Frailty and Outcomes in Liver Transplantation: A Dissertation

In recent years, the transplant community has explored and adopted tools for quantifying clinical insight into illness severity and frailty. This dissertation work explores the interplay between objective and subjective assessments of physical health status and the implications for liver transplant candidate and recipient outcomes. The first aim characterizes national epidemiologic trends and the impact of Centers for Medicare and Medicaid quality improvement policies on likelihood of waitlist removal based on the patient being too frail to benefit from liver transplant (“too sick to transplant”). This aim includes more than a decade (2002–2012) of comprehensive national transplant waitlist data (Scientific Registry of Transplant Recipients (SRTR)). The second aim will assess and define objective parameters of liver transplant patient frailty by measuring decline in lean core muscle mass (“sarcopenia”) using abdominal CT scans collected retrospectively at a single U.S. transplant center between 2006 and 2015. The relationship between these objective sarcopenia measures and subjective functional status assessed using the Karnofsky Functional Performance (KPS) scale are described and quantified. The third aim quantifies the extent to which poor functional status (KPS) pre-transplant is associated with worse post-transplant survival and includes national data on liver transplantations conducted between 2005 and 2014 (SRTR). The results of this dissertation will help providers in the assessment of frailty and subsequent risk of adverse outcomes and has implications for strategic clinical management in anticipation of surgery. This research will also to serve to inform national policy on the design of transplant center performance measures

Donor Diabetes and Prolonged Cold Ischemia Time Synergistically Increase the Risk of Graft Failure After Liver Transplantation

BACKGROUND: Both prolonged cold ischemia time (CIT) and donor history of diabetes mellitus (DM) are associated with reduced graft survival after liver transplantation. However, it is unknown whether the adverse effect of prolonged CIT on posttransplant graft survival is more pronounced after transplant with DM versus non-DM donor grafts. METHODS: The study sample included 58 226 liver transplant recipients (2002-2015) from the Scientific Registry of Transplant Recipients. Multivariable Cox survival regression with interaction analysis was used to quantify the extent to which history of donor DM (n = 6478) potentiates the adverse effect of prolonged ( \u3e /=8 hours) CIT (n = 18 287) on graft survival. RESULTS: Donor DM and CIT 8 hours or longer were each associated with increased risk of graft failure (GF) (adjusted hazard ratio [aHR], 1.19; 95% confidence interval [CI], 1.06-1.35 and aHR, 1.42; 95% CI, 1.32-1.53, respectively) compared with transplanted grafts without either risk factor. However, the combination of DM and CIT 8 hours or longer was associated with a higher risk of GF than either factor alone (aHR, 1.79; 95% CI, 1.55-2.06) and had a synergy index of 1.30. The interaction was significant on a multiplicative scale in the later postoperative period, days 31 to 365 (P = 0.047). CONCLUSIONS: These results suggest that liver grafts from DM donors are more susceptible to the adverse effects of prolonged CIT than livers from non-DM donors. We need to be cognizant that they are more susceptible to ischemic injury, and this may be considered during the allocation process

Association Between Sarcopenia and Functional Status in Liver Transplant Patients

OBJECTIVES: A growing body of evidence shows that frailty and functional performance predict liver transplant outcomes. The Organ Procurement and Transplant Network uses the Karnofsky Performance Status scale to adjust for transplant center case mix in assessing quality measures. This study explores the strength of the relationship between Karnofsky Performance Status scores and objective measures of frailty. MATERIALS AND METHODS: This observational study includes 136 adult, first-time liver transplant recipients at UMass Memorial (2006-2015) who had 2 abdominal computed tomography scans available (at \u3c /= 90 days pretransplant and \u3e /= 7 days before that). We analyzed the relationship between Karnofsky Performance Status and muscle wasting using absolute and change in psoas muscle size and quality pretransplant. RESULTS: The mean age was 55 years, mean Model for End-Stage Liver Disease was 22, and 34% of patients were women. In the study group, 50% of patients had sarcopenia pretransplant and 71.3% demonstrated declined lean psoas area at an average rate of 11% per month. Patients who experienced muscle wasting at a rate of \u3e /= 1% per month had 2.83 times the risk (95% confidence interval, 1.18-6.80) of being severely impaired/disabled pretransplant. The risk increased by 2.32-fold (95% confidence interval, 1.44-3.75) for every standard deviation decrease in pretransplant lean psoas area. CONCLUSIONS: Provider-assessed physical health status moderately correlates with objective measures of frailty

Impact of recipient functional status on 1-year liver transplant outcomes

BACKGROUND: The Karnofsky Performance Status (KPS) scale has been widely validated for clinical practice for over 60 years.AIM: To examine the extent to which poor pre-transplant functional status, assessed using the KPS scale, is associated with increased risk of mortality and/or graft failure at 1-year post-transplantation.METHODS: This study included 38278 United States adults who underwent first, non-urgent, liver-only transplantation from 2005 to 2014 (Scientific Registry of Transplant Recipients). Functional impairment/disability was categorized as severe, moderate, or none/normal. Analyses were conducted using multivariable-adjusted Cox survival regression models.RESULTS: The median age was 56 years, 31% were women, median pre-transplant Model for End-Stage for Liver Disease score was 18. Functional impairment was present in 70%; one-quarter of the sample was severely disabled. After controlling for key recipient and donor factors, moderately and severely disabled patients had a 1-year mortality rate of 1.32 [confidence interval (CI): 1.21-1.44] and 1.73 (95%CI: 1.56-1.91) compared to patients with no impairment, respectively. Subjects with moderate and severe disability also had a multivariable-adjusted 1-year graft failure rate of 1.13 (CI: 1.02-1.24) and 1.16 (CI: 1.02-1.31), respectively.CONCLUSION: Pre-transplant functional status is a useful prognostic indicator for 1-year post-transplant patient and graft survival.</p

