Lauren D. Nephew

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Expanding the Donor Pool with Utilization of Extended Criteria DCD Livers
(AASLD, 2019) Mihaylov, Plamen; Mangus, Richard; Ekser, Burcin; Cabrales, Arianna; Timsina, Lava; Fridell, Jonathan; Lacerda, Marco; Ghabril, Marwan; Nephew, Lauren; Chalasani, Naga; Kubal, Chandrashekhar A.; Pediatrics, School of Medicine
Utilization of donation after circulatory death donor (DCD) livers for transplantation has remained cautious in the U.S. The aim of this study was to demonstrate the expansion of DCD liver transplant (LT) program with the use of extended criteria DCD livers. After institutional review board approval, 135 consecutive DCD LTs were retrospectively studied. ECD DCD livers were defined as those with one of the followings: 1) donor age >50 years, 2) donor BMI >35 kg/m2, 3) donor functional warm ischemia time (fWIT) >30 minutes, and 4) donor liver macrosteatosis >30%. An optimization protocol was introduced in July 2011 to improve outcomes of DCD LT, which included thrombolytic donor flush, and efforts to minimize ischemic times. The impact of this protocol on outcomes was evaluated in terms of graft loss, ischemic cholangiopathy (IC) and change in DCD LT volume. Of 135 consecutive DCD LT, 62 were ECD DCDs. 24 ECD DCD LT were performed before (Era I) and 38 after the institution of optimization protocol (Era II), accounting for an increase in the use of ECD DCD livers from 39% to 52%. Overall outcomes of ECD DCD LT improved in Era II, with a significantly lower incidence of IC (5% vs. 17% in Era I; P = 0.03) and better 1‐year graft survival (93% vs. 75% in Era I, P = 0.07). Survival outcomes for ECD DCD LT in Era II were comparable to matched deceased donor (DBD) LT. With the expansion of the DCD donor pool, the number of DCD LT performed at our center gradually increased in Era II to account for > 20% of the center's LT volume. In conclusion, with the optimization of perioperative conditions, ECD DCD livers can be successfully transplanted to expand the donor pool for LT.
Racial Disparities in Liver Transplantation for Hepatocellular Carcinoma Are Not Explained by Differences in Comorbidities, Liver Disease Severity, or Tumor Burden
(Wiley, 2018-12-03) Dakhoul, Lara; Gawrieh, Samer; Jones, Keaton R.; Ghabril, Marwan; McShane, Chelsey; Orman, Eric; Vilar‐Gomez, Eduardo; Chalasani, Naga; Nephew, Lauren; Medicine, School of Medicine
Black patients have higher mortality and are less likely to receive liver transplantation for hepatocellular carcinoma (HCC) than white patients. Reasons for these disparities have not been fully elucidated. Comorbid disease, liver disease severity, cirrhosis etiologies, and tumor characteristics were compared between black and white patients with HCC seen at the Indiana University Academic Medical Center from January 2000 to June 2014. Logistic regression was used to investigate the primary outcome, which was liver transplantation. Log-rank testing was used to compare survival between the two groups. Subgroup analysis explored reasons for failure to undergo liver transplantation in patients within Milan criteria. The cohort included 1,032 (86%) white and 164 (14%) black patients. Black and white patients had similar Model for End-Stage Liver Disease (MELD) and Child-Pugh scores (CPSs). There was a trend toward larger tumor size (5.3 cm versus 4.7 cm; P = 0.05) in black patients; however, Barcelona Clinic Liver Cancer (BCLC) staging and Milan criteria were similar. Black patients were less likely to undergo liver transplantation than white patients; this was a disparity that was not attenuated (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.21-0.90) on multivariable analysis. Substance abuse was more frequently cited as the reason black patients within Milan criteria failed to undergo transplantation compared to white patients. Survival was similar between the two groups. Conclusion: Racial differences in patient and tumor characteristics were small and did not explain the disparity in liver transplantation. Higher rates of substance abuse in black patients within Milan criteria who failed to undergo transplantation suggest social factors contribute to this disparity in this cohort.
