Continuous Risk Score Predicts Waitlist and Post-transplant Outcomes in Hepatocellular Carcinoma Despite Exception Changes.

BACKGROUND & AIMS: Continuous risk-stratification of candidates and urgency-based prioritization have been utilized for liver transplantation (LT) in patients with non-hepatocellular carcinoma (HCC) in the United States. Instead, for patients with HCC, a dichotomous criterion with exception points is still used. This study evaluated the utility of the hazard associated with LT for HCC (HALT-HCC), an oncological continuous risk score, to stratify waitlist dropout and post-LT outcomes. METHODS: A competing risk model was developed and validated using the UNOS database (2012-2021) through multiple policy changes. The primary outcome was to assess the discrimination ability of waitlist dropouts and LT outcomes. The study focused on the HALT-HCC score, compared with other HCC risk scores. RESULTS: Among 23,858 candidates, 14,646 (59.9%) underwent LT and 5196 (21.8%) dropped out of the waitlist. Higher HALT-HCC scores correlated with increased dropout incidence and lower predicted 5-year overall survival after LT. HALT-HCC demonstrated the highest area under the curve (AUC) values for predicting dropout at various intervals post-listing (0.68 at 6 months, 0.66 at 1 year), with excellent calibration (R2 = 0.95 at 6 months, 0.88 at 1 year). Its accuracy remained stable across policy periods and locoregional therapy applications. CONCLUSIONS: This study highlights the predictive capability of the continuous oncological risk score to forecast waitlist dropout and post-LT outcomes in patients with HCC, independent of policy changes. The study advocates integrating continuous scoring systems like HALT-HCC in liver allocation decisions, balancing urgency, organ utility, and survival benefit.

Revising model for end-stage liver disease from calendar-time cross-sections with correction for selection bias.

BACKGROUND: Eurotransplant liver transplant candidates are prioritized by Model for End-stage Liver Disease (MELD), a 90-day waitlist survival risk score based on the INR, creatinine and bilirubin. Several studies revised the original MELD score, UNOS-MELD, with transplant candidate data by modelling 90-day waitlist mortality from waitlist registration, censoring patients at delisting or transplantation. This approach ignores biomarkers reported after registration, and ignores informative censoring by transplantation and delisting. METHODS: We study how MELD revision is affected by revision from calendar-time cross-sections and correction for informative censoring with inverse probability censoring weighting (IPCW). For this, we revised UNOS-MELD on patients with chronic liver cirrhosis on the Eurotransplant waitlist between 2007 and 2019 (n = 13,274) with Cox models with as endpoints 90-day survival (a) from registration and (b) from weekly drawn calendar-time cross-sections. We refer to the revised score from cross-section with IPCW as DynReMELD, and compare DynReMELD to UNOS-MELD and ReMELD, a prior revision of UNOS-MELD for Eurotransplant, in geographical validation. RESULTS: Revising MELD from calendar-time cross-sections leads to significantly different MELD coefficients. IPCW increases estimates of absolute 90-day waitlist mortality risks by approximately 10 percentage points. DynReMELD has improved discrimination over UNOS-MELD (delta c-index: 0.0040, p < 0.001) and ReMELD (delta c-index: 0.0015, p < 0.01), with differences comparable in magnitude to the addition of an extra biomarker to MELD (delta c-index: ± 0.0030). CONCLUSION: Correcting for selection bias by transplantation/delisting does not improve discrimination of revised MELD scores, but substantially increases estimated absolute 90-day mortality risks. Revision from cross-section uses waitlist data more efficiently, and improves discrimination compared to revision of MELD exclusively based on information available at listing.

Dynamic impact of liver allocation policy change on donor utilization.

Liver allocation policy was changed to reduce variance in median MELD scores at transplant (MMaT) in February 2020. "Acuity circles" replaced local allocation. Understanding the impact of policy change on donor utilization is important. Ideal (I), standard (S), and non-ideal (NI) donors were defined. NI donors include older, higher BMI donors with elevated transaminases or bilirubin, history of hepatitis B or C, and all DCD donors. Utilization of I, S, and NI donors was established before and after allocation change and compared between low MELD (LM) centers (MMaT ≤ 28 before allocation change) and high MELD (HM) centers (MMaT > 28). Following reallocation, transplant volume increased nationally (67 transplants/center/year pre, 74 post, p .0006) and increased for both HM and LM centers. LM centers significantly increased use of NI donors and HM centers significantly increased use of I and S donors. Centers further stratify based on donor utilization phenotype. A subset of centers increased transplant volume despite rising MMaT by broadening organ acceptance criteria, increasing use of all donor types including DCD donors (98% increase), increasing living donation, and transplanting more frequently for alcohol associated liver disease. Variance in donor utilization can undermine intended effects of allocation policy change.

