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.

Racial Disparities in Liver Transplantation for Hepatocellular Carcinoma: Analysis of the National Inpatient Sample From 2007 to 2014.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a deadly disease, with patients' best hope for a cure being liver transplantation; however, access to health care resources, such as donor organs, between ethnic groups has historically been unbalanced. Ensuring equitable access to donor livers is crucial to minimize disparities in HCC outcomes. As a result, we sought to better elucidate the differences in transplantation rates among various ethnic groups. MATERIALS AND METHODS: The National Inpatient Sample (NIS) was utilized to evaluate for disparities in liver transplantation in patients whose primary or secondary diagnosis was recorded as HCC or hepatoma. The study included admissions between 2007 and 2014 to centers with at least 1 documented liver transplant. RESULTS: A total of 7244 transplants were performed over 70,406 weighted admissions. Black race was associated with lower transplantation rates, with an adjusted odds ratio of 0.46 (95% confidence interval: 0.42-0.51, P <0.01) when accounting for a number of possible confounders including socioeconomic and geographic factors. CONCLUSIONS: Our study observed decreased rates of liver transplant in blacks compared with whites for HCC. Furthermore, improved economic status and private insurance had a significantly higher odds ratio for transplantation. Hospital-level studies are needed to clarify confounding factors not apparent in large administrative datasets and help better investigate factors that lead to less optimal transplant rates among blacks. Interventions may include more optimal screening policies and procedures, improved interdisciplinary management, and earlier referrals.

Addressing the Burden and Management Strategies for Disparities and Inequities Among Liver Transplant Professionals: The ILTS Experience.

Medical professional environments are becoming increasingly multicultural, international, and diverse in terms of its specialists. Many transplant professionals face challenges related to gender, sexual orientation or racial background in their work environment or experience inequities involving access to leadership positions, professional promotion, and compensation. These circumstances not infrequently become a major source of work-related stress and burnout for these disadvantaged, under-represented transplant professionals. In this review, we aim to 1) discuss the current perceptions regarding disparities among liver transplant providers 2) outline the burden and impact of disparities and inequities in the liver transplant workforce 3) propose potential solutions and role of professional societies to mitigate inequities and maximize inclusion within the transplant community.

Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.

Equitable Access to Liver Transplant: Bridging the Gaps in the Social Determinants of Health.

The COVID-19 pandemic and social justice movement have highlighted the impact of social determinants of health (SDOH) and structural racism in the United States on both access to care and patient outcomes. With the evaluation for liver transplantation being a highly subjective process, there are multiple ways for SDOH to place vulnerable patients at a disadvantage. This policy corner focuses on three different methods to reverse the deleterious effects of SDOH-identify and reduce implicit bias, expand and optimize telemedicine, and improve community outreach.

Gender and Racial Disparity Among Liver Transplantation Professionals: Report of a Global Survey.

Equality, diversity, and inclusion (EDI) are fundamental principles. Little is known about the pattern of practice and perceptions of EDI among liver transplant (LT) providers. International Liver Transplant Society (ILTS) EDI Committee survey around topics related to discrimination, mentorship, and gender. Answers were collected and analyzed anonymously. Worldwide female leadership was also queried via publicly available data. The survey was e-mailed to 1312 ILTS members, 199 responses (40.7% female) were collected from 38 countries (15.2% response rate). Almost half were surgeons (45.7%), 27.6% hepatologists and 26.6% anesthetists. Among 856 LT programs worldwide, 8.2% of leadership positions were held by females, and 22% of division chiefs were female across all specialties. Sixty-eight of respondents (34.7%) reported some form of discrimination during training or at their current position, presumably related to gender/sexual orientation (20.6%), race/country of origin (25.2%) and others (7.1%). Less than half (43.7%) received mentorship when discrimination occurred. An association between female responses and discrimination, differences in compensation, and job promotion was observed. This survey reveals alarmingly high rate of experience with racial and gender disparity, lack of mentorship, and very low rates of female leadership in the LT field and calls to action to equity and inclusion.

Poorly differentiated hepatocellular carcinoma: resection is equivalent to transplantation in patients with low liver fibrosis.

