Validation of the five-variable Model for End-stage Liver Disease (5vMELD) for prediction of mortality on the liver transplant waiting list.

BACKGROUND: Modifications to the Model for End-Stage Liver Disease (MELD) have been proposed to improve prioritization of liver transplant (LT) candidates. Using a U.S. database, we derived a revised MELD including sodium and albumin [5-variable MELD (5vMELD)] that improved prediction of waiting list mortality. Our objectives were to confirm the association between hypoalbuminaemia and mortality and to externally validate 5vMELD in Canadian LT candidates. METHODS: Among adults registered on the LT waiting list at the University of Alberta (01/2000-10/2009), Cox regression determined the association between albumin and 1-year waiting list mortality. The discrimination of MELD, MELDNa and 5vMELD for predicting 1-year mortality were compared using c-statistics. RESULTS: Among 677 patients, 17% died and 51% underwent LT within 1 year of listing. Median serum albumin was 3.1 g/dl (IQR 2.6-3.6) and 70% of patients were hypoalbuminaemic (albumin <3.5 g/dl). One-year mortality in patients with normal serum albumin and hypoalbuminaemia were 14% and 29% respectively (P = 0.004). For patients with serum albumin between 2.0 and 4.0 g/dl, an approximately linear, inverse relationship was observed between albumin and 1-year mortality [adjusted hazard ratio (HR) 1.45; 95% CI 1.03-2.03; P = 0.03]. For this outcome, the c-statistic of 5vMELD (0.778) was superior to those of MELD (0.754) and MELDNa (0.765) (both P ≤ 0.05). CONCLUSIONS: Hypoalbuminaemia is an independent predictor of mortality on the LT waiting list. Compared with MELD and MELDNa, 5vMELD improves prediction of mortality suggesting that modification of these scores to include serum albumin should be considered as a means of prioritizing LT candidates.

Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy.

BACKGROUND: Although most patients with autoimmune hepatitis (AIH) respond to treatment with prednisone and/or azathioprine, some patients are intolerant or refractory to standard therapy. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and has demonstrated efficacy in other autoimmune conditions. AIMS: To evaluate the safety and efficacy of rituximab in patients with refractory AIH in an open-label, single-centre pilot study. METHODS: Six patients with definite, biopsy-proven AIH who failed prednisone and azathioprine treatment received two infusions of rituximab 1000 mg two weeks apart and were followed for 72 weeks. RESULTS: Rituximab was well tolerated with no serious adverse events. By week 24, mean (± SD) aspartate aminotransferase (AST) levels had significantly improved (90.0±23.3 U/L versus 31.3±4.2 U/L; P=0.03) and mean immunoglobulin G levels had fallen (16.4±2.0 g/L versus 11.5±1.1 g/L; P=0.056). The prednisone dose was weaned in three of four subjects, with one subject flaring after steroid withdrawal. Inflammation grade improved in all four subjects who underwent repeat liver biopsy at week 48. Regulatory T cell levels examined by FoxP3 immunohistochemistry paralleled inflammatory activity and did not increase on follow-up biopsies. There was no significant change in serum chemokine or cytokine levels from baseline to week 24 (n=5), although interferon-gamma-induced protein 10 levels improved in three of five subjects. CONCLUSIONS: Rituximab was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results support further investigation of rituximab as a treatment for AIH.

Revision of MELD to include serum albumin improves prediction of mortality on the liver transplant waiting list.

BACKGROUND: Allocation of donor livers for transplantation in most regions is based on the Model for End-Stage Liver Disease (MELD) or MELD-sodium (MELDNa). Our objective was to assess revisions to MELD and MELDNa that include serum albumin for predicting waiting list mortality. METHODS: Adults registered for liver transplantation in the United States (2002-2007) were identified from the United Network for Organ Sharing (UNOS) database. Cox regression was used to determine the association between serum albumin and 3-month mortality, and to derive revised MELD and MELDNa scores incorporating albumin ('MELD-albumin' and '5-variable MELD [5vMELD]'). RESULTS: Among 40,393 patients, 9% died and 24% underwent transplantation within 3 months of listing. For serum albumin concentrations between 1.0 and 4.0 g/dL, a linear, inverse relationship was observed between albumin and 3-month mortality (adjusted hazard ratio per 1 g/dL reduction in albumin: 1.44; 95% CI 1.35-1.54). The c-statistics for 3-month mortality of MELD-albumin and MELD were 0.913 and 0.896, respectively (P<0.001); 5vMELD was superior to MELDNa (c-statistics 0.922 vs. 0.912, P<0.001). The potential benefit of 5vMELD was greatest in patients with low MELD (<15). Among low MELD patients who died, 27% would have gained ≥10 points with 5vMELD over MELD versus only 4-7% among low MELD survivors and high MELD (≥15) candidates (P<0.0005). CONCLUSION: Modification of MELD and MELDNa to include serum albumin is associated with improved prediction of waiting list mortality. If validated and shown to be associated with reduced mortality, adoption of 5vMELD as the basis for liver allograft allocation may improve outcomes on the liver transplant waiting list.