The trials and tribulations of liver allocation.

Allocation policies are necessary to ensure a fair distribution of a scarce resource. The goal of any liver transplant allocation policy is to achieve the best possible outcomes for the waiting list population, irrespective of the indication for transplant, whilst maximizing organ utilization. Organ allocation for liver transplantation has evolved from simple centre-based approaches driven by local issues, to complex, evidence-based algorithm prioritizing according to need. Despite the rapid evolution of allocation policies, there remain a number of challenges and new approaches are required to ensure transparency and equity on the decision-making process and the best possible outcomes for patients on the waiting list. New ways of modelling, together with novel outcome criteria, will be required to enable a dynamic adaptability of the allocation policies to the ever changing demographics of the donor population and the changing landscape of indications for transplantation.

Waiting list outcome of Peld/Meld exceptions: A single-center experience in Argentina.

As PELD/MELD-based allocation policy was adopted in Argentina in 2005, a system of exception points has been in place in order to award increased waitlist priority to those patients whose severity of illness is not captured by the PELD/MELD score. We aimed to investigate the WL outcome of patients with granted PELD/MELD exceptions. A retrospective cohort study was conducted in children under 18 years old. WL outcomes were evaluated using univariable analysis. From 07/2005 to 01/2014, 408 children were listed for LT. There were 304 classified by calculated PELD/MELD. During this time, 85 (30%) PELD/MELD exceptions were granted. In this cohort, 89.4% (76 of 85) were transplanted and 7.1% (6 of 85) died while on the WL. The remaining 3 pts (3.5%) were removed from the WL due to other causes. We compared the impact of PELD/MELD exceptions in those 85 patients to outcomes in 87 non-exception patients with PELD/MELD ≥19 points. Patients with the exception had significantly better access to WL and lower WL mortality. Our data suggest that children listed by PELD/MELD exceptions had an advantage compared to children with CLD with equivalent PELD/MELD listing priorities.

Inequity in organ allocation for patients awaiting liver transplantation: Rationale for uncapping the model for end-stage liver disease.

BACKGROUND & AIM: The goal of organ allocation is to distribute a scarce resource equitably to the sickest patients. In the United States, the Model for End-stage Liver Disease (MELD) is used to allocate livers for transplantation. Patients with greater MELD scores are at greater risk of death on the waitlist and are prioritized for liver transplant (LT). The MELD is capped at 40 however, and patients with calculated MELD scores >40 are not prioritized despite increased mortality. We aimed to evaluate waitlist and post-transplant survival stratified by MELD to determine outcomes in patients with MELD >40. METHODS: Using United Network for Organ Sharing data, we identified patients listed for LT from February 2002 through to December 2012. Waitlist candidates with MELD ⩾40 were followed for 30days or until the earliest occurrence of death or transplant. RESULTS: Of 65,776 waitlisted patients, 3.3% had MELD ⩾40 at registration, and an additional 7.3% had MELD scores increase to ⩾40 after waitlist registration. A total of 30,369 (46.2%) underwent LT, of which 2,615 (8.6%) had MELD ⩾40 at transplant. Compared to MELD 40, the hazard ratio of death within 30days of registration was 1.4 (95% CI 1.2-1.6) for patients with MELD 41-44, 2.6 (95% CI 2.1-3.1) for MELD 45-49, and 5.0 (95% CI 4.1-6.1) for MELD ⩾50. There was no difference in 1- and 3-year survival for patients transplanted with MELD >40 compared to MELD=40. A survival benefit associated with LT was seen as MELD increased above 40. CONCLUSIONS: Patients with MELD >40 have significantly greater waitlist mortality but comparable post-transplant outcomes to patients with MELD=40 and, therefore, should be given priority for LT. Uncapping the MELD will allow more equitable organ distribution aligned with the principle of prioritizing patients most in need. Lay summary: In the United States (US), organs for liver transplantation are allocated by an objective scoring system called the Model for End-stage Liver Disease (MELD), which aims to prioritize the sickest patients for transplant. The greater the MELD score, the greater the mortality without liver transplant. The MELD score, however, is artificially capped at 40 and thus actually disadvantages the sickest patients with end-stage liver disease. Analysis of the data advocates uncapping the MELD score to appropriately prioritize the patients most in need of a liver transplant.

Outcomes in liver transplantation: does sex matter?

