Predictors of liver transplantation outcomes

Errata

This article is corrected by:

  1. Errata: Correction: Intestinal mucus-derived nanoparticle-mediated activation of Wnt/β-catenin signaling plays a role in induction of liver natural killer T cell energy in mice Volume 63, Issue 4, 1404, Article first published online: 3 March 2016

91

Frailty Score Predicts Outcomes Among Liver Transplant Candidates and Recipients

Christopher J. Sonnenday1, Michael Volk2, Michael J. Englesbe1

1Department of Surgery, University of Michigan, Ann Arbor, MI; 2Department of Medicine, University of MIchigan, Ann Arbor, MI

Appropriate organ allocation must balance minimizing waitlist mortality and maximizing post-transplant outcomes. While MELD predicts waitlist death, additional metrics are needed to identify transplant candidates at risk for poor outcomes. Frailty, a syndrome of decreased physiologic reserve associated with adverse health outcomes, may provide a novel measure of risk stratification among candidates for transplantation. Single center prospective trial of patients referred for transplant evaluation and assessed for quality of life (sf36), depression, and frailty. The frailty instrument has 5 elements (walking speed, grip strength, unintentional weight loss, self-reported exhaustion, and weekly physical activity). Each element has criteria that indicate frailty, such that each patient has a frailty score between 0 (not frail) and 5 (highly frail). The frailty instrument has been validated in geriatrics but not studied in liver disease. Clinical data and outcomes were recorded for all patients, and deaths confirmed via the SSDMF. Since 2009, 502 subjects have been enrolled in the clinical trial, with median follow-up of 21 months (range 3-45 mos). Frailty was normally distributed among study subjects, and not correlated with age, sex, BMI, cause of liver disease, or number of comorbidities. Frailty was weakly positively correlated with MELD score (=0.25, P<0.01), but mean MELD score among high frailty (3-5) and low frailty (0-2) subjects was equivalent (12.5). High frailty was associated with higher depression (6 vs. 3, P<0.01), and decreased quality of life (sf36 32 vs. 53, P<0.01). Pre-transplant mortality was increased among high frailty patients (HR=2.7, P=0.02), and interacted with high MELD to produce poor pre-transplant survival (median survival, high frailty with MELD>15 = 6 mos). Among 73 patients in the study who underwent transplantation, 1-year survival was equivalent among high frailty and low frailty patients (90%). However, high frailty patients had higher rates of biliary complications (33 vs 20%), renal failure (29 vs 14%), discharge to a skilled nursing facility (20 vs 9.3%) and 90-day readmission rates (67 vs 43%). Reoperation rates increased in a linear fashion from 8% for nonfrail patients (score 0) to 100% in highly frail patients (score 5). Frailty is a useful risk stratification domain for liver transplant candidates associated with decreased pre-transplant survival and increased post-transplant complications and resource utilization. Given the equivalent post-transplant survival among high frailty patients, further study is needed to determine if high frailty patients with a MELD>15 would benefit from expedited allocation.

Disclosures:

The following people have nothing to disclose: Christopher J. Sonnenday, Michael Volk, Michael J. Englesbe

92

The Unintended Effect of the MELD Exception Study Group (MESSAGE) Recommendations: More MELD Exceptions

