Obstacles to implement machine perfusion technology in routine clinical practice of transplantation: Why are we not there yet?

Machine perfusion of solid human organs is an old technique, and the basic principles were presented as early as 1855 by Claude Barnard. More than 50 years ago, the first perfusion system was used in clinical kidney transplantation. Despite the well-known benefits of dynamic organ preservation and significant medical and technical development in the last decades, perfusion devices are still not in routine use. This article describes the various challenges to implement this technology in practice, critically analyzing the role of all involved stakeholders, including clinicians, hospitals, regulatory, and industry, on the background of regional differences worldwide. The clinical need for this technology is discussed first, followed by the current status of research and the impact of costs and regulations. Considering the need for strong collaborations between clinical users, regulatory bodies, and industry, integrated road maps and pathways required to achieve a wider implementation are presented. The role of research development, clear regulatory pathways, and the need for more flexible reimbursement schemes is discussed together with potential solutions to address the most relevant hurdles. This article paints an overall picture of the current liver perfusion landscape and highlights the role of clinical, regulatory, and financial stakeholders worldwide.

Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial.

BACKGROUND AND AIMS: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial. APPROACH AND RESULTS: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Clinical Application of Thromboelastography in Patients With Cirrhosis: A Single Center Experience.

INTRODUCTION: Thromboelastography (TEG) is a functional test of coagulation used to guide transfusions. Despite literature supporting its utility, its use remains limited to select populations. In patients with cirrhosis, conventional coagulation tests are notoriously inaccurate, and TEG may be a better measure of coagulopathy. We aimed to assess the utilization of TEG in patients with cirrhosis to steward blood transfusions in this high-risk group. METHODS: A single-center retrospective chart review of all patients ≥18 y old with a diagnosis of liver cirrhosis who had TEG results documented in the electronic medical record from January 1 to November 1, 2021. RESULTS: There were 277 TEG results on 89 patients with cirrhosis. Overall, 91% of the TEGs performed were associated with a clinical indication for transfusion. However, of the patients who were transfused, abnormal TEG values, including elevated R time and reduced maximum amplitude, did not correspond to transfusion of indicated blood products (fresh frozen plasma and platelets). A reduction in alpha angle showed a statistically significant association with transfusion of cryoprecipitate (P < 0.05). When assessing conventional coagulation tests, abnormal values were not significantly associated with transfusion (P = 0.07). CONCLUSIONS: Despite TEG suggesting that transfusions could be avoided in many cirrhotic patients, patients are still being transfused platelets and fresh frozen plasma in the absence of evidence of coagulopathy on TEG. Our finding suggests the need for education about appropriate utilization of TEG. More research is needed to understand the role of these tests to guide transfusion practices in patients with cirrhosis.

Using organ perfusion to optimize donor livers.

PURPOSE OF REVIEW: The shortage of donor organs has led to the use of marginal extended criteria donor (ECD) livers to increase access to liver transplant. Ex-vivo machine perfusion allows for treatment and assessment of organs during preservation, potentially facilitating safe use of ECD livers at risk for worse clinical outcomes. This article reviews the latest published literature on the application of ex-vivo machine perfusion technologies in liver transplantation. RECENT FINDINGS: Multiple randomized controlled trials on the use of hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) have been published in the past 5 years demonstrating improved graft function and decreased biliary complications after machine perfusion. Novel applications of machine perfusion include pretransplant organ viability testing, expansion to pediatric transplant, and prolonged preservation. SUMMARY: There is now a body of evidence that HMP and NMP treatment improves clinical outcomes in ECD livers. There is a wide horizon for future applications of these preservation techniques to further optimize donor livers and to facilitate more liver transplants for those on the waitlist.

Novel Benchmark Values for Redo Liver Transplantation: Does the Outcome Justify the Effort?