Single-Center Experience With Liver Transplant Using Donors With Very High Transaminase Levels

OBJECTIVES: Elevation of transaminases has been used as a marker of hepatic ischemic injury and as a crucial parameter for liver graft assessment. However, analysis of serum transaminases has limitations regarding the quantitative assessment of liver necrosis and is not a reliable predictor of outcomes. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all liver transplants (N = 238) performed at the UMass Memorial Medical Center from 2009 to 2013. RESULTS: Fourteen liver grafts showed high peak aminotransferases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at \u3e 1000 U/L. This high aminotransferase group was compared with 224 donors with low transaminase levels (ALT/AST \u3c 1000 U/L). The high transaminase donors had a median peak AST level of 3216 U/L (range, 1823-13?030 U/L) and ALT level of 2677 U/L (range, 812-7080 U/L). The high transaminase donors showed higher levels of lactate dehydrogenase, international normalized ratio, total bilirubin, and gamma-glutamyltransferase compared with low transaminase donors; however, only lactate dehydrogenase results reached statistical significance. None of the grafts from the high transaminase donors showed primary nonfunction. Three-year graft and patient survival rates were similar in both groups (75% vs 80% [P = .48] and 72% vs 82% [P = .33], respectively). In an analysis of the discard rate of livers over a 10-year period in the United States using the Scientific Registry of Transplant Recipients database, the discard rate of livers with high aminotransferase levels was 69.14% compared with 22.23% for livers with low transaminase levels. CONCLUSIONS: Liver grafts from donors with high transaminase levels can lead to clinical results that are similar to liver grafts from donors who had lower peak transaminase levels

Functional status predicts postoperative mortality after liver transplantation

BACKGROUND: Frail patients are more vulnerable to perioperative stressors of liver transplantation (LT). Program Specific Reports, used in transplant center auditing, risk-adjust for frailty using the Karnofsky Performance Status (KPS) scale. We evaluate the extent to which functional impairment/disability is associated with increased risk of postoperative death. METHODS: We included 24 505 first-time LT recipients from the Scientific Registry of Transplant Recipients (2006-2011). We categorized patients as Severe, Moderate, or Normal function/disability using the KPS scale and evaluated risk of 30- and 90-day mortality. Analyses took potential center-specific differences in KPS measurement protocols into account using hierarchal logistic modeling. RESULTS: Over one-quarter of our population was Severely impaired/disabled, and 30.5% had no functional limitations. Severely and Moderately impaired/disabled patients had 2.56 (95% CI 1.91-3.44) and 1.40 (95% CI 1.10-1.78) times the odds of 30-day mortality, respectively, after adjusting for key recipient and donor factors. Estimates remained consistent regardless of Model for End-Stage Liver Disease score, medical condition, or clustering analyses by center. Technical/operative complications and multiorgan failure/hemorrhage were more common causes of death among more Severely disabled patients than in higher functioning groups. CONCLUSIONS: Pre-transplant functional status, assessed using the KPS scale, is a reliable predictor of post-LT mortality in the United States

Decade-Long Trends in Liver Transplant Waitlist Removal Due to Illness Severity: The Impact of Centers for Medicare and Medicaid Services Policy

BACKGROUND: The central tenet of liver transplant organ allocation is to prioritize the sickest patients first. However, a 2007 Centers for Medicare and Medicaid Services regulatory policy, Conditions of Participation (COP), which mandates publically reported transplant center performance assessment and outcomes-based auditing, critically altered waitlist management and clinical decision making. We examine the extent to which COP implementation is associated with increased removal of the sickest patients from the liver transplant waitlist. STUDY DESIGN: This study included 90,765 adult (aged 18 years and older) deceased donor liver transplant candidates listed at 102 transplant centers from April 2002 through December 2012 (Scientific Registry of Transplant Recipients). We quantified the effect of COP implementation on trends in waitlist removal due to illness severity and 1-year post-transplant mortality using interrupted time series segmented Poisson regression analysis. RESULTS: We observed increasing trends in delisting due to illness severity in the setting of comparable demographic and clinical characteristics. Delisting abruptly increased by 16% at the time of COP implementation, and likelihood of being delisted continued to increase by 3% per quarter thereafter, without attenuation (p \u3c 0.001). Results remained consistent after stratifying on key variables (ie, Model for End-Stage Liver Disease and age). The COP did not significantly impact 1-year post-transplant mortality (p = 0.38). CONCLUSIONS: Although the 2007 Centers for Medicare and Medicaid Services COP policy was a quality initiative designed to improve patient outcomes, in reality, it failed to show beneficial effects in the liver transplant population. Patients who could potentially benefit from transplantation are increasingly being denied this lifesaving procedure while transplant mortality rates remain unaffected. Policy makers and clinicians should strive to balance candidate and recipient needs from a population-benefit perspective when designing performance metrics and during clinical decision making for patients on the waitlist