Patrick G. Northup, Nicolas M. Intagliata, Neeral L. Shah, Curtis K. Argo

Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA

The MELD Exception Study Group consensus conference (MESSAGE) was convened in 2006 in order to establish standardized recommendations for non-HCC MELD exceptions. The recommendations of the MESSAGE conference were published in late 2006 and the implication was that special case MELD exceptions would decrease in number. It was the aim of this study to determine differences in MELD exceptions before and after publication of the MESSAGE recommendations. Methods: Data from all adult, non-status one, initial transplant candidates who were listed for liver transplantation between January 2005 and December 2012 were analyzed. Because of significant changes in HCC exceptions from 2002-2004, these years were excluded from the analysis. Candidates listed for transplantation were divided into two groups: 1) Those listed prior to widespread publication of the MESSAGE criteria and 2) those listed after. The groups were compared for numbers and type of MELD exceptions as well as waiting list and transplantation characteristics. Regional variations in exception percentages were analyzed in the pre- and post-MESSAGE eras as well. Results: 78, 595 transplant candidates were analyzed. All types of MELD exceptions increased in percentage in the post-MESSAGE era (Table). Special case exceptions increased by a relative 23% between eras (p<0.0001). There were strong regional variations in the use of all exceptions but lower transplant volume regions had higher utilization of exceptions in the P〇ST era. Overall transplantation rates decreased between the two eras (55.4% PRE vs. 46.1% POST, p<0.0001) and waiting list sizes increased. While there was benefit to the candidates with exceptions, non-exception candidates had worse outcomes between the two eras. Compared to candidates with exceptions, those without MELD exception had longer waiting time (237 days vs. 426, p<0.0001), higher lab MELD at waiting list removal (22 vs 13, p<0.0001), higher waiting list mortality (24.6% vs. 4.49%, P<0.0001), and lower transplantation rates (40.6% vs. 79.1%, p<0.0001). Conclusions: The number of all types of MELD exceptions has increased since MESSAGE and is associated with an increase in non-exception candidate morbidity and mortality. Further changes in exception policy should anticipate the possibility of untoward effects on non-exception candidates.

Percentage of All Transplant Candidates

Exception TypePre-MESSSAGE Era (n=18, 403)Post-MESSAGE Era (n=60,192)
None77.1%71.3%
HCC(T2orT3A)16.1%20.0%
Special Case 5.6% 7.1%
HPS/PPHTN 1.1% 1.4%
Metabolic Disorders 0.2% 0.3%

Disclosures:

Patrick G. Northup - Grant/Research Support: Hemosonics, Bristol Meyer Squibb

Neeral L. Shah - Grant/Research Support: Hemosonics

Curtis K. Argo - Consulting: Wellstat Diagnostics; Independent Contractor: Genentech/Roche

The following people have nothing to disclose: Nicolas M. Intagliata

93

Glycosylated Hemoglobin as a novel Predictor of Renal Impairment after Orthotopic Liver Transplantation

Steffen Gerbermann1, Hanna E. Tönissen1, Arndt Weinmann1, Sandro Koch1, Maria Hoppe-Lotichius2, 3, Tim Zimmermann1, Jens Mittler3, Peter R. Galle1, Hauke Lang3, Gerd Otto2, Martin F. Sprinzl1

1Medical Department, University Mainz, Mainz, Germany; 2Department of Transplant Surgery, University Mainz, Mainz, Germany; 3Deportment of Surgery, University Mainz, Mainz, Germany

Introduction: Renal failure is regularly observed after orthotopic liver transplantation (OLT) and therefore contributes to morbidity and time of hospitalization. Metabolic risk factors for acute renal failure (ARF) after OLT are lacking. Hence we searched for the impact of metabolic markers such as glycosylated hemoglobin (HBa1c) on the incidence of acute renal failure post 〇 LT. Methods: In this retrospective single-center study of 〇LT recipients (n =172) we searched for prevalence rates of renal failure during a 2-year follow-up after 〇 LT. We searched for base line risk factors associated with new onset of acute renal impairment after 〇LT. Explorative statistical tests (SPSS 20.0) were performed at a local significance level of a=0.05.Results: We identified an increase of serum creatinin between baseline (median 1.05 mg/dl, range 0.49 - 7.36 mg/dl) and two years after OLT (median 1.18, range 0.67 - 4.73 mg/dl). Acute renal failure affected 31.9% (n=51/160) within a median of 26 days (mean 92 days) after 〇LT. Hemodialysis was performed in 26.3% (n=40/152) and was started within a median interval of 5 days (mean 55 days) after 〇LT. Obesity (BMI>30 kg/m2), history of alcohol abuse, high creatinin levels and low HbA1c at baseline were linked to acute renal failure. Low HbA1c as well as high creatinin levels at baseline were additionally linked to de novo hemodialysis. Post hoc analysis of HBa1c levels identified their negative correlation with serum bilirubin (p = 0.008) and a positive correlation with serum albumin (P = 0.01 3). Conclusion: Our data confirmed the high prevalence of acute renal failure after 〇LT. Besides pre-existing obesity, renal insufficiency and history of alcohol abuse, also low HbA1c (≤4.4%) levels were associated with both hepatic and renal impairment in patients receiving 〇LT. Reduced HbA1c levels might therefore be a risk factor for post 〇LT renal complications, as it may represent increased erythrocyte turnover and impaired gluconeogenesis in end stage liver disease.