OBJECTIVE: To define benchmark cutoffs for redo liver transplantation (redo-LT). BACKGROUND: In the era of organ shortage, redo-LT is frequently discussed in terms of expected poor outcome and wasteful resources. However, there is a lack of benchmark data to reliably evaluate outcomes after redo-LT. METHODS: We collected data on redo-LT between January 2010 and December 2018 from 22 high-volume transplant centers. Benchmark cases were defined as recipients with model of end stage liver disease (MELD) score ≤25, absence of portal vein thrombosis, no mechanical ventilation at the time of surgery, receiving a graft from a donor after brain death. Also, high-urgent priority and early redo-LT including those for primary nonfunction (PNF) or hepatic artery thrombosis were excluded. Benchmark cutoffs were derived from the 75th percentile of the medians of all benchmark centers. RESULTS: Of 1110 redo-LT, 373 (34%) cases qualified as benchmark cases. Among these cases, the rate of postoperative complications until discharge was 76%, and increased up to 87% at 1-year, respectively. One-year overall survival rate was excellent with 90%. Benchmark cutoffs included Comprehensive Complication Index CCI ® at 1-year of ≤72, and in-hospital and 1-year mortality rates of ≤13% and ≤15%, respectively. In contrast, patients who received a redo-LT for PNF showed worse outcomes with some values dramatically outside the redo-LT benchmarks. CONCLUSION: This study shows that redo-LT achieves good outcome when looking at benchmark scenarios. However, this figure changes in high-risk redo-LT, as for example in PNF. This analysis objectifies for the first-time results and efforts for redo-LT and can serve as a basis for discussion about the use of scarce resources.

Hypothermic machine perfusion for liver graft preservation.

PURPOSE OF REVIEW: Ex-vivo machine perfusion has emerged as a promising alternative to static cold storage (SCS) for preservation of liver grafts over the last decade. This review describes the mechanistic benefits associated with hypothermic machine perfusion (HMP) for preservation of liver grafts and highlights clinical outcomes of liver transplantation using HMP technology. RECENT FINDINGS: Over the last decade, several single-centre studies have shown decreased biliary complications, decreased early allograft dysfunction (EAD) rates and improved patient survival in liver transplant recipients after application of HMP for liver graft preservation. This has led to initiation of prospective, multicentre, randomized controlled trials (RCTs) in both Europe and North America focused on clinical outcomes in liver transplant recipients using HMP-preserved liver grafts. In addition, recent single-centre studies have shown the utility of perfusate biomarker analysis during HMP in predicting EAD after liver transplantation. SUMMARY: HMP technology has potential to increase the available donor liver organ pool for liver transplant recipients and improve clinical outcomes after liver transplantation. Broader clinical application of HMP in resuscitation and preservation of liver grafts is anticipated over the next decade once regulatory, logistical and financial challenges are overcome.

Best practice recommendations for the use of hepatitis C viremic donor organs for hepatitis C virus naïve recipients.

The combination of the transplant organ deficit, the increase in HCV nucleic acid positive donors (HCV NAT+), and the development of direct-acting antiviral agents (DAAs) has resulted in a rapid increase in HCV NAT+ organ transplants into HCV naïve recipients. Early clinical experience with HCV NAT+ donor organs has shown promising outcomes; however, best practices are lacking to guide transplant programs during all phases of patient care. Transplant programs developing protocols for the utilization of HCV NAT+ organs will need a multidisciplinary team to address all aspects of pre-transplant and post-transplant patient care. Reports of fibrosing cholestatic hepatitis in HCV NAT+ organ transplant recipients receiving delayed DAA initiation highlight the need for the transplant community to develop safe and effective protocols. A failure to do so will inevitably lead to the erosion of public trust from cases of missed or inadequately treated donor-derived HCV infections. Herein, we provide best practice guidelines for the utilization of HCV NAT+ organs into HCV-negative recipients based on literature review and expert opinion from the faculty of the ASTS Standards and Quality Committee.

Liver Transplantation for Cholangiocarcinoma: Insights into the Prognosis and the Evolving Indications.

PURPOSE OF REVIEW: Cholangiocarcinoma (CCA) is a rare malignancy of the biliary ducts that can be classified as intrahepatic, perihilar, or distal based on anatomic location. Although surgical resection can be curative, complete excision with negative margins is often difficult to achieve. In patients with unresectable disease, long-term survival is rarely seen with medical therapy alone. A multimodal treatment approach, including liver transplantation (LT) for select patients with unresectable CCA, should be considered. RECENT FINDINGS: While currently only an approved indication for early, liver-limited, perihilar cholangiocarcinoma, promising results have been achieved for LT in localized intrahepatic disease. The absolute indication for transplant for intrahepatic tumors is currently the subject of multiple investigations. Continued advances in neoadjuvant/adjuvant therapy and better understanding of tumor biology may further augment the number of candidates for surgical therapies, with liver transplant acting as a promising tool to improve patient outcomes. Thorough consideration for any expansion in the indication for liver transplant in malignancy is necessary in order to balance patient outcomes with utilization of the scarce donor organ resources.