Gender, renal function, and outcomes on the liver transplant waiting list: assessment of revised MELD including estimated glomerular filtration rate.

BACKGROUND & AIMS: The Model for End-Stage Liver Disease (MELD) allocation system for liver transplantation (LT) may present a disadvantage for women by including serum creatinine, which is typically lower in females. Our objectives were to investigate gender disparities in outcomes among LT candidates and to assess a revised MELD, including estimated glomerular filtration rate (eGFR), for predicting waiting list mortality. METHODS: Adults registered for LT between 2002 and 2007 were identified using the UNOS database. We compared components of MELD, MDRD-derived eGFR, and the 3-month probability of LT and death between genders. Discrimination of MELD, MELDNa, and revised models including eGFR for mortality were compared using c-statistics. RESULTS: A total of 40,393 patients (36% female) met the inclusion criteria; 9% died and 24% underwent LT within 3 months of listing. Compared with men, women had lower median serum creatinine (0.9 vs. 1.0 mg/dl), eGFR (72 vs. 83 ml/min/1.73 m(2)), and mean MELD (16.5 vs. 17.2; all p <0.0005), but within most MELD strata, had higher bilirubin and INR. After adjusting for relevant covariates including creatinine and body weight, women were less likely than men to receive a LT (hazard ratio [HR] 0.85; 95% CI 0.79-0.87) and had greater 3-month mortality (HR 1.13; 95% CI 1.05-1.21). Revision of MELD and MELDNa to include eGFR did not improve discrimination for 3-month mortality (c-statistics: MELD 0.896, MELD-eGFR 0.894, MELDNa 0.911, MELDNa-eGFR 0.905). CONCLUSIONS: Women are disadvantaged under MELD potentially due to its inclusion of creatinine. However, since including eGFR in MELD does not improve mortality prediction, alternative refinements are necessary.

CX(3)CR1 and vascular adhesion protein-1-dependent recruitment of CD16(+) monocytes across human liver sinusoidal endothelium.

UNLABELLED: The liver contains macrophages and myeloid dendritic cells (mDCs) that are critical for the regulation of hepatic inflammation. Most hepatic macrophages and mDCs are derived from monocytes recruited from the blood through poorly understood interactions with hepatic sinusoidal endothelial cells (HSECs). Human CD16(+) monocytes are thought to contain the precursor populations for tissue macrophages and mDCs. We report that CD16(+) cells localize to areas of active inflammation and fibrosis in chronic inflammatory liver disease and that a unique combination of cell surface receptors promotes the transendothelial migration of CD16(+) monocytes through human HSECs under physiological flow. CX(3)CR1 activation was the dominant pertussis-sensitive mechanism controlling transendothelial migration under flow, and expression of the CX(3)CR1 ligand CX(3)CL1 is increased on hepatic sinusoids in chronic inflammatory liver disease. Exposure of CD16(+) monocytes to immobilized purified CX(3)CL1 triggered beta1-integrin-mediated adhesion to vascular cell adhesion molecule-1 and induced the development of a migratory phenotype. Following transmigration or exposure to soluble CX(3)CL1, CD16(+) monocytes rapidly but transiently lost expression of CX(3)CR1. Adhesion and transmigration across HSECs under flow was also dependent on vascular adhesion protein-1 (VAP-1) on the HSECs. CONCLUSION: Our data suggest that CD16(+) monocytes are recruited by a combination of adhesive signals involving VAP-1 and CX(3)CR1 mediated integrin-activation. Thus a novel combination of surface molecules, including VAP-1 and CX(3)CL1 promotes the recruitment of CD16(+) monocytes to the liver, allowing them to localize at sites of chronic inflammation and fibrosis.