Disclosures:

Arndt Weinmann - Speaking and Teaching: Bayer Healthcare

Peter R. Galle - Advisory Committees or Review Panels: Bayer, BMS, Lilly, Daiichi, Jennerex; Consulting: Medimmune; Grant/Research Support: Roche, Lilly; Speaking and Teaching: Bayer, BMS

The following people have nothing to disclose: Steffen Gerbermann, Hanna E. Tönissen, Sandra Koch, Maria Hoppe-Lotichius, Tim Zimmermann, Jens Mittler, Hauke Lang, Gerd Otto, Martin F. Sprinzl

94

Impact of the Donor Risk Index (DRI) on Fibrosis Progression in Hepatitis C virus (HCV) Infected Liver Transplant Recipients

Chris J. Maxwell1, Sameer Desale2, Bhaskar Kallakury1, Elizabeth Landry1, Jonathan C. Julia1, Jacqueline Laurin1, Rohit Satoskar1, Thomas Fishbein1, Kirti Shetty1

1Georgetown University Hospital, Washington, DC; 2Medstar Health Research Institute, Washington, DC

Liver transplantation (LT) is a life-saving therapy in advanced cirrhosis, but its use is limited by the availability of suitable organs. While it is recognized that HCV-infected LT recipients suffer compromised outcomes overall, the contribution of donor factors to HCV recurrence and progression is not well-elucidated. We therefore undertook this study to assess the impact of the donor risk index (DRI) and other donor characteristics on fibrosis progression, graft and patient survival in a cohort of HCV-infected LT recipients. Methods: Adults who had undergone LT at our center between 1998 and 2012 for HCV were included in survival analysis. Those who had at least 2 post-LT protocol liver biopsy (LBx) specimens available were included in histological assessment. Patients were excluded for concomitant HIV/ HBV, post-LT follow-up < 4 months, prior LT, or undetectable HCV RNA post- LT. Institutional Review Board approval was obtained. Biopsy samples were reviewed by a single pathologist for steatosis, fibrosis stage and inflammatory grade (METAVIR). Data was abstracted and entered into a prospectively maintained web-based database (REDCap). Hazard ratio for bivariate analysis were computed using Cox proportional hazard regression analysis. Results: A total of 312 patients were included in the overall analysis; 72% male, 32% African American (AA). Of donors, 59% were male, 38% AA and 24% aged over 60 years. Survival analysis: 83 patients died over a median follow up of 58.5 months (95% CI: 46.5-67.3, mean survival 110.4 months. Fourteen patients underwent re-transplantation. Mean time to graft failure = 84.3 months, median follow-up = 59 months, 95 % CI (48.2, 68.3). DRI was significantly associated with patient death (ρ=0.04) but not second LT. 〇f 104 patients who had at least one post-LT LBx demonstrating F0/F1 fibrosis, 70 progressed to >F2 (median time to progression from LT: 31.3 months, median follow up 81.5 months). On multivariate analysis, significant donor-specific predictors of fibrosis progression were: donor age > 60 years, donation after cardiac death (DCD), race mismatch: white donor/ black recipient. DRI significantly correlated with fibrosis progression (p= 0.03, HR 1.97). Conclusions: 1.Fibrosis progression in HCV infected LT recipients is strongly associated with donor characteristics: specifically donor age, DCD criteria and race mismatch. 2.DRI, an objective measure of donor quality, appears to correlate both with rate of histological progression and overall survival.