BACKGROUND: Organ allocation criteria for liver transplantation focus on tumor size and multifocality while tumor differentiation and existing liver damage are omitted. This study analyzes the impact of hepatocellular carcinoma (HCC) grade and liver fibrosis comparing resection (SX) to transplantation (LT). METHODS: The National Cancer Database was queried between 2004 and 2016 for solitary HCC meeting Milan criteria undergoing SX vs LT. Two groups were created: low fibrosis (LF) vs high fibrosis (HF) and stratified by grade. Cox multivariable regression models, Kaplan-Meier survival analyses and log-rank tests were performed. RESULTS: 1515 patients were identified; 780 had LT and 735 had SX. Median overall survival (mOS) was 39.7 months; LT mOS was 47.9 months vs SX mOS of 34.9 months (P < .001). Multivariate analysis revealed SX, no chemotherapy, longer hospital stays, and age to be associated with worse survival. However, while transplantation conferred survival benefit for well-moderately differentiated tumors, SX vs LT did not impact survival for poorly differentiated HCC in LF patients, independent of tumor size. DISCUSSION: HCC differentiation and liver fibrosis, but not size, synergistically determine efficacy of SX vs LT. Therefore, current HCC transplantation criteria should incorporate tumor grade or liver fibrosis for optimal organ allocation.

Clinical and biomarker assessment of frailty in liver transplantation.

PURPOSE OF REVIEW: Liver cirrhosis results in progressive decline, or frailty, which leads to poor outcomes and decreased survival. Multiple biomarkers and clinical assessment tools for quantifying frailty in liver transplant candidates exist, but a universal scoring protocol is lacking. Criteria vary between studies and correlation with patient outcome is not always clear. This review aims to summarize the pertinent biomarkers and assessment tools of frailty in cirrhosis. RECENT FINDINGS: As cirrhosis progresses, the resultant 'frailty' is an inseparable independent predictor of pre and posttransplant mortality. Pro-inflammatory, neuroendocrine, and adipokine factors are dysregulated - leading to paradoxical anorexia and downregulation of orexigenic signals. The resulting catabolic utilization of amino and fatty acids leads to progressive malnutrition and sarcopenia. Both functional and imaging criteria define sarcopenia in cirrhotic patients, and degree of debilitation correlates with mortality. Liver-disease-specific frailty biomarkers and scoring tools are optimal to assess physical dysfunction in cirrhotics to promote early diagnosis and intervention. SUMMARY: Liver cirrhosis and resulting frailty are progressive and portend a poor patient prognosis. A comprehensive, validated algorithm for detecting and quantifying frailty specific to liver disease would allow for standardization and facile application in the clinical setting. Early diagnosis is key for timely intervention and improved patient outcomes.

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.

Factors predicting kidney delayed graft function among recipients of simultaneous liver-kidney transplantation: A single-center experience.

BACKGROUND: Kidney delayed graft function (kDGF) remains a challenging problem following simultaneous liver and kidney transplantation (SLKT) with a reported incidence up to 40%. Given the scarcity of renal allografts, it is crucial to minimize the development of kDGF among SLKT recipients to improve patient and graft outcomes. We sought to assess the role of preoperative recipient and donor/graft factors on developing kDGF among recipients of SLKT. METHODS: A retrospective review of 194 patients who received SLKT in the period from January 2004 to March 2017 in a single center was performed to assess the effect of preoperative factors on the development of kDGF. RESULTS: Kidney delayed graft function was observed in 95 patients (49%). Multivariate analysis revealed that donor history of hypertension, cold static preservation of kidney grafts [versus using hypothermic pulsatile machine perfusion (HPMP)], donor final creatinine, physiologic MELD, and duration of delay of kidney transplantation after liver transplantation were significant independent predictors for kDGF. kDGF is associated with worse graft function and patient and graft survival. CONCLUSIONS: Kidney delayed graft function has detrimental effects on graft function and graft survival. Understanding the risks and combining careful perioperative patient management, proper recipient selection and donor matching, and graft preservation using HPMP would decrease kDGF among SLKT recipients.

Propensity-Matched Analysis of Patients with Mixed Hepatocellular-Cholangiocarcinoma and Hepatocellular Carcinoma Undergoing Liver Transplantation.