Clinical Implications of Donor Warm and Cold Ischemia Time in Donor After Circulatory Death Liver Transplantation.

The use of donation after circulatory death (DCD) liver allografts has been constrained by limitations in the duration of donor warm ischemia time (DWIT), donor agonal time (DAT), and cold ischemia time (CIT). The purpose of this study is to assess the impact of longer DWIT, DAT, and CIT on graft survival and other outcomes in DCD liver transplants. The Scientific Registry of Transplant Recipients was queried for adult liver transplants from DCD donors between 2009 and 2015. Donor, recipient, and center variables were included in the analysis. During the study period, 2107 patients underwent liver transplant with DCD allografts. In most patients, DWIT and DAT were <30 minutes. DWIT was <30 minutes in 1804 donors, between 30 and 40 minutes in 248, and >40 minutes in 37. There was no difference in graft survival, duration of posttransplant hospital length of stay, and readmission rate between DCD liver transplants from donors with DWIT <30 minutes and DWIT between 30 and 40 minutes. Similar outcomes were noted for DAT. In the multivariate analysis, DAT and DWIT were not associated with graft loss. The predictors associated with graft loss were donor age, donor sharing, CIT, recipient admission to the intensive care unit, recipient ventilator dependence, Model for End-Stage Liver Disease score, and low-volume transplant centers. Any CIT cutoff >4 hours was associated with increased risk for graft loss. Longer CIT was also associated with a longer posttransplant hospital stay, higher rate of primary nonfunction, and hyperbilirubinemia. In conclusion, slightly longer DAT and DWIT (up to 40 minutes) were not associated with graft loss, longer posttransplant hospitalization, or hospital readmissions, whereas longer CIT was associated with worse outcomes after DCD liver transplants.

Pure Laparoscopic Donor Hepatectomies: Ready for Widespread Adoption?

OBJECTIVE: In order to minimize the impact of donation, fully laparoscopic donor hepatectomy (LDH) is being investigated at a few centers throughout the world. We report here our experience with 51 living donor pure laparoscopic hepatectomies. BACKGROUND: Adoption of minimal access techniques to living donor liver transplantation (LDLT) has been slowed by concerns about donor safety and the quality of the grafts. METHODS: Of 344 donor hepatectomies (DHs) for living donor liver transplantation (LDLT) since 1998, 51 pure LDH have been performed since 2009. We report here our experience with 51 living donor pure laparoscopic hepatectomy (LH), based on prospectively collected data. There were 31 left lateral sectionectomy and 20 full lobectomies LH. We matched full lobe LH to open DH prior to introduction of LH. RESULTS: LH increased from 21% of all DH in first 5 years of performing LH to 45% of DH in the most recent 3 years. Laparoscopic donors were more likely female, had lower body mass index, smaller total livers, and smaller allografts but longer operating room times. In the total LD experience, total 5 donors were converted to open surgery (10%), 2 donors required transfusion (4%), and there was 2 donor bile leaks (4%). Recipient patient and graft 1-year survival was 98% and 94%. CONCLUSIONS: Our experience indicates that LDH for LDLT can be safely used with appropriate attention to learning curve and progression from left lateral sectionectomy to right hepatectomy.

Hypothermic machine perfusion in liver transplantation.

A finite supply of donor organs has led many transplant centers to accept marginal liver allografts with increasing frequency. These allografts may be at higher risk of primary nonfunction, early allograft dysfunction, and other recipient complications following liver transplantation. Machine perfusion preservation is an emerging technology that limits ischemia/reperfusion injury associated with preservation and may lead to improved outcomes following transplantation. Increased used of machine perfusion in liver preservation may permit an expansion of the donor pool. In this review, we examine the major clinical experience of hypothermic machine perfusion in human liver transplantation.Liver Transplantation 24 276-281 2018 AASLD.

Roux-en-Y enterolith leading to obstruction and ischemic necrosis after pediatric orthotopic liver transplantation.