A growing literature has highlighted important differences in transplant-related outcomes between men and women. In the United States there are fewer women than men on the liver transplant waitlist and women are two times less likely to receive a deceased or living-related liver transplant. Sex-based differences exist not only in waitlist but also in post-transplant outcomes, particularly in some specific liver diseases, such as hepatitis C. In the era of individualized medicine, recognition of these differences in the approach to pre and post-liver transplant care may impact short and long-term outcomes.

Addressing geographic disparities in liver transplantation through redistricting.

Severe geographic disparities exist in liver transplantation; for patients with comparable disease severity, 90-day transplant rates range from 18% to 86% and death rates range from 14% to 82% across donation service areas (DSAs). Broader sharing has been proposed to resolve geographic inequity; however, we hypothesized that the efficacy of broader sharing depends on the geographic partitions used. To determine the potential impact of redistricting on geographic disparity in disease severity at transplantation, we combined existing DSAs into novel regions using mathematical redistricting optimization. Optimized maps and current maps were evaluated using the Liver Simulated Allocation Model. Primary analysis was based on 6700 deceased donors, 28 063 liver transplant candidates, and 242 727 Model of End-Stage Liver Disease (MELD) changes in 2010. Fully regional sharing within the current regional map would paradoxically worsen geographic disparity (variance in MELD at transplantation increases from 11.2 to 13.5, p = 0.021), although it would decrease waitlist deaths (from 1368 to 1329, p = 0.002). In contrast, regional sharing within an optimized map would significantly reduce geographic disparity (to 7.0, p = 0.002) while achieving a larger decrease in waitlist deaths (to 1307, p = 0.002). Redistricting optimization, but not broader sharing alone, would reduce geographic disparity in allocation of livers for transplant across the United States.

The impact of perceived donor liver quality on post-transplant outcome.

BACKGROUND: We analysed the impact of perceived liver donor quality on transplant recipient outcomes. METHODS: this prospective cohort study included all deceased liver donors during 2008-2018 in the Swiss Transplant Cohort Study. Perceived low-quality liver donors were defined when refused for ≥5 top listed recipients or for all recipients in at least one centre before being transplanted. The effect of liver donor quality on relisting or recipient death at 1 week and 1 year after transplantation was analysed using Kaplan-Meier and Cox proportional hazard models. A 1:3 matching was also performed using a recipient score. RESULTS: Of 973 liver donors, 187 (19.2%) had perceived poor-quality. Males, obesity, donation after circulatory death and alanine aminotransferase values were significantly associated with perceived poor-quality, with no significant effect of the perceived quality on re-listing or death within the first week and first year post-transplant [(aHR) = 1.45, 95% CI: (0.6, 3.5), P = 0.41 and aHR = 1.52 (95% CI 0.98-2.35), P = 0.06], adjusting by recipient age and gender, obesity, diabetes, prior liver transplantation and model for end-stage liver disease (MELD) score. At 1 year, prior liver transplantation and higher MELD score associated with higher risk of re-listing or death. CONCLUSION: Comparable post-transplant outcomes with different perceived quality liver donors stresses the need to improve donor selection in liver transplantation.

MELD-Na Alterations on the Liver Transplant Waiting List and Their Impact on Listing Outcome.

BACKGROUND: Dynamic MELD deterioration (Delta MELD) during waiting time was shown to have significant impact on post-transplant survival. The aim of this study was to analyze the impact of MELD-Na score alterations on waiting list outcomes in liver transplant candidates. METHOD: 36,806 patients listed at UNOS for liver transplantation in 2011-2015 were analyzed according to their delisting reasons. Several different MELD-Na alterations during waiting time were analyzed (e.g., maximal change, last change before delisting/transplantation). Outcome estimates were calculated according to MELD-Na scores at listing and Delta MELD. RESULTS: Patients who died while on the waiting list showed a significantly higher deterioration in MELD-Na during the waiting time (6.8 ± 8.4 points) than stable patients who remained actively listed (-0.1 ± 5.2 points; p < 0.01). Patients who were considered too healthy for transplantation improved by more than 3 points on average during the waiting time. The mean peak MELD-Na alteration during the waiting time was 10.0 ± 7.6 for patients who died on the waiting list, compared to 6.6 ± 6.1 in the group of patients who finally underwent transplantation. CONCLUSIONS: Deterioration of MELD-Na during waiting time and maximal MELD-Na deterioration have a significant negative impact on the liver transplant waiting list outcome.

National Liver Allocation Policy-Consensus Document by the Liver Transplantation Society of India for a Nationally Uniform System of Allocation of Deceased Donor Liver Grafts.

