Investigating the utility of each MELD edition in predicting liver transplant outcomes.

Treatment of Recurrent Hepatitis C in Liver Transplant Recipients

Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy.

First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases.

Model for end-stage liver disease (MELD) for liver allocation: A 5-year score card

Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.

The Survival Impact of Liver Transplantation in the MELD Era, and the Future for Organ Allocation and Distribution

In a MELD-based economy, how can we fight off inflation?

Innovative Approaches to Improving Organ Availability for Small Bowel Transplant Candidates

Liver Transplantation for Hepatocellular Carcinoma: Impact of the MELD Allocation System and Predictors of Survival

Evidence-Based Incorporation of Serum Sodium Concentration Into MELD

See Article on Page 1011

In the early 1980s, organ allocation in the United States was initially based on anecdotal experience, self-interest, and single-center opinions with little in the way of scientific evidence, mathematical survival modeling, or validation to support these patterns of organ allocation. As liver transplantation (LT) became more successful, the disparity between the number of patients on the waiting list and available donor organs became an issue as a result of increasing wait-list deaths, and thus, a more justifiable donor organ allocation scheme became necessary. An initial attempt at establishing organ allocation policy came in 1987 when the U.S. government established the Organ Procurement and Transplantation Network as part of the Transplantation Act. The Organ Procurement Transplantation Network operates under federal contract with the United Network for Organ Sharing (UNOS). Since the formation of the Organ Procurement Transplantation Network, attempts to improve and standardize organ allocation have been ongoing and evolving. LT, liver transplantation; UNOS, United Network for Organ Sharing; MELD, Model for End-Stage Liver Disease; PELD, Pediatric End-Stage Liver Disease; HCC, hepatocellular carcinoma; MESSAGE, MELD Exceptional Case Study Group. Liver allocation policy was initially based on patients' location of care. Patients requiring continuous intensive care, including patients with acute esophageal variceal bleeding not responding to endoscopic therapy; patients who developed hepatorenal syndrome; and patients with intractable ascites or intubated with stage 4 portosystemic encephalopathy received first priority. Organ allocation was prioritized next to patients requiring continuous hospitalization, and finally to patients who were cared for at home.1 However, as the waiting list continued to grow, waiting time became a major factor in determining who received a donor organ. Before February 2002, liver allocation was prioritized according to 4 UNOS-defined categories: status 1, 2A, 2B, and 3. These categories were based on whether the patient required admission to an intensive care unit and on the patient's Child-Turcotte-Pugh score.2 One problem with this scheme was that there were no established criteria for defining which patients truly required intensive care unit admission, thus allowing less ill patients to remain in the intensive care unit and gain an advantage for liver organ allocation. Furthermore, there were large numbers of patients in each of the 4 UNOS listing strata, and deaths on the waiting list continued to increase. Consequently, waiting time became the tiebreaker and the ultimate major determinant of organ allocation in the United States. However, as demonstrated by Freeman and others,3, 4 waiting list mortality did not correlate with waiting time. As a result of these disparities, the Department of Health and Human Services issued its Final Rule mandate in 1998 stating that donor livers should be allocated according to medical urgency and that a more continuous system should be used as mentioned by the Institute of Medicine.5, 6 In response to the Department of Health and Human Services mandate, UNOS formed the Liver Allocation Committee, and in February 2002, the Model for End-Stage Liver Disease (MELD) was adapted for the allocation of donor livers in the United States. The MELD score was initially developed to predict mortality in patients receiving transjugular intrahepatic portosystemic shunts to treat variceal bleeding or resistant ascites. The initial model, called the Mayo Model for End-Stage Liver Disease, consisted of 3 objective variables: serum creatinine, serum total bilirubin, international normalized ratio, and a fourth variable based on liver disease etiology.7 During further assessment, the name was changed to the MELD scoring system, and investigators found that etiology contributed minimally to predicting short-term survival. Thus, the final MELD model used for liver allocation policy is based on serum creatinine, serum total bilirubin, and international normalized ratio. The MELD score has been retrospectively and prospectively shown to be highly predictive of short-term mortality in patients with all causes of end-stage liver disease who are awaiting LT.8 The model has been validated for prediction of 3-month and 1-year mortality (and inversely survival) in a broad spectrum of patients with chronic liver disease.9 The advantages of the MELD system for organ allocation are that all variables are objective and statistically weighted, and the model has a continuous scale with no ceiling or floor effects, thereby reducing a large number of ties (multiple patients with equal waiting times) and virtually eliminating dependence on waiting time for ranking candidates except as a tiebreaker for patients with equal MELD scores. Since the implementation of MELD system, assessment of the UNOS liver allocation policy has revealed marked changes in the dynamics of organ allocation.10 The mean MELD score at transplantation increased from 17 in the pre-MELD era to 22 in the post-MELD era. Despite a shift to sicker patients receiving transplants, there have been no differences in 1-year patient and graft survival rates since implementation of the MELD system. And there has been a reduction in median waiting time from 656 days to 416 days. The major reason for the reduction in waiting time has been the removal of waiting as a criterion for liver offer. Thus, the most ill patients receive an offer first, regardless of how long they have waited. This also removed the