Disclosures:

Kirti Shetty - Grant/Research Support: Ikaria, Novartis, Onyx-Bayer, Hyperion; Speaking and Teaching: Merck-Schering Plough, Salix, Gilead, Onyx

The following people have nothing to disclose: Chris J. Maxwell, Sameer Desale, Bhaskar Kallakury, Elizabeth Landry, Jonathan C. Julia, Jacqueline Laurin, Rohit Satoskar, Thomas Fishbein

95

Nonalcoholic steatohepatitis (NASH) is an independent predictor of portal vein thrombosis (PVT) at the time liver transplantation (LT)

Danielle Brandman1, Jennifer L. Dodge2, John P. Roberts2, Norah Terrault1,2

1Gastroenterology, University of California San Francisco, San Francisco, CA; 2Surgery, University of California Son Francisco, San Francisco, CA

INTRODUCTION PVT may increase the complexity of the LT surgery and may even preclude LT. Whether specific disease or recipient factors present a higher risk of PVT in LT recipients is unknown. METHODS All adult primary LT recipients between 3/1/02-12/31/11 from the UNOS-OPTN database were included. PVT status was available on 97% of LT recipients. We defined probable NASH (PN) as cryptogenic cirrhosis + diabetes (DM), hypertension, or BMI>40; NASH/PN was analyzed as one group. RESULTS Prevalence of PVT at LT increased from 3% in 2002 to 10% in 2011.〇 f 41, 036 LT recipients (31% female, 73% white, median age 55 yrs), 2569 (6%) had PVT at LT, 1765 (69%) of whom did not have PVT at time of LT listing. Patients (pts) with PVT were older, more often male, had NASH, DM, and less often had HCV. MELD at LT and HCC prevalence were similar between pts with and without PVT. Independent predictors of PVT at LT were older age, Hispanic race, previous abdominal surgery, TIPS, listing BMI, DM and NASH (multivariable 〇R 1.55, p<0.001; Table). Female gender and black race were associated with decreased risk of PVT. While PVT was more common in pts with DM+NASH than DM+non-NASH (11% vs 7%, p<0.001), there was no interaction between NASH and DM. The association between NASH and PVT persisted in pts with BMI<30 (OR 1.25, p=0.04), but was attenuated in non-DM pts (〇R 1.15, p=0.19). 1-, 3- and 5- yr post-LT survival was poorer in patients with vs without PVT at LT (85 vs 90%; 80 vs 83%; 77 vs 80%; p<0.0001). After adjusting for age, race, MELD, NASH, HCC, dialysis, prior abdominal surgery, TIPS, DM and yr of LT, PVT was an independent predictor of post-LT death (HR 1.21, p<0.001). CONCLUSIONS PVT impacts post-LT survival, and NASH, particularly in DM pts, is an independent predictor of PVT, with metabolic and/or inflammatory factors likely to be causative. Given the increase in NASH as an indication for LT, as well as PVT over time, strategies to identify pts at risk for PVT and to improve their post-LT outcomes are needed.

U ni variable OR (95% CI)Multivariable OR (95% CI)*
  1. *Adjusted for year of LT, lab MELD score at LT

Diagnosis//CV NASH/PN Alcohol Cholestatic HBV Other Ref 1.84 (1.65,2.04) 1.22 (1.09, 1.37) 1.01 (0.88, 1.15) 1.18 (0.95, 1.46) 1.34 (1.11,1.63)Ref 1.55 (1.38, 1.74) 1.19 (1.06, 1.34) 1.13(0.98, 1.31) 1.32 (1.05, 1.65) 1.42 (1.16, 1.73)
Recipient age (years)1.02 (1.01, 1.02)1.01 (1.009, 1.01)
Female gender0.91 (0.84, 0.999)0.80 (0.73,0.89)
Race C<3Mca5/an Black Hispanic Asian Other Ref 0.71 (0.60, 0.84) 1.25 (1.12, 1.40) 0.93 (0.75, 1.15) 1.24(0.86, 1.80)Ref 0.73 (0.61, 0.88) 1.27 (1.12, 1.43) 0.99 (0.77, 1.28) 1.26(0.86, 1.86)
HCC0.97 (0.89, 1.06)-
Previous malignancy 1.13(1.01, 1.27)-
Previous abdominal surgery 1.59 (1.46,1.72)1.53 (1.40,1.67)
TIPS 1.40 (1.23,1.58) 1.31 (1.14,1.49)
BMI at listing 1.02 (1.01, 1.03)1.01 (1.003,1.02)
Pre-LT DM 1.44 (1.32,1.57)1.21 (1.10,1.34)

Disclosures:

Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Consulting: BMS; Grant/Research Support: Eisai, Biotest, Vertex, Gilead, AbbVie, Novartis

The following people have nothing to disclose: Danielle Brandman, Jennifer L. Dodge, John P. Roberts

96

Waitlist outcomes for hepatopulmonary syndrome: Does oxygenation matter?

