Liver transplantation provides survival benefit at all levels of frailty: From the Multicenter Functional Assessment in Liver Transplantation Study.

BACKGROUND AND AIMS: Offering LT to frail patients may reduce waitlist mortality but may increase post-LT mortality. LT survival benefit is the concept of balancing these risks. We sought to quantify the net survival benefit with LT by liver frailty index (LFI). APPROACH AND RESULTS: We analyzed data in the multicenter Functional Assessment in LT (FrAILT) study from 2012 to 2021. Pre-LT cohort included ambulatory patients with cirrhosis awaiting LT, without HCC; the post-LT cohort included those who underwent LT. Primary outcomes were pre-LT and post-LT mortality. We computed 1-, 3-, and 5-year restricted mean survival times (RMSTs) from adjusted Cox models. The survival benefit was calculated as a net gain in life-years with LT. Pre-LT cohort included 2628 patients: median Model for End-Stage Liver Disease-Sodium was 18 (IQR: 14-22); 731 (28%) were frail; 440 (17%) died before LT. Post-LT cohort included 1335 patients: median Model for End-Stage Liver Disease-Sodium was 20 (IQR: 14-24); 325 (24%) were frail; 103 (8%) died after LT. Pre-LT RMST decreased substantially as LFI increased. Post-LT RMST also decreased as LFI increased but only modestly. There was no LFI threshold at which pre-LT and post-LT RMST intersected-patients had net survival benefits at all LFI values. CONCLUSIONS: Pre-LT and, to a lesser degree, post-LT mortality increased as LFI increased. Transplant offered a survival benefit at all LFI values, driven by a reduction in pre-LT mortality. No threshold of LFI was identified at which the risk of post-LT mortality exceeded pre-LT mortality. LT offers net survival benefits even in the presence of advanced frailty among those selected for LT.

Association between protein-energy malnutrition and healthcare use among adult patients after liver transplantation: A retrospective cohort study.

BACKGROUND: Protein-energy malnutrition is associated with poor surgical outcomes in liver transplant patients, but its impact on healthcare use has not been precisely characterized. We sought to quantify the burden of protein-energy malnutrition in hospitalized patients undergoing liver transplantation. METHODS: Current Procedural Terminology codes were used to identify United States hospitalizations between 2011 and 2018 for liver transplantation using the Nationwide Inpatient Sample. Patients <18 years old were excluded. Protein-energy malnutrition was identified by International Classification of Diseases Ninth and Tenth Revision codes. Multivariable regression was used to determine associations between protein-energy malnutrition and hospital outcomes, including hospital length of stay and hospital charges/costs. RESULTS: Of 9856 hospitalizations, 2835 (29%) had protein-energy malnutrition. Patients with protein-energy malnutrition had greater comorbidity burden and in-hospital acuity (eg, dialysis, sepsis, vasopressors, or mechanical ventilation). The adjusted median difference of protein-energy malnutrition vs no protein-energy malnutrition for length of stay was 6.4 days (95% CI, 5.6-7.1; P < 0.001), for hospital charges was $108,063 (95% CI, $93,172-$122,953; P < 0.001), and for hospital costs was $23,636 (95% CI, $20,390-$26,882; P < 0.001). CONCLUSION: Among patients undergoing liver transplantation, protein-energy malnutrition was associated with increased length of stay and hospital charges/costs. The additional cost of protein-energy malnutrition to liver transplantation programs was $23,636 per protein-energy malnutrition hospitalization. Our data justify the development of and investment in personnel and programs dedicated to reversing-or even preventing-protein-energy malnutrition in patients awaiting liver transplantation.

Clinically relevant cut-points for changes in the Liver Frailty Index are associated with waitlist mortality in patients with cirrhosis.