incentive to "list patients early" to gain waiting time at a time when their liver disease was not very severe. Perhaps the most important indicator of the superiority of the MELD system over the previous allocation system was a reduction in waiting list mortality by 3.5% after its implementation. These changes clearly met the requirements of the Department of Health and Human Services, which state that organs should be allocated on the basis of medical urgency rather than waiting time. However, at the time the MELD liver allocation system was implemented, policy makers recognized that not all LT candidates benefited from LT because they faced a high risk of dying from their intrinsic liver disease. These patients would not have their need for LT accurately characterized by their calculated MELD or Pediatric End-Stage Liver Disease (PELD) score.11 Hepatocellular carcinoma (HCC) is one such example. Rule makers defined the need for LT for these candidates as the risk of progressing beyond tumors meeting the so-called Milan criteria, a stage at which excellent posttransplant results could be achieved.12 At the initial time of MELD and PELD policy implementation, there were no good data quantifying the risk of HCC progression, so estimates of probability were arbitrarily assigned and equated to the MELD-defined probability of death, resulting in awarding of additional MELD points to the calculated MELD scores.11 Thus, with additional points, the initial assessment of the MELD allocation system demonstrated that there was a reduction from 24 to 7% in patients with HCC falling off the waiting list.13 Subsequently, many studies have examined the progression of HCC in waiting LT candidates,14 and the HCC prioritization policy has been revised several times. There are patients with other conditions for which the need for LT is not accurately defined by the MELD score because their prognoses depend on factors other than liver disease mortality risk.15 As such, these patients have potential for being underserved (wait list removals or death) if they are ranked for allocation of deceased donor livers solely on the basis of a calculated MELD score derived from their pretransplant laboratory values. Some of these conditions, in addition to HCC, such as the progressive pulmonary compromise seen in hepatopulmonary syndrome, familial amyloid polyneuropathy, metabolic liver diseases such as urea cycle defects or hereditary oxaluria, have been identified and termed the so called "exceptional diagnoses."16 In addition, because the MELD/PELD score accurately predicts death from liver disease in approximately 80 to 85% of patients, as many as 15 to 20% of patients with chronic liver disease may not be accurately prioritized by their MELD/PELD score. It was recognized that it is unlikely that any scoring system would serve all potential LT candidates equally well, and for these reasons, the original MELD allocation policy included a mechanism by which centers could request increased priority for any patient for whom the MELD/PELD score was thought to inaccurately estimate their need for LT. The policy stipulated that these requests would be reviewed by a regional peer review system to determine the appropriateness of the requested increase in priority on the basis of medical evidence from the literature or expert opinion. The goals behind allowing certain disease entities to receive increased priority on the waiting list as MELD exceptions are severalfold: (1) decrease patient risk of death on the waiting list; (2) increase timeliness of LT before the underlying liver disease progresses to the point that the patient can no longer be considered a LT candidate; (3) decrease the risk of disease of recurrence after LT; (4) prevent disease progression that is dependent on a metabolic or genetic disease that may preclude LT, and (5) improve survival after LT. With the exception of HCC, however, MELD-equated priority guidelines were not identified for these other exceptional diseases. After the first year of use of the MELD allocation policy, Rodriguez-Luna and collagues17 assessed Regional Review Board practices. They found that large variations existed throughout the country in how exceptional cases were handled. Because these differences exist and there are no guidelines available for the consistent assessment of exceptional case applications other than for HCC, UNOS convened a study group, MELD Exceptional Case Study Group (MESSAGE), a subcommittee of the UNOS Liver and Intestinal Committee, to develop a consensus and to advance the field and provide written recommendations to UNOS, the Liver and Intestinal Committee within UNOS, and guidelines to the Regional Review Boards to aid in the assignment or denial of assignment of MELD score upgrades. Thus, the goals of MESSAGE and the conference were to make evidence-based recommendations when possible and create a uniform approach to a number of conditions that were believed to be underserved when the calculated MELD score was used. The MESSAGE group, with the assistance of the Scientific Registry of Transplant recipients and UNOS, identified 17 diagnoses or groups of diagnoses for which MELD exceptions were requested for Regional Review Board deliberation. The members of this committee reviewed the literature for evidence or expert opinion to support or refute the validity of waiting list death, waiting list removals for progressive disease, waiting list removals as too ill, and evidence of nonhepatic end-organ injury that would obviate LT for patients with these diagnoses and determine if these patients with specific diagnoses should receive increased waiting-list priority. These findings were presented at a national conference held in Chicago, March 1 to 2, 2006, where final recommendations were reached. The MESSAGE committee members and the members of the Liver and Intestinal Committee who were involved in this project emphasize that the Regional Review Boards across the country have held widely divergent opinions on which conditions should receive additional MELD points, if any, and on how much priority should be given for exceptional case requests. The purpose of the MESSAGE group's work was to provide a consistent, evidence-based approach for listing patients with additional MELD points across the liver transplant programs and regions within the UNOS. This series of articles summarize MESSAGE's deliberations and conclusions reached at this conference.