Biliary complications are a common cause of morbidity after liver transplantation, with biliary stone formation being a known occurrence generally upstream of a stricture. A 12-year-old boy, who underwent an orthotopic liver transplantation at 11 months of age for biliary atresia, presented acutely with fever and abdominal pain. Cross-sectional imaging revealed Roux-en-Y limb dilatation and thickening. He was explored and was found to have an ischemic Roux limb secondary to an obstructing enterolith. A segmental bowel resection and revision of his hepaticojejunostomy was performed. While rare, biliary enteroliths may present as either a bowel obstruction or cholangitis and should be considered in the differential diagnosis of a patient following biliary reconstruction. Additionally, anatomic etiologies should be considered and potentially surgically corrected.

Recurrence After Liver Transplantation for Hepatocellular Carcinoma: A New MORAL to the Story.

OBJECTIVE: We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC). BACKGROUND: The Milan criteria are used to allocate livers to patients with HCC requiring liver transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk. METHODS: Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012. RESULTS: A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence. CONCLUSIONS: The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.

Expanding the Margins: High Volume Utilization of Marginal Liver Grafts Among >2000 Liver Transplants at a Single Institution.

OBJECTIVE: Marginal livers (ML) have been used to expand the donor pool. National utilization of MLs is variable, and in some centers, they are never used. We examined the outcomes of MLs in the largest single center series of MLs used to date and compared outcomes to standard (SL) and living donor (LD) livers. METHODS: Analysis of a prospectively maintained database of all liver transplants performed at our institution from 1998 to 2016. ML grafts were defined as livers from donors >70, livers discarded regionally and shared nationally, livers with cold ischemic time >12 hours, livers from hepatitis C virus positive donors, livers from donation after cardiac death donors, livers with >30% steatosis, and livers split between 2 recipients. RESULTS: A total of 2050 liver transplant recipients were studied, of these 960 (46.8%) received ML grafts. ML recipients were more likely to have lower MELDs and have hepatocellular carcinoma. Most MLs used were from organs turned down regionally and shared nationally (69%) or donors >70 (22%). Survival of patients receiving MLs did not significantly differ from patients receiving SL grafts (P = 0.08). ML and SL recipients had worse survival than LDs (P < 0.01). Despite nearly half of our recipients receiving MLs, overall survival was significantly better than national survival over the same time period (P = 0.04). Waitlist mortality was significantly lower in our series compared with national results (19% vs 24.0%, P < 0.0001). CONCLUSIONS: Outcomes of recipients of ML grafts are comparable to SL transplants. Despite liberal use of these grafts, we have been able to successfully reduce waitlist mortality while exceeding national post-transplant survival metrics.

Leaning to the Left: Increasing the Donor Pool by Using the Left Lobe, Outcomes of the Largest Single-center North American Experience of Left Lobe Adult-to-adult Living Donor Liver Transplantation.

OBJECTIVE: Centers offering adult living donor liver transplantation (LDLT) mostly use right lobe grafts due to fears of providing recipients with insufficient hepatic volume, and the technical challenges presented by using left lobe grafts (LLGs). LLGs therefore represent approximately 5% of adult LDLTs performed in the United States. Here we present the largest North American experience with the use of LLG for adult LDLT. METHODS: Analysis of a prospectively maintained database of LDLTs performed from 1998 to 2015 at our institution. RESULTS: A total of 214 adult LDLTs were studied. Fifty-six patients (26%) received LLG. LLG recipients were more likely to be women, had significantly lower BMI, graft weight, and graft-weight-recipient-weight ratios (P < 0.05 for all). There were no significant differences in vascular or biliary complication between the groups. No significant differences existed in patient or graft survival at 1, 3, and 5 years (P = 0.747 and P = 0.398 respectively). Despite significantly increased risk of small-for-size syndrome in LLG, there was no increased risk of retransplant within 90-days or perioperative mortality in LLG recipients (P = 0.308 and P = 0.932 respectively). Graft type did not predict patient or graft outcomes on regression analysis (P = 0.857 and 0.399 respectively). CONCLUSIONS: Despite smaller graft sizes, outcomes of adult LDLT using LLG are comparable to right lobe grafts transplants. Left lobes can provide an important resource in an era of severe organ shortages, and these data should serve to allay the concerns of the transplant community in the United States.