Trends in Characteristics, Mortality, and Other Outcomes of Patients With Newly Diagnosed Cirrhosis
(American Medical Association, 2019-06-05) Orman, Eric S.; Roberts, Anna; Ghabril, Marwan; Nephew, Lauren; Desai, Archita; Patidar, Kavish; Chalasani, Naga; Medicine, School of Medicine
Importance: Changes in the characteristics of patients with cirrhosis are likely to affect future outcomes and are important to understand in planning for the care of this population. Objective: To identify changes in demographic and clinical characteristics and outcomes in patients with newly diagnosed cirrhosis. Design, Setting, and Participants: A retrospective cohort study of patients with a new diagnosis of cirrhosis was conducted using the Indiana Network for Patient Care, a large statewide regional health information exchange, between 2004 and 2014. Patients with at least 1 year of continuous follow-up before the cirrhosis diagnosis were followed up through August 1, 2015. The analysis was conducted from December 2018 to January 2019. Exposures: Age, cause of cirrhosis, and year of diagnosis. Main Outcomes and Measures: Overall rates for mortality, liver transplant, hepatocellular carcinoma, and hepatic decompensation (composite of ascites, hepatic encephalopathy, or variceal bleeding). Results: A total of 9261 patients with newly diagnosed cirrhosis were identified (mean [SD] age, 57.9 [12.6] years; 5109 [55.2%] male). A 69% increase in new diagnoses occurred over the course of the study period (620 in 2004 vs 1045 in 2014). The proportion of those younger than 40 years increased by 0.20% per year (95% CI, 0.04% to 0.36%; P for trend = .02), and the proportion of those aged 65 years and older increased by 0.81% per year (95% CI, 0.51% to 1.11%; P for trend < .001). The proportion of patients with alcoholic cirrhosis increased by 0.80% per year (95% CI, 0.49% to 1.12%), and the proportion with nonalcoholic steatohepatitis increased by 0.59% per year (95% CI, 0.30% to 0.87%), whereas the proportion with viral hepatitis decreased by 1.36% per year (95% CI, -1.68% to -1.03%) (P < .001 for all). In patients younger than 40 years, 40 to 64 years, and 65 years and older, mortality rates were 6.4 (95% CI, 5.4 to 7.6), 9.9 (95% CI, 9.5 to 10.4), and 16.2 (95% CI, 15.2 to 17.2) per 100 person-years, respectively (P < .001). Mortality rates decreased during the study period (11.9 [95% CI, 10.7-13.1] per 100 person-years in 2004 vs 10.0 [95% CI, 8.1-12.2] per 100 person-years in 2014; annual adjusted hazard ratio, 0.87 [95% CI, 0.86 to 0.88]) and were lower in those with alcoholic cirrhosis compared with patients with viral hepatitis (adjusted hazard ratio, 0.89 [95% CI, 0.80 to 0.98]). Rates of hepatocellular carcinoma were low in patients younger than 40 years (0.5 [95% CI, 0.2 to 0.9] per 100 person-years). Liver transplant rates were low throughout the study period (0.3 [95% CI, 0.3-0.4] per 100 person-years). In patients with compensated cirrhosis, rates of hepatic decompensation were lower in patients younger than 40 years (adjusted subhazard ratio 0.78; 95% CI, 0.62 to 0.99) and in patients with nonalcoholic steatohepatitis (adjusted subhazard ratio, 0.51; 95% CI, 0.43 to 0.60). Conclusions and Relevance: The population of patients with newly diagnosed cirrhosis in Indiana has experienced changes in the age distribution and cause of cirrhosis, with decreasing mortality rates. These findings support investment in the prevention and treatment of alcoholic liver disease and nonalcoholic steatohepatitis, particularly in younger and older patients. Additional study is needed to identify the reasons for decreasing mortality rates.
Black Adult Patients With Acute Liver Failure Are Sicker and More Likely to Undergo Liver Transplantation Than White Patients
(Wiley, 2019) Nephew, Lauren; Zia, Zahra; Ghabril, Marwan; Orman, Eric; Lammert, Craig; Chalasani, Naga; Medicine, School of Medicine
Racial and ethnic differences in the presentation and outcomes of patients wait‐listed with acute liver failure (ALF) have not been explored. Adult patients with ALF wait‐listed for liver transplantation (LT) from 2002 to 2016 were investigated using the United Network for Organ Sharing database. Clinical characteristics and causative etiologies were compared between white, black, Hispanic, and Asian patients with ALF who were wait‐listed as status 1. A competing risk analysis was used to explore differences in LT and wait‐list removal rates. Kaplan‐Meier survival curves were used to explore differences in 1‐year posttransplant survival. There were 8208 patients wait‐listed with a primary diagnosis of ALF; 4501 were wait‐listed as status 1 (55.3% of whites, 64.4% of blacks, 51.6% of Hispanics, 40.7% of Asians; P < 0.001). Black patients had higher bilirubin and Model for End‐Stage Liver Disease at wait‐listing than other groups. White patients were the most likely to have acetaminophen toxicity as a causative etiology, whereas black patients were the most likely to have autoimmune liver disease. Black patients were significantly more likely to undergo LT than white patients (hazard ratio, 1.20; 95% confidence interval, 1.08‐1.30). There was no difference in wait‐list removal because of death or clinical deterioration among racial/ethnic groups. The 1‐year posttransplant survival was lowest in black patients (79.6%) versus white (82.8%), Hispanic (83.9%), and Asian (89.3%) patients (P = 0.02). In conclusion, etiologies of ALF vary by race and ethnicity. Black patients with ALF were more likely to be wait‐listed as status 1 and undergo LT than white patients, but they were sicker at presentation. The 1‐year posttransplant survival rate was lowest among black patients.