TO THE EDITOR: We thank Bari and Sharma1 for their interest and editorial regarding our study demonstrating that low, rather than high, body mass index (BMI) confers increased risk for post–liver transplantation (LT) death and graft loss, specifically among patients with low Model for End‐Stage Liver Disease (MELD) scores.1 In response to their comments, we would like to make the following remarks to clarify their interpretation of our data and to provide additional data. First, we need to make 2 clarifications with respect to comments made in the editorial. Bari and Sharma1 astutely point out that implementation of the Share 15 policy could have influenced the associations we found between low BMI–low MELD patients with respect to their risk for death and graft loss. Although this would otherwise be an important factor to consider in an analysis such as ours, the patient population we studied spanned LT recipients in calendar years 2002 to 2011. Implementation of National Share 15 did not occur until June 2013; as such, in the context of our analyses and patient cohort, the implementation of National Share 15 is not applicable. However, it is true that Regional Share 15 was implemented in January 2005. Stratification of our analyses by the year 2005 generates a very uneven distribution of the data and results in unstable estimates for the time period spanning the 3‐year interval from 2002 to the end of 2004. Despite this, we did find that the significance of the interaction between low MELD and low BMI remains significant for the time period spanning 2005‐2011, which was during the Regional Share 15 era. The editorial also comments that our finding of increased risk for mortality and graft loss after LT among low MELD–low BMI patients might be explained by differences in the donor risk index (DRI) among recipients. However, as we stated in our manuscript, our multivariate analyses included DRI in the models, and the interaction between low MELD and low BMI with respect to mortality and graft loss remained significant, indicating that our findings were not accounted for by biases toward giving higher DRI organs to the low MELD–low BMI patients. The editorial further suggests that consideration of serum sodium and LT year should be included in the multivariate analyses and also that it is of interest to investigate the associations between low MELD and low BMI, using an even lower cutoff for MELD (25th percentile, which would be MELD ≤ 12). We agree with Bari and Sharma1 that these analyses are of interest, and we provide the results of the suggested analyses here. With the addition of serum sodium and LT year to the multivariate analyses (which also included age, sex, ethnicity, liver disease diagnosis, hepatocellular carcinoma diagnosis, diabetes, ascites, and DRI), the interaction between low MELD and low BMI remained statistically significant, and the statistical significance was maintained regardless of the MELD cutoff we used (MELD ≤ 12, MELD ≤ 19, or MELD ≤ 26). Data are shown for risk of death and risk of graft loss at 3 months after LT, stratified by MELD cutoff in Table 1. These data demonstrate that as the MELD score decreases, the hazard ratios for risk of death or graft loss among low MELD–low BMI patients increase in a stepwise fashion. Table 1 - Hazard Ratio for Death or Graft Loss at 3 Months After LT Among Low BMI (<18.5 kg/m2) Patients Stratified by MELD Score Outcome (3 Months After LT) Hazard Ratio (95% Confidence Interval)a P Values MELD ≤ 12 Patient death 3.22 (1.84‐5.64) <0.001 Graft loss 2.36 (1.43‐3.88) 0.002 MELD ≤ 19 Patient death 2.06 (1.32‐3.21) 0.005 Graft loss 1.66 (1.16‐2.38) 0.005 MELD ≤ 26 Patient death 1.67 (1.14‐2.45) 0.02 Graft loss 1.37 (1.00‐1.89) 0.03 aAll models are adjusted for age, sex, ethnicity, serum sodium, LT year, liver disease diagnosis, hepatocellular carcinoma diagnosis, diabetes, ascites, and DRI. We conclude our letter by addressing the concepts of functional status and sarcopenia as they apply to our study and interpretation of our results. Although we included the Karnofsky Performance Score (KPS) in a subset of our multivariate analyses as the only available marker in the United Network for Organ Sharing (UNOS) data set of a patient's functional status, the KPS is well‐known to be inconsistently applied across transplant programs and, as such, is unfortunately not an ideal variable for assessing functional status in UNOS analyses for this reason. Regardless, as we discuss in our article, our demonstration of increased risk for patient death and graft loss after LT among low MELD–low BMI patients is highly suggestive that malnourishment, sarcopenia, and decreased functional status could be underlying factors related to the risk for poor outcomes in these patients. Our findings are strongly supported by data from Tandon et al.3 demonstrating that, among patients listed for LT, sarcopenic patients with low MELD (<15) had an increased mortality risk compared to low MELD patients without sarcopenia, which dovetails nicely with our findings of increased risk for death and graft loss among low MELD–low BMI patients after LT. Thus, our work presents compelling data to suggest that measures of malnourishment, sarcopenia, and functional status are important assessments to be made in low MELD, low BMI patients.