Mixed hepatocellular-cholangiocarcinomas (HCC-CCAs) are rare tumors with both hepatocellular and biliary differentiation. While liver transplantation (LT) is the gold standard treatment for patients with unresectable hepatocellular carcinoma (HCC), it is contraindicated in known HCC-CCA because of concerns of poor prognosis. We sought to compare posttransplant oncologic outcomes for HCC-CCA and a matched cohort of HCC LT recipients. A retrospective, single-center analysis (1984-2015) identified 12 patients with mixed HCC-CCA who were matched 1:3 to patients with HCC on both pretransplant (radiologic diameter and alpha-fetoprotein) and explant (pathologic diameter, grade/differentiation, and vascular invasion) tumor characteristics. Compared with HCC patients matched on pretransplant characteristics (n = 36), HCC-CCA had higher explant tumor grade, more poorly differentiated tumors, but similar T stage and vascular invasion. HCC-CCA recipients trended toward inferior recurrence-free survival at 5 years (28% versus 61%; P = 0.12) and greater recurrence (HCC-CCA: 50%, median time to recurrence 297 days versus HCC: 22%, median time to recurrence 347 days; P = 0.07). However, when matched to a separate HCC cohort with similar explant pathology, HCC-CCA had similar 5-year recurrence-free survival (42% versus 44%; P = 0.45) and posttransplant recurrence (50% versus 27%; P = 0.13). All 6 HCC-CCA recurrences occurred with poorly differentiated tumors (median survival 21.3 months), without a single recurrence in 5 of the 12 HCC-CCA patients with well-moderately differentiated tumors (median survival 60.2 months). Mixed HCC-CCA tumors are more likely poorly differentiated tumors compared with HCC with similar pretransplant characteristics. However, compared with HCC with similar pathologic characteristics, they display similar recurrence-free survival and are not inherently more aggressive tumors. Low-grade, well-moderately differentiated HCC-CCAs have excellent survival with a low risk for post-LT recurrence, and they should not be excluded from LT. Improved pretransplant identification of pathologic characteristics in HCC-CCA may allow for successful utilization of LT in this subset of patients.

Conquering combined thoracic organ and liver transplantation: indications and outcomes for heart-liver and lung-liver transplantation.

PURPOSE OF REVIEW: Combined thoracic organ and liver transplantation has been shown to be a viable treatment option for patients with end-stage disease lung or heart and disease. There are increasing number of cases reported in the literature, as the number of institutions utilizing this strategy is growing. Herein, we review the current literature of combined thoracic and liver transplantation. RECENT FINDINGS: A larger number of combined heart or lung and liver transplants (CHLT and CLLT) are being performed. A recent literature search showed approximately 231 CHLT and 89 CLLT and being described. One-year patient survival ranged from 71 to 80% for CLLT and 80-93% for CHLT, respectively. Indications for combined transplant and disease-specific outcomes are still being evaluated. Additionally, salvage modalities such as extracorporeal membrane oxygenation and ex-vivo lung perfusion are also being described. SUMMARY: Combined thoracic and liver transplant continues to be a viable treatment option for patients with end-stage disease that would likely not survive single transplant alone. Salvage modalities, such as extracorporeal membrane oxygenation and ex-vivo lung perfusion, may help in extending candidacy for this combined transplant. Outcomes, to date, are similar to results observed for solitary thoracic organ recipients, justifying CHLT and CLLT as a viable option for these patients. Continued identification of outcomes is needed to justify allocation of dual organs to a single recipient.

Predicting Mortality in Patients Developing Recurrent Hepatocellular Carcinoma After Liver Transplantation: Impact of Treatment Modality and Recurrence Characteristics.