Background: Deceased donor liver transplantation (DDLT) is increasing in India and now constitutes nearly one-third of all liver transplantation procedures performed in the country. There is currently no uniform national system of allocation of deceased donor livers. Methods: A national task force consisting of 19 clinicians involved in liver transplantation from across the country was constituted under the aegis of the Liver Transplantation Society of India to develop a consensus document addressing the above issues using a modified Delphi process of consensus development. Results: The National Liver Allocation Policy consensus document includes 46 statements covering all aspects of DDLT, including minimum listing criteria, listing for acute liver failure, DDLT wait-list management, system of prioritisation based on clinical urgency for adults and children, guidelines for allocation of paediatric organs and allocation priorities for liver grafts recovered from public sector hospitals. Conclusion: This document is the first step in the setting up of a nationally consistent policy of deceased donor liver allocation.

Utilization of a SARS-CoV-2-positive donor for liver transplantation.

Liver transplantation rates have been negatively affected by the pandemic caused by coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current practice in the liver transplant community is to avoid utilizing SARS-CoV-2-positive donors for liver transplantation unless there is a compelling reason such as recipient illness severity. In this case, we report the use of a donor who had a positive exposure to and symptom history for COVID-19 and tested positive for SARS-CoV-2 on admission for a liver transplant recipient with primary sclerosing cholangitis and a Model of End-Stage Liver Disease score of 23 with no known COVID-19 exposures. We focus on the decision to accept this particular organ, as well as the discussion with the recipient about the unknowns of disease transmission and risk associated with this donor. The current case argues that transplant programs should begin to consider low-risk donors with positive SARS-CoV-2 testing for recipients who have the potential to benefit from liver transplantation, which may not only be those with the most severe illness.

Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future.

Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation and has been the treatment of choice due to the oncologic benefit for patients with advanced chronic liver disease (AdvCLD) and small tumors for the last 25 years. For HCC patients undergoing liver transplantation, alpha fetoprotein (AFP) has increasingly been applied as an independent predictor for overall survival, disease free recurrence, and waitlist drop out. In addition to static AFP, newer studies evaluating the AFP dynamic response to downstaging therapy show enhanced prognostication compared to static AFP alone. While AFP has been utilized to select HCC patients for transplant, despite years of allocation policy changes, the US allocation system continues to take a uniform approach to HCC patients, without discriminating between those with favorable or unfavorable tumor biology. We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.

Advantages of using indocyanine green in liver transplantation: a narrative review.

Objective: To assess the role of indocyanine green in liver transplantation and to lay the foundation for its application in clinical practice. Background: Liver transplantation offers the best prognosis for patients with end-stage liver disease. However, this invasive procedure involves multiple well-known challenges, including complications due to graft rejection and dysfunction, surgical risks, and critical postoperative management. Intraoperative methods to assess graft function rely on conventional methods, such as blood chemistries and Doppler ultrasound. However, these methods are limited in their abilities to assess liver conditions, predict functional outcomes of the graft, and prevent surgical complications. Thus, identifying a more effective and comprehensive detection method is necessary. Methods: The information used to write this narrative review was collected from the references' opinions and conclusions. Conclusions: Indocyanine green can effectively monitor blood flow during surgery, evaluate donor graft function, and monitor the recipients functional status during and after surgery. It may also help surgeons to predict the prognosis of patients throughout the liver transplantation process, from assessing patients for liver transplantation status to postoperative management. Therefore indocyanine green should be routinely used in liver transplantation to help re-organize the transplant waiting list and improve the surgical outcomes of liver transplantation patients.

Survival following simultaneous liver-lung versus liver alone transplantation: Results of the US national experience.

BACKGROUND: There are little data to compare the post-transplant survival between lung-liver transplant (LLT) and liver-alone recipients. This study was undertaken to compare survival between LLT and liver-alone transplant. METHODS: UNOS data for patients undergoing LLT from 2002 to 2017 was analyzed. LLT recipients (n = 81) were matched 1:4 to liver-alone recipients (n = 324) by propensity score and patient survival was compared in the matched cohorts. RESULTS: Unadjusted 1, 3, and 5-year patient survival in the matched cohort was significantly worse in the LLT (82.5%, 72.2%, and 62.2%) versus liver-alone (92.2%, 82.8%, and 80.9%; p = 0.005). This difference persisted after adjusting for covariates with residual imbalance (HR 2.05, 95% CI 1.37-3.08; p = 0.001). CONCLUSION: LLT has significantly worse survival than liver-alone transplant. With an increasing organ shortage, medical necessity criteria such as those developed for simultaneous liver-kidney transplantation should be developed for simultaneous lung-liver transplants to assure liver allografts are only allocated when truly needed.