Richard B. Freeman Jr., Robert G. Gish, Ann Harper, Gary L. Davis, John Vierling, Leslie Lieblein, Goran Klintmalm, Jamie Blazek, Robert Hunter, and Jeffrey Punch Division of Transplantation, Department of Surgery, Tufts–New England Medical Center, Boston, MA; Departments of Medicine and Transplantation and the Division of Hepatology and Complex GI, Physicians Foundation, California Pacific Medical Center, San Francisco, CA; United Network for Organ Sharing, Richmond, VA; Baylor Regional Transplant Institute, Baylor University Medical Center, Dallas, TX; Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA; Ochsner Multi-Organ Transplant Center, New Orleans, LA; and Department of Surgery, University of Michigan, Ann Arbor, MI

The model for end-stage liver disease (MELD) system is a good tool to predict short-term mortality among living donor liver transplantation (AALDLT) recipients and has also been suggested to prohibited live liver donation for recipients with MELD scores[25 [1]. A partial liver graft transplanted into an adult recipient is often defined as a small-for-size graft. It is generally accepted that such graft would be tolerated when the graft-to-body weight ratio (GBWR) is higher than 0.8. However, transplanted liver will suffer small-for-size syndrome (SFSS) and irreversible damage when GBWR \0.8. In AALDLT, graft size and pre-transplant MELD scores are important factors for patient post-transplant survival [2]. Here we evaluated the outcome of using a SFSG in AALDLT recipients with different MELD scores in a single liver transplant center. Clinical data of 118 patients who had right-lobe AALDLT from January 2004 to December 2011 were retrospectively analyzed. According to MELD, patients were divided into group L (MELD score B25, n = 102) and group H (MELD score [25, n = 16). To analyze the risk of the graft size, the patients were further stratified into group LS (MELD score B25, GBWR\0.8, n = 23), group LN (MELD score B25, GBWR C0.8, n = 79), group HS (MELD score [25, GBWR \0.8, n = 5), and group HN (MELD score [25, GBWR C0.8, n = 11). MELD scores between the two groups were significantly different. There was no significant difference in preoperative demographic data as well as postoperative liver function data. The length of ICU and hospital stay, graft loss, and mortality were similar in both groups. Complication rate was also similar between two groups (10.8 vs 6.3 %, P = 1.000). The 1and 3-year survival rate were similar between group L and group H (85.2 vs 74 %, 78.9 vs 74 %, P = 0.692). After stratified into groups LS, LN, HS, and HN, there were no significant differences among groups in 1and 3-year survival rate. Multivariate analysis revealed that accompanied hepatocellular carcinoma (HCC), GBWR, and MELD scores did not predict the 1and 3-year survival rate. Recipients with high MELD scores usually have worse preoperative conditions and experience a more complicated peri-operative course. However, there are still debates on this subject. Hayashi et al. [3] reported that there was no correlation between the 1-year survival rate and MELD scores. According to Yi et al. [4], the 1-year survival rate without HCC was found to be similar between those two groups as well as the rate of postoperative complications. In our report, the postoperative complication rate, ICU and hospital stay length after AALDLT did not differ between recipients. Pneumonia was still the first cause of death. We attributed these advanced results to a high level of perioperative intensive care for high MELD score recipients. When using a graft with GBWR less than 0.8 in AALDLT, recipients possibly suffer postoperative irreversible liver damage. However, Yi et al. [4] also reported that a high MELD score ([25) was not an important predictor of the 1-year survival rate in cases with an SFSG. Reconstruction of the MHV is well known as an important factor to reduce the incidence of graft failure in an SFSG. In our study, although there was no significant difference in survival rates among groups with versus without MHV, we might H. Li B. Li (&) Department of Liver and Vascular Surgery, Center of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China e-mail: doclibo@126.com