David S. Goldberg1, Sachin Batra2, Rajasekhar Tanikella2, Steven M. Kowut3, Michael B. Fallon2

1Department of Internal Medicine/ Division of Gastroentrology & Hepatology, University of Pennsylvania, Philadelphia, PA; 2Department of Internal Medicine, Division of Gastroentrology, Hepatology and Nutrition, University of Texas Health Science at Houston, Houston, TX; 3Deportment of Internal Medicine, Division of Pulmonary, Allergy and Critical Care, University of Pennsylvania, Philadelphia, PA

Introduction: Patients with hepatopulmonary syndrome (HPS) are at increased risk of mortality, and are eligible for MELD exception points. Early reports found an increased risk of postliver transplant (LT) mortality in those with a PaO2 <50mmHg but recent studies suggest otherwise. However, these data are based on small single or multi-center cohorts. Methods: We studied HPS patients applying for MELD exceptions from 2/2002-11/2012 by reviewing all exception narratives submitted to a regional review board and linking these data with a UNOS STAR file. We analyzed outcomes stratified by PaO2 using traditional cutpoints of <50, 50-59, and >60mmHg, and then used cubic splines to determine the best cutpoints to predict post-LT survival. We fit multivariable models for pre- and post-LT mortality, accounting for patient and donor factors, time period of listing or LT, and UNOS region. Results: 1, 075 patients applied for an HPS exception during this period. 975 (90.7%) were approved, and of those, 865 (88.2%) had room-air PaO2 data available for analysis. Of the 865, 233 (26.9%) had PaO2<50, 519 (60.0%) a PaO2 of 50-59, and 113 (13.1%) a PaO2 of 60-69.Seventy-five (8.7%) patients were removed pre-LT for death or being too sick, with no differences based on PaO2.636 (73.5%) patients had an LT, of whom 114 (17.9%) died. The unadjusted 3-year post-LT survival was significantly higher for those with a room-air PaO2 of 50-59, and this difference persisted in multivariable models (P=0.006). Based on the cubic spline analysis, the best cutpoints to predict post-LT survival were PaO2 <44.0, 44.1-54.0, 54.1-61.0, and 61.169.9.The multivariable model using these cutpoints performed significantly better (determined by the AIC) and the discrimination of 1-, 3-, and 5- year post-LT survival was markedly better (Table 1). In comparison to the PaO2 of ≤44.0 group, those with a PaO2 of 44.1-54.0 (HR-0.61, 95% CI: 0.43-0.88) and PaO2 of 54.1-61.0 (HR-0.46, 95% CI: 0.30-0.70) had significantly better post-LT survival. Conclusions: The PaO2 in arterial blood is associated with post-LT mortality in HPS patients receiving MELD exceptions. We defined PaO2 cutpoints to risk stratify post-LT survival. Consideration of revising HPS exception policies to define lower limits of PaO2 for exception points may be appropriate to ensure acceptable post-LT outcomes in HPS patients.

Pa02 category, mmHg
Standard Pa02Cubic spline Pa02
< 5050-5960-69<44.0441.−54.054.1-61.061.1-69.9
1-year survival86.9%93.0%87.4%82.6%91.4%93.0%84.0%
3-year survival75.9%86.0%77.9%68.6%83.1%86.7%72.2%
5-year survival69.8%80.1%75.6%59.5%77.5%82.1%69.2%

Disclosures:

Michael B. Fallon - Advisory Committees or Review Panels: Bayer/Onyx; Grant/Research Support: Ikaria Therapeutics, Gilead, ANADYS, Mochida, Eaisi, Research Triangle Institute

The following people have nothing to disclose: David S. Goldberg, Sachin Batra, Rajasekhar Tanikella, Steven M. Kawut

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