The Graz Liver Allocation Strategy-Impact of Extended Criteria Grafts on Outcome Considering Immunological Aspects.

Background: Transplant centers are forced to use livers of extended criteria donors for transplantation due to a dramatic organ shortage. The outcome effect of extended donor criteria (EDCs) remains unclear. Thus, this study was designed to assess the impact of EDCs on outcome including immunological aspects after liver transplantation (LT). Patients and Methods: Between November 2016 and March 2018, 49 patients (85.7% male) with a mean age of 57 ± 11 years underwent LT. The impact of EDCs on outcome after LT was assessed retrospectively using both MedOcs and ENIS (Eurotransplant Network Information System). Results: About 80% of grafts derived from extended criteria donors. Alanine aminotransferase/aspartate aminotransferase (AST/ALT) levels elevated more than three times above normal values in organ donors was the only significant risk factor for primary dysfunction (PDF) and primary non-function (PNF)/Re-LT and early non-anastomotic biliary strictures (NAS). Balance of risk (BAR) score did not differ between EDC and non-EDC recipients. PDF (14.3% of all patients) and PNF (6.1% of all patients) occurred in 23.1% of EDC-graft recipients and in 10.0% of non-EDC-graft recipients (RR 2.31, p = 0.663). The 90-day mortality was 3.6%. There was no difference of early non-anastomotic biliary tract complications and biopsy proven rejections (BPR). There was no correlation of PDF/PNF with BPR and NAS, respectively; however, 66.7% of the patients with BPR also developed early NAS (p < 0.001). Conclusion: With the Graz liver allocation strategy, excellent survival can be achieved selecting livers with no more than 2 not outcome-relevant EDCs for patients with MELD >20. Further, BPR is associated with biliary complications.

The growing impact of alpha-fetoprotein in the field of liver transplantation for hepatocellular cancer: time for a revolution.

The role of alpha-fetoprotein (AFP) in the specific setting of the diagnosis and prognosis of patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still controversial. Recently, a marked interest for this marker has been reported, mainly related to its ability to predict the outcome of HCC patients after LT. The growing number of papers in PubMed indicates that AFP has begun a "second life" in the particular context of LT. Looking at the most recent International Guidelines on HCC, it looks obvious that time is ripe to reevaluate the value of AFP in relation to its prognostic ability to identify HCC patients at high-risk for drop-out before and recurrence after LT. Many discrepancies exist worldwide regarding the use of biomarkers in HCC. In contrast to the Western world, AFP is widely used in Asian countries, the reason why being unclear. Indeed, in the (merely Western-dominated) HCC treatment algorithms, the role of AFP as a prognostic tumor marker is still considered to be "under investigation". One should however realize that the underestimation of the value of AFP in the LT context will hamper further refinements of both the liver allograft allocation process and the selection of the best candidates for this procedure. Moreover, AFP has an important role to play in the monitoring of bridging and/or downstaging procedures bringing eventually the patient to transplantation. So, time has come to reconsider the role and value of AFP (dynamics) in the field of transplant oncology.

Current Issues in Liver Transplantation.

The state of liver transplantation continues to evolve. This article focuses on 3 separate yet important issues within this field. First, there is a proposal to change the allocation of donor livers in the United States. The fundamental premise of this proposal is to equalize access to donor livers across the country. To accomplish this goal, the proposal is to increase the geographic area of liver allocation. As might be expected, there is a great deal of controversy surrounding the possibility of a major change in liver allocation and distribution. A second area of interest, and perhaps the most important therapeutic breakthrough in the field of hepatology, is the introduction of direct-acting antiviral agents against hepatitis C virus (HCV) infection. With cure rates up to 100%, an increasing proportion of liver transplant candidates and recipients are being cured of HCV infection with therapies that have minimal side effects. Consequently, the impact of HCV infection on patient and graft survival will likely improve substantially over the next few years. Finally, this article reviews the role of donor-specific antibodies (DSAs) in antibody-mediated rejection. Long recognized as an important factor in graft survival in renal transplantation, DSAs have recently been shown to be a strong predictor of graft and patient survival in liver transplantation. However, the importance of DSAs in liver transplantation is uncertain, in large part due to the absence of proven therapies.

Is MELD score failing patients with liver disease and hepatorenal syndrome?

There is a need to reassess the application of MELD and the impact of renal insufficiency with consideration for developing an algorithm with exception points that would lead to timely allocation of livers to patients with hepatorenal syndrome prior to occurrence of permanent renal damage without jeopardizing post-transplant survival.