Physical frailty is a critical determinant of mortality in patients with cirrhosis and can be objectively measured using the Liver Frailty Index (LFI), which is potentially modifiable. We aimed to identify LFI cut-points associated with waitlist mortality. Ambulatory adults with cirrhosis without HCC awaiting liver transplantation from 9 centers from 2012 to 2021 for ≥3 months with ≥2 pre-liver transplantation LFI assessments were included. The primary explanatory variable was the change in LFI from first to second assessments per 3 months (∆LFI); we evaluated clinically relevant ∆LFI cut-points at 0.1, 0.2, 0.3, and 0.5. The primary outcome was waitlist mortality (death or delisting for being too sick), with transplant considered as a competing event. Among 1029 patients, the median (IQR) age was 58 (51-63) years; 42% were female; and the median lab Model for End-Stage Liver Disease-Sodium at first assessment was 18 (15-22). For each 0.1 improvement in ∆LFI, the risk of overall mortality decreased by 6% (cause-specific hazard ratio: 0.94, 95% CI: 0.92-0.97, p < 0.001). ∆LFI was associated with waitlist mortality at cut-points as low as 0.1 (cause-specific hazard ratio: 0.63, 95% CI: 0.46-0.87) and 0.2 (HR: 0.61, 95% CI: 0.42-0.87). An improvement in LFI per 3 months as small as 0.1 in the pre-liver transplantation period is associated with a clinically meaningful reduction in waitlist mortality. These data provide estimates of the reduction in mortality risk associated with improvements in LFI that can be used to assess the effectiveness of interventions targeting physical frailty in patients with cirrhosis.

Renalase Levels are Decreased in Maternal Blood and Placental Tissues in Pregnancies Associated with Preterm Preeclampsia.

Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors associated with PEC during pregnancy is crucial for placental, fetal, and maternal health. Renalase (RNLS) is an anti-inflammatory secretory flavoprotein associated with hypertension. Recent data demonstrated a correlation between maternal serum RNLS and PEC, and work from our group identified RNLS expression in the placenta. However, it remains unknown whether RNLS levels in placenta are altered by preeclampsia. Additionally, it is unclear if there is a differential effect of preterm and term PEC on RNLS. We demonstrate that serum RNLS was reduced in preterm cases of PEC. Similarly, placental RNLS was diminished in the chorion of preterm cases of PEC. However, a reduction of RNLS in the decidua was observed with all cases of PEC, while the levels of RNLS within the placental villi were similar in all cases. Overall, we demonstrate that RNLS correlates with PEC both systemically in maternal serum and locally within the placenta, with variable effects on the different layers of the placenta and more pronounced in preterm cases.

Alcohol-Related Care Among Veterans With Unhealthy Alcohol Use: The Role of Long-Term Opioid Therapy Receipt.

OBJECTIVES: Long-term opioid therapy (LTOT) is potentially dangerous among patients with unhealthy alcohol use because of possible adverse interactions. We examined receipt of alcohol-related care among patients with unhealthy alcohol use receiving LTOT and without opioid receipt. METHODS: We use data collected from 2009 to 2017 in the Women Veterans Cohort Study, a national cohort of Veterans engaged in Veterans Health Administration care. We included patients who screened positive for unhealthy alcohol use (score ≥5) using the Alcohol Use Disorder Identification Consumption questionnaire. Our primary exposure was LTOT (receipt of prescribed opioids for ≥90 days) versus no opioid receipt at the time of the first positive Alcohol Use Disorder Identification Consumption. Our primary outcome was receipt of brief intervention within 14 days of positive alcohol screen. Unadjusted and 4 adjusted modified Poisson regression models assessed prevalence and relative rates (RRs) of outcomes. RESULTS: Among eligible veterans, 6222 of 113,628 (5.5%) received LTOT at screening. Among patients receiving LTOT, 67.5% (95% confidence interval [CI], 66.3%-68.6%) had a documented brief intervention within 14 days of positive screen, compared with 70.1% (95% CI, 69.8%-70.4%) among patients without opioid receipt (RR, 0.96; 95% CI, 0.95-0.98; P < 0.001). Within adjusted models, the rate of brief intervention among patients receiving LTOT remained lower than patients without opioid receipt. CONCLUSIONS: Among patients with unhealthy alcohol use, patients receiving LTOT had significantly lower rates of brief intervention receipt compared with those without opioid receipt, and they should be a focus for interventions to improve alcohol-related care and safer opioid prescribing.

The liver frailty index is a predictor of healthcare utilization after liver transplantation in older adults.