Development and Validation of a Model to Predict Acute Kidney Injury in Hospitalized Patients With Cirrhosis
(Wolters Kluwer, 2019-09) Patidar, Kavish R.; Xu, Chenjia; Shamseddeen, Hani; Cheng, Yao-Wen; Ghabril, Marwan S.; Mukthinuthalapati, V.V. Pavan K.; Fricker, Zachary P.; Akinyeye, Samuel; Nephew, Lauren D.; Desai, Archita P.; Anderson, Melissa; El-Achkar, Tarek M.; Chalasani, Naga P.; Orman, Eric S.; Medicine, School of Medicine
OBJECTIVES: Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis which contributes to morbidity and mortality. Improved prediction of AKI in this population is needed for prevention and early intervention. We developed a model to identify hospitalized patients at risk for AKI. METHODS: Admission data from a prospective cohort of hospitalized patients with cirrhosis without AKI on admission (n = 397) was used for derivation. AKI development in the first week of admission was captured. Independent predictors of AKI on multivariate logistic regression were used to develop the prediction model. External validation was performed on a separate multicenter cohort (n = 308). RESULTS: In the derivation cohort, the mean age was 57 years, the Model for End-Stage Liver Disease score was 17, and 59 patients (15%) developed AKI after a median of 4 days. Admission creatinine (OR: 2.38 per 1 mg/dL increase [95% CI: 1.47-3.85]), international normalized ratio (OR: 1.92 per 1 unit increase [95% CI: 1.92-3.10]), and white blood cell count (OR: 1.09 per 1 × 10/L increase [95% CI: 1.04-1.15]) were independently associated with AKI. These variables were used to develop a prediction model (area underneath the receiver operator curve: 0.77 [95% CI: 0.70-0.83]). In the validation cohort (mean age of 53 years, Model for End-Stage Liver Disease score of 16, and AKI development of 13%), the area underneath the receiver operator curve for the model was 0.70 (95% CI: 0.61-0.78). DISCUSSION: A model consisting of admission creatinine, international normalized ratio, and white blood cell count can identify patients with cirrhosis at risk for in-hospital AKI development. On further validation, our model can be used to apply novel interventions to reduce the incidence of AKI among patients with cirrhosis who are hospitalized.