OBJECTIVE: To evaluate predictors of mortality and impact of treatment in patients developing recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT). SUMMARY OF BACKGROUND DATA: Despite well-described clinicopathologic predictors of posttransplant HCC recurrence, data on prognosis following recurrence are scarce. METHODS: Multivariate predictors of mortality following HCC recurrence were identified to develop a risk score model to stratify prognostic subgroups among 106 patients developing posttransplant recurrence from 1984 to 2014, including analysis of recurrence treatment modality on survival. RESULTS: Of 857 patients undergoing LT, 106 (12.4%) developed posttransplant HCC recurrence (median 15.8 months following LT) with a median post-recurrence survival of 10.6 months. Patients receiving surgical therapy (n = 25) had a median survival of 27.8 months, significantly superior to patients receiving nonsurgical therapy (10.6 months) and best supportive care (3.7 months, P < 0.001). Multivariate predictors of mortality following recurrence included model for end-stage liver disease at LT >23, time to recurrence, >3 recurrent nodules, maximum recurrence size, bone recurrence, alphafetoprotein at recurrence, donor serum sodium, and pretransplant recipient neutrophil-lymphocyte ratio. A risk score model based on multivariate predictors accurately stratified recurrent HCC patients into prognostic subgroups, with low-risk patients (<10 points) demonstrating excellent median survival of 70.6 months, significantly superior to the medium-risk (12.2 months, 10-16 points) and high-risk (3.4 months, >16 points) groups (C-statistic 0.75, P < 0.001). CONCLUSIONS: In the largest single-center report of recurrent HCC following LT, surgical treatment in well-selected patients is associated with significantly improved survival and should be pursued. A risk score model accurately stratifies prognostic subgroups, and may help guide treatment strategies.

Avoiding Futility in Simultaneous Liver-kidney Transplantation: Analysis of 331 Consecutive Patients Listed for Dual Organ Replacement.

OBJECTIVE: We sought to evaluate outcomes and predictors of renal allograft futility (RAF-patient death or need for renal replacement therapy at 3 months) after simultaneous liver-kidney transplantation (SLKT). BACKGROUND: Model for End-Stage Liver Disease (MELD) prioritization of liver recipients with renal dysfunction has significantly increased utilization of SLKT. Data on renal outcomes after SLKT in the highest MELD recipients are scarce, as are accurate predictors of recovery of native kidney function. Without well-established listing guidelines, SLKT potentially wastes renal allografts in both high-acuity liver recipients at risk for early mortality and recipients who may regain native kidney function. METHODS: A retrospective single-center multivariate regression analysis was performed for adult patients undergoing SLKT (January 2004 to August 2014) to identify predictors of RAF. RESULTS: Of 331 patients dual-listed for SLKT, 171 (52%) expired awaiting transplant, 145 (44%) underwent SLKT, and 15 (5%) underwent liver transplantation alone. After SLKT, 39% experienced delayed graft function and 20.7% had RAF. Compared with patients without RAF, RAF recipients had greater MELD scores, length of hospitalization, intraoperative base deficit, incidence of female donors, kidney and liver donor risk indices, kidney cold ischemia, and inferior overall survival. Multivariate predictors of RAF included pretransplant dialysis duration, kidney cold ischemia, kidney donor risk index, and recipient hyperlipidemia. CONCLUSIONS: With 20% short-term loss of transplanted kidneys after SLKT, our data strongly suggest that renal transplantation should be deferred in liver recipients at high risk for RAF. Consideration for a kidney allocation variance to allow for delayed renal transplantation after liver transplantation may prevent loss of scarce renal allografts.

BK virus as a mediator of graft dysfunction following kidney transplantation.

PURPOSE OF REVIEW: BK virus is a significant risk factor for kidney allograft dysfunction and loss among renal transplant recipients. Currently, there is no proven effective treatment except for the reduction of immunosuppression. In this review, we discuss diagnostic challenges and current treatment options for BK in kidney transplant recipients. RECENT FINDINGS: Antiviral and antibiotic therapies have been employed for BK viraemia with variable efficacy. In addition, novel therapeutic regimens such as adoptive transfer of targeted T cells have been described as possible treatment options for recipients with BK nephropathy. BK can also be seen in the native kidneys of pancreas, heart, lung and liver transplant recipients, suggesting that BK screening measures should be employed to other solid organ transplant recipients. SUMMARY: Early screening for BK combined with reduction of immunosuppression remains the mainstay of treatment for BK viraemia. New therapeutic advances demonstrate promise in vitro; however, the in-vivo efficacy will be demonstrated by future studies.