BACKGROUND: Older adults have higher healthcare utilization after liver transplantation (LT), yet objective risk stratification tools in this population are lacking. We evaluated the Liver Frailty Index (LFI) as one potential tool. METHODS: Ambulatory LT candidates ≥65 years without hepatocellular carcinoma (HCC) who underwent LT from 1/2012 to 6/2022 at 8 U.S. centers were included. Estimates of the difference in median using quantile regression were used to assess the adjusted association between LFI and hospitalized days within 90 days post-LT. RESULTS: Of 131 LT recipients, median (interquartile range [IQR]) (1st -3rd quartiles) age was 68 years (66-70); median pre-LT MELD-Na was 19 (15-24). Median LFI was 4.1 (3.6-4.7); 27% were frail (LFI≥4.5). Median hospitalized days within 90 days post-LT was 11 (7-20). Compared with non-frail patients, frail patients were hospitalized for a median of 5 days longer post-LT (95% CI .30-9.7, p = .04). Each .5 unit increase in pre-LT LFI was associated with an increase of 1.16 days (95%CI .42-2.69, p = .02) in hospitalized days post-LT. CONCLUSION: Among older adults undergoing LT, frailty was associated with more hospitalized days within 90 days after LT. The LFI can identify older adults who might benefit from pre-LT or early post-LT programs which may reduce post-LT healthcare utilization, such as early rehabilitation or post-hospital discharge programs.

Clinical Characteristics Associated With Posttransplant Survival Among Adults 70 Years Old or Older Undergoing Liver Transplantation.

GOALS: We sought to identify pre-liver transplantation (LT) characteristics among older adults associated with post-LT survival. BACKGROUND: The proportion of older patients undergoing deceased-donor liver transplantation (DDLT) has increased over time. STUDY: We analyzed adult DDLT recipients in the United Network for Organ Sharing registry from 2016 through 2020, excluding patients listed as status 1 or with a model of end-stage liver disease exceptions for hepatocellular carcinoma. Kaplan-Meier methods were used to estimate post-LT survival probabilities among older recipients (age ≥70 y). Associations between clinical covariates and post-LT mortality were assessed using Cox regressions. RESULTS: Of 22,862 DDLT recipients, 897 (4%) were 70 years old or older. Compared with younger recipients, older recipients had worse overall survival ( P < 0.01) (1 y: 88% vs 92%, 3 y: 77% vs 86%, and 5 y: 67% vs 78%). Among older adults, in univariate Cox regressions, dialysis [hazards ratio (HR): 1.96, 95% CI: 1.38-2.77] and poor functional status [defined as Karnofsky Performance Score (KPS) <40] (HR: 1.82, 95% CI: 1.31-2.53) were each associated with mortality, remaining significant on multivariable Cox regressions. The effect of dialysis and KPS <40 at LT on post-LT survival (HR: 2.67, 95% CI: 1.77-4.01) was worse than the effects of either KPS <40 (HR: 1.52, 95% CI: 1.03-2.23) or dialysis alone (HR: 1.44, 95% CI: 0.62-3.36). Older recipients with KPS >40 without dialysis had comparable survival rates compared with younger recipients ( P = 0.30). CONCLUSIONS: While older DDLT recipients had worse overall post-LT survival compared with younger recipients, favorable survival rates were observed among older adults who did not require dialysis and had poor functional status. Poor functional status and dialysis at LT may be useful to stratify older adults at higher risk for poor post-LT outcomes.

The impact of a blood-culture diagnostic stewardship intervention on utilization rates and antimicrobial stewardship.

Blood-culture overutilization is associated with increased cost and excessive antimicrobial use. We implemented an intervention in the adult intensive care unit (ICU), combining education based on the DISTRIBUTE algorithm and restriction to infectious diseases and ICU providers. Our intervention led to reduced blood-culture utilization without affecting safety metrics.

The tele-liver frailty index (TeLeFI): development of a novel frailty tool in patients with cirrhosis via telemedicine.