Association of State Medicaid Expansion With Racial/Ethnic Disparities in Liver Transplant Wait-listing in the United States
(JAMA, 2020-10-08) Nephew, Lauren D.; Mosesso, Kelly; Desai, Archita; Ghabril, Marwan; Orman, Eric S.; Patidar, Kavish R.; Kubal, Chandrashekhar; Noureddin, Mazen; Chalasani, Naga; Medicine, School of Medicine
Importance Millions of Americans gained insurance through the state expansion of Medicaid, but several states with large populations of racial/ethnic minorities did not expand their programs. Objective To investigate the implications of Medicaid expansion for liver transplant (LT) wait-listing trends for racial/ethnic minorities. Design, Setting, and Participants A cohort study was performed of adults wait-listed for LT using the United Network of Organ Sharing database between January 1, 2010, and December 31, 2017. Poisson regression and a controlled, interrupted time series analysis were used to model trends in wait-listing rates by race/ethnicity. The setting was LT centers in the United States. Main Outcomes and Measures (1) Wait-listing rates by race/ethnicity in states that expanded Medicaid (expansion states) compared with those that did not (nonexpansion states) and (2) actual vs predicted rates of LT wait-listing by race/ethnicity after Medicaid expansion. Results There were 75 748 patients (median age, 57.0 [interquartile range, 50.0-62.0] years; 48 566 [64.1%] male) wait-listed for LT during the study period. The cohort was 8.9% Black and 16.4% Hispanic. Black patients and Hispanic patients were statistically significantly more likely to be wait-listed in expansion states than in nonexpansion states (incidence rate ratio [IRR], 1.54 [95% CI, 1.44-1.64] for Black patients and 1.21 [95% CI, 1.15-1.28] for Hispanic patients). After Medicaid expansion, there was a decrease in the wait-listing rate of Black patients in expansion states (annual percentage change [APC], −4.4%; 95% CI, −8.2% to −0.6%) but not in nonexpansion states (APC, 0.5%; 95% CI, −4.0% to 5.2%). This decrease was not seen when Black patients with hepatitis C virus (HCV) were excluded from the analysis (APC, 3.1%; 95% CI, −2.4% to 8.9%), suggesting that they may be responsible for this expansion state trend. Hispanic Medicaid patients without HCV were statistically significantly more likely to be wait-listed in the post–Medicaid expansion era than would have been predicted without Medicaid expansion (APC, 13.2%; 95% CI, 4.0%-23.2%). Conclusions and Relevance This cohort study found that LT wait-listing rates have decreased for Black patients with HCV in states that expanded Medicaid. Conversely, wait-listing rates have increased for Hispanic patients without HCV. Black patients and Hispanic patients may have benefited differently from Medicaid expansion.
Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis
(Springer, 2019-01-07) Dakhoul, Lara; Jones, Keaton R.; Gawrieh, Samer; Ghabril, Marwan; McShane, Chelsey; Vuppalanchi, Raj; Vilar-Gomez, Eduardo; Nephew, Lauren; Chalasani, Naga; Lammert, Craig; Medicine, School of Medicine
Background: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood. Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design. Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case. Results: Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC. Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC.
Systemic racism and overcoming my COVID-19 vaccine hesitancy
(Elsevier, 2021-02) Nephew, Lauren D.; Medicine, School of Medicine
Extra-hepatic comorbidity burden significantly increases 90-day mortality in patients with cirrhosis and high model for endstage liver disease
(BMC, 2020-09-16) Coppel, Scott; Mathur, Karan; Ekser, Burcin; Patidar, Kavish R.; Orman, Eric; Desai, Archita P.; Vilar-Gomez, Eduardo; Kubal, Chandrashekhar; Chalasani, Naga; Nephew, Lauren; Ghabril, Marwan; Medicine, School of Medicine
Background We examined how extra-hepatic comorbidity burden impacts mortality in patients with cirrhosis referred for liver transplantation (LT). Methods Adults with cirrhosis evaluated for their first LT in 2012 were followed through their clinical course with last follow up in 2019. Extra-hepatic comorbidity burden was measured using the Charlson Comorbidity Index (CCI). The endpoints were 90-day transplant free survival (Cox-Proportional Hazard regression), and overall mortality (competing risk analysis). Results The study included 340 patients, mean age 56 ± 11, 63% male and MELD-Na 17.2 ± 6.6. The CCI was 0 (no comorbidities) in 44%, 1–2 in 44% and > 2 (highest decile) in 12%, with no differences based on gender but higher CCI in patients with fatty and cryptogenic liver disease. Thirty-three (10%) of 332 patients not receiving LT within 90 days died. Beyond MELD-Na, the CCI was independently associated with 90-day mortality (hazard ratio (HR), 1.32 (95% confidence interval (CI) 1.02–1.72). Ninety-day mortality was specifically increased with higher CCI category and MELD ≥18 (12% (CCI = 0), 22% (CCI = 1–2) and 33% (CCI > 2), (p = 0.002)) but not MELD-Na ≤17. At last follow-up, 69 patients were alive, 100 underwent LT and 171 died without LT. CCI was associated with increased overall mortality in the competing risk analysis (Sub-HR 1.24, 95%CI 1.1–1.4). Conclusions Extra-hepatic comorbidity burden significantly impacts short-term mortality in patients with cirrhosis and high MELD-Na. This has implications in determining urgency of LT and mortality models in cirrhosis and LT waitlisting, especially with an ageing population with increasing prevalence of fatty liver disease.
Admission plasma uromodulin and the risk of acute kidney injury in hospitalized patients with cirrhosis: a pilot study
(American Physiