam Herber, Johann Pratschke, Karl Heinz Weiss, Elmar Jaeckel and Frank Tacke
J. Clin. Med. 2020, 9(11), 3570; https://doi.org/10.3390/jcm9113570 - 05 Nov 2020
Cited by 13 | Viewed by 2470
Abstract
Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but [...] Read more.
Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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12 pages, 1261 KiB  
Article
Sirolimus Prolongs Survival after Living Donor Liver Transplantation for Hepatocellular Carcinoma Beyond Milan Criteria: A Prospective, Randomised, Open-Label, Multicentre Phase 2 Trial
by Kwang-Woong Lee, Seong Hoon Kim, Kyung Chul Yoon, Jeong-Moo Lee, Jae-Hyung Cho, Suk Kyun Hong, Nam-Joon Yi, Sung-Sik Han, Sang-Jae Park and Kyung-Suk Suh
J. Clin. Med. 2020, 9(10), 3264; https://doi.org/10.3390/jcm9103264 - 12 Oct 2020
Cited by 11 | Viewed by 2328
Abstract
Sirolimus (SRL) has been reported to benefit patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). This study aimed to compare SRL with tacrolimus (TAC) in living-donor LT (LDLT) recipients beyond the Milan criteria. This study was initially designed to enrol 45 recipients [...] Read more.
Sirolimus (SRL) has been reported to benefit patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). This study aimed to compare SRL with tacrolimus (TAC) in living-donor LT (LDLT) recipients beyond the Milan criteria. This study was initially designed to enrol 45 recipients who underwent LDLT for HCC beyond the Milan criteria. At 1 month after LT, the patients were randomly assigned to either SRL or TAC-based treatment, with both groups receiving mycophenolate mofetil. The primary outcome was three-year recurrence-free survival (RFS) and the secondary outcome was overall survival (OS). A total of 42 patients completed the study. HCC recurrence occurred in 8 of 22 (36.4%) patients in the SRL group and in 5 of 22 (25%) patients in the TAC group. No differences in RFS and OS were found between the two groups in simple comparison. The type of immunosuppressant remained a nonsignificant factor for recurrence in multivariate analysis; however, SRL significantly prolonged OS (TAC hazard ratio: 15 [1.3–172.85], p = 0.03) after adjusting for alpha-fetoprotein and positron emission tomography standardised uptake value ratio (tumour/background liver). In conclusion, SRL does not decrease HCC recurrence but prolongs OS after LDLT for HCC beyond the Milan criteria. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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14 pages, 1933 KiB  
Article
Effect of CYP3A5 on the Once-Daily Tacrolimus Conversion in Stable Liver Transplant Patients
by Jong Man Kim, Je Ho Ryu, Kwang-Woong Lee, Suk Kyun Hong, Kwangho Yang, Gyu-Seong Choi, Young-Ae Kim, Ju-Yeun Lee, Nam-Joon Yi, Choon Hyuck David Kwon, Chong Woo Chu, Kyung-Suk Suh and Jae-Won Joh
J. Clin. Med. 2020, 9(9), 2897; https://doi.org/10.3390/jcm9092897 - 08 Sep 2020
Cited by 3 | Viewed by 2433
Abstract
Cytochrome P450 (CYP) 3A5 polymorphism influences tacrolimus metabolism, but its effect on the drug pharmacokinetics in liver transplant recipients switched to once-daily extended-release formulation remains unknown. The aim of this study is to analyze the effect of CYP3A5 polymorphism on liver [...] Read more.
Cytochrome P450 (CYP) 3A5 polymorphism influences tacrolimus metabolism, but its effect on the drug pharmacokinetics in liver transplant recipients switched to once-daily extended-release formulation remains unknown. The aim of this study is to analyze the effect of CYP3A5 polymorphism on liver function after once-daily tacrolimus conversion in liver transplant patients. A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT 02882113). Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (p = 0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (−42.9% vs. −26.1%) and dose/kg-adjusted trough level of tacrolimus (−40.0% vs. −23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. A pharmacokinetic analysis was performed in 10 patients and tacrolimus absorption in the non-expressor group was slower than in the expressor group. In line with this observation, the area under the curve for once-daily tacrolimus correlated with trough level (Cmin) in the non-expressors and peak concentration (Cmax) in the expressors. CYP3A5 genotyping in liver transplant recipients leads to prediction of pharmacokinetics after switching from a twice-daily regimen to a once-daily dosage form, which makes it possible to establish an appropriate dose of tacrolimus. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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15 pages, 1656 KiB  
Article
Global Longitudinal Strain at Rest as an Independent Predictor of Mortality in Liver Transplant Candidates: A Retrospective Clinical Study
by Mare Mechelinck, Bianca Hartmann, Sandra Hamada, Michael Becker, Anne Andert, Tom Florian Ulmer, Ulf Peter Neumann, Theresa Hildegard Wirtz, Alexander Koch, Christian Trautwein, Anna Bettina Roehl, Rolf Rossaint and Marc Hein
J. Clin. Med. 2020, 9(8), 2616; https://doi.org/10.3390/jcm9082616 - 12 Aug 2020
Cited by 20 | Viewed by 2357
Abstract
Speckle tracking echocardiography enables the detection of subclinical left ventricular dysfunction at rest in many heart diseases and potentially in severe liver diseases. It could also possibly serve as a predictor for survival. In this study, 117 patients evaluated for liver transplantation in [...] Read more.
Speckle tracking echocardiography enables the detection of subclinical left ventricular dysfunction at rest in many heart diseases and potentially in severe liver diseases. It could also possibly serve as a predictor for survival. In this study, 117 patients evaluated for liver transplantation in a single center between May 2010 and April 2016 with normal left ventricular ejection fraction were included according to clinical characteristics of their liver disease: (1) compensated (n = 29), (2) clinically significant portal hypertension (n = 49), and (3) decompensated (n = 39). Standard echocardiography and speckle tracking echocardiography were performed at rest and during dobutamine stress. Follow-up amounted to three years to evaluate survival and major cardiac events. Altogether 67% (78/117) of the patients were transplanted and 32% (31/96 patients) died during the three-year follow-up period. Global longitudinal strain (GLS) at rest was significantly increased (became more negative) with the severity of liver disease (p < 0.001), but reached comparable values in all groups during peak stress. Low (less negative) GLS values at rest (male: >−17/female: >−18%) could predict patient survival in a multivariate Cox regression analysis (p = 0.002). GLS proved valuable in identifying transplant candidates with latent systolic dysfunction. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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16 pages, 308 KiB  
Article
Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers
by Cornelius Engelmann, Martina Sterneck, Karl Heinz Weiss, Silke Templin, Steffen Zopf, Gerald Denk, Dennis Eurich, Johann Pratschke, Johannes Weiss, Felix Braun, Martin-Walter Welker, Tim Zimmermann, Petra Knipper, Dirk Nierhoff, Thomas Lorf, Elmar Jäckel, Hans-Michael Hau, Tung Yu Tsui, Aristoteles Perrakis, Hans-Jürgen Schlitt, Kerstin Herzer and Frank Tackeadd Show full author list remove Hide full author list
J. Clin. Med. 2020, 9(8), 2352; https://doi.org/10.3390/jcm9082352 - 23 Jul 2020
Cited by 9 | Viewed by 4297
Abstract
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of [...] Read more.
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3–6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
14 pages, 2304 KiB  
Article
The Effects of MELD-Based Liver Allocation on Patient Survival and Waiting List Mortality in a Country with a Low Donation Rate
by Paul V. Ritschl, Leke Wiering, Tomasz Dziodzio, Maximilian Jara, Jochen Kruppa, Uwe Schoeneberg, Nathanael Raschzok, Frederike Butz, Brigitta Globke, Philippa Seika, Max Maurer, Matthias Biebl, Wenzel Schöning, Moritz Schmelzle, Igor M. Sauer, Frank Tacke, Robert Öllinger and Johann Pratschke
J. Clin. Med. 2020, 9(6), 1929; https://doi.org/10.3390/jcm9061929 - 19 Jun 2020
Cited by 8 | Viewed by 2593
Abstract
The Model for End-Stage Liver Disease (MELD)-based allocation system was implemented in Germany in 2006 in order to reduce waiting list mortality. The purpose of this study was to evaluate post-transplant results and waiting list mortality since the introduction of MELD-based allocation in [...] Read more.
The Model for End-Stage Liver Disease (MELD)-based allocation system was implemented in Germany in 2006 in order to reduce waiting list mortality. The purpose of this study was to evaluate post-transplant results and waiting list mortality since the introduction of MELD-based allocation in our center and in Germany. Adult liver transplantation at the Charité—Universitätsmedizin Berlin was assessed retrospectively between 2005 and 2012. In addition, open access data from Eurotransplant (ET) and the German Organ Transplantation Foundation (DSO) were evaluated. In our department, 861 liver transplantations were performed from 2005 to 2012. The mean MELD score calculated with the laboratory values last transmitted to ET before organ offer (labMELD) at time of transplantation increased to 20.1 from 15.8 (Pearson’s R = 0.121, p < 0.001, confidence interval (CI) = 0.053–0.187). Simultaneously, the number of transplantations per year decreased from 139 in 2005 to 68 in 2012. In order to overcome this organ shortage the relative number of utilized liver donors in Germany has increased (85% versus 75% in non-German ET countries). Concomitantly, 5-year patient survival decreased from 79.9% in 2005 to 60.3% in 2012 (p = 0.048). At the same time, the ratio of waiting list mortality vs. active-listed patients nearly doubled in Germany (Spearman’s rho = 0.903, p < 0.001, CI = 0.634–0.977). In low-donation areas, MELD-based liver allocation may require reconsideration and inclusion of prognostic outcome factors. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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14 pages, 1889 KiB  
Article
Tryptophan Metabolism via the Kynurenine Pathway: Implications for Graft Optimization during Machine Perfusion
by Anna Zhang, Cailah Carroll, Siavash Raigani, Negin Karimian, Viola Huang, Sonal Nagpal, Irene Beijert, Robert J. Porte, Martin Yarmush, Korkut Uygun and Heidi Yeh
J. Clin. Med. 2020, 9(6), 1864; https://doi.org/10.3390/jcm9061864 - 15 Jun 2020
Cited by 5 | Viewed by 2507
Abstract
Access to liver transplantation continues to be hindered by the severe organ shortage. Extended-criteria donor livers could be used to expand the donor pool but are prone to ischemia-reperfusion injury (IRI) and post-transplant graft dysfunction. Ex situ machine perfusion may be used as [...] Read more.
Access to liver transplantation continues to be hindered by the severe organ shortage. Extended-criteria donor livers could be used to expand the donor pool but are prone to ischemia-reperfusion injury (IRI) and post-transplant graft dysfunction. Ex situ machine perfusion may be used as a platform to rehabilitate discarded or extended-criteria livers prior to transplantation, though there is a lack of data guiding the utilization of different perfusion modalities and therapeutics. Since amino acid derivatives involved in inflammatory and antioxidant pathways are critical in IRI, we analyzed differences in amino acid metabolism in seven discarded non-steatotic human livers during normothermic- (NMP) and subnormothermic-machine perfusion (SNMP) using data from untargeted metabolomic profiling. We found notable differences in tryptophan, histamine, and glutathione metabolism. Greater tryptophan metabolism via the kynurenine pathway during NMP was indicated by significantly higher kynurenine and kynurenate tissue concentrations compared to pre-perfusion levels. Livers undergoing SNMP demonstrated impaired glutathione synthesis indicated by depletion of reduced and oxidized glutathione tissue concentrations. Notably, ATP and energy charge ratios were greater in livers during SNMP compared to NMP. Given these findings, several targeted therapeutic interventions are proposed to mitigate IRI during liver machine perfusion and optimize marginal liver grafts during SNMP and NMP. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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16 pages, 3042 KiB  
Article
Increased Cell-Free DNA Plasma Concentration Following Liver Transplantation Is Linked to Portal Hepatitis and Inferior Survival
by Felix Krenzien, Shadi Katou, Alba Papa, Bruno Sinn, Christian Benzing, Linda Feldbrügge, Can Kamali, Philipp Brunnbauer, Katrin Splith, Ralf Roland Lorenz, Paul Ritschl, Leke Wiering, Robert Öllinger, Wenzel Schöning, Johann Pratschke and Moritz Schmelzle
J. Clin. Med. 2020, 9(5), 1543; https://doi.org/10.3390/jcm9051543 - 20 May 2020
Cited by 10 | Viewed by 3145
Abstract
Donor organ quality is crucial for transplant survival and long-term survival of patients after liver transplantation. Besides bacterial and viral infections, endogenous damage-associated molecular patterns (DAMPs) can stimulate immune responses. Cell-free DNA (cfDNA) is one such DAMP that exhibits highly proinflammatory effects via [...] Read more.
Donor organ quality is crucial for transplant survival and long-term survival of patients after liver transplantation. Besides bacterial and viral infections, endogenous damage-associated molecular patterns (DAMPs) can stimulate immune responses. Cell-free DNA (cfDNA) is one such DAMP that exhibits highly proinflammatory effects via DNA sensors. Herein, we measured cfDNA after liver transplantation and found elevated levels when organs from resuscitated donors were transplanted. High levels of cfDNA were associated with high C-reactive protein, leukocytosis as well as granulocytosis in the recipient. In addition to increased systemic immune responses, portal hepatitis was observed, which was associated with increased interface activity and a higher numbers of infiltrating neutrophils and eosinophils in the graft. In fact, the cfDNA was an independent significant factor in multivariate analysis and increased concentration of cfDNA was associated with inferior 1-year survival. Moreover, cfDNA levels were found to be decreased significantly during the postoperative course when patients underwent continuous veno-venous haemofiltration. In conclusion, patients receiving livers from resuscitated donors were characterised by high postoperative cfDNA levels. Those patients showed pronounced portal hepatitis and systemic inflammatory responses in the short term leading to a high mortality. Further studies are needed to evaluate the clinical relevance of cfDNA clearance by haemoadsorption and haemofiltration in vitro and in vivo. Full article
(This article belongs to the Special Issue Liver Transplantation: Improving Results under Worsening Conditions)
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