Frailty is a critical determinant of outcomes in cirrhosis patients. The increasing use of telemedicine has created an unmet need for virtual frailty assessment. We aimed to develop a telemedicine-enabled frailty tool (tele-liver frailty index). Adults with cirrhosis in the liver transplant setting underwent ambulatory frailty testing with the liver frailty index (LFI) in-person, then virtual administration of (1) validated surveys (eg, SARC-F and Duke Activity Status Index [DASI]), (2) chair stands, and (3) balance. Two models were selected and internally validated for predicting LFI ≥4.4 using: (1) Bayesian information criterion (BIC), (2) C-statistics, and (3) ease of use. Of 145 patients, the median (interquartile range) LFI was 3.7 (3.3-4.2); 15% were frail. Frail (vs not frail) patients reported significantly greater impairment on all virtually assessed instruments. We selected 2 parsimonious models: (1) DASI + chair/bed transfer (SARC-F) (BIC 255, C-statistics 0.78), and (2) DASI + chair/bed transfer (SARC-F) + virtually assessed chair stands (BIC 244, C-statistics 0.79). Both models had high C-statistics (0.76-0.78) for predicting frailty. In conclusion, the tele-liver frailty index is a novel tool to screen frailty in liver transplant patients via telemedicine pragmatically and may be used to identify patients who require in-person frailty assessment, more frequent follow-up, or frailty intervention.

Women with cirrhosis have lower self-rated health than men.

BACKGROUND: Women systematically experience lower rates of liver transplantation (LT) and higher rates of waitlist mortality than men. Self-rated health has been associated with patient outcomes in the global population. We, therefore, assessed gender differences in self-rated and clinician-rated health among LT candidates. METHODS: Ambulatory LT candidates without hepatocellular carcinoma were enrolled from 2012 to 2018. Participants and their hepatologists were asked separately to rate the participant's overall general health on a 6-point scale (0="excellent" to 5="very poor"). Logistic regression was used to assess the associations between covariates and superior self-assessment, defined as 1 SD above the mean self-assessment score. RESULTS: Of 855 participants, the median (interquartile range) self-rated health score was 2 (1-3); 156 (18%) were categorized as superior self-rated health. The correlation between self-rated and clinician-rated health was positive (Spearman's rho 0.3, P<0.001). In univariate analysis, being a woman was associated with lower odds of superior self-rated health (OR 0.7, 95% CI 0.5-1.0, P=0.04), which persisted on multivariable analysis (aOR 0.7, 95% CI 0.4-1.0, P=0.05), controlling for race, frailty, work status, comorbidities, Model for End-Stage Liver Disease-Na, hepatic encephalopathy, and ascites. CONCLUSION: These findings highlight the need for well-designed quality-based research to determine how our patients perceive health to highlight opportunities to offer more comprehensive, quality-based care.

Plasma renalase levels are associated with the development of acute pancreatitis.

BACKGROUND/OBJECTIVES: Severe acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans. METHODS: Plasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis. RESULTS: Control (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 µg/ml, Mild 5.1 µg/ml, Severe 6.0 µg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 µg/ml, Mild 0.9 µg g/ml, Severe 1.2 µg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = -0.31, p = 0.023). CONCLUSION: Low plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes.

Racial and Ethnic Disparities Among Patients Hospitalized for Acute Cholangitis in the United States.

GOALS: We sought to determine whether race/ethnicity is associated with hospitalization outcomes among patients admitted with acute cholangitis. BACKGROUND: Few studies have evaluated the association between race and outcomes in patients with acute cholangitis. STUDY: We analyzed United States hospitalizations from 2009 to 2018 using the Nationwide Inpatient Sample (NIS). We included patients 18 years old or above admitted with an ICD9/10 diagnosis of cholangitis. Race/ethnicity was categorized as White, Black, Hispanic, or Other. We used multivariable regression to determine the association between race/ethnicity and in-hospital outcomes of interest, including endoscopic retrograde cholangiopancreatography (ERCP), early ERCP (<48 h from admission), length of stay (LOS), and in-hospital mortality. RESULTS: Of 116,889 hospitalizations for acute cholangitis, 70% identified as White, 10% identified as Black, 11% identified as Hispanic, and 9% identified as Other. The proportion of non-White patients increased over time. On multivariate analysis controlling for clinical and sociodemographic variables, compared with White patients, Black patients had higher in-hospital mortality (adjusted odds ratio: 1.4, 95% confidence interval: 1.2-1.6, P <0.001). Black patients were also less likely to undergo ERCP, more likely to undergo delayed ERCP, and had longer LOS ( P <0.001 for all). CONCLUSIONS: In this contemporary cohort of hospitalized patients with cholangitis, Black race was independently associated with fewer and delayed ERCP procedures, longer LOS, and higher mortality rates. Future studies with more granular social determinants of health data should further explore the underlying reasons for these disparities to develop interventions aimed at reducing racial disparities in outcomes among patients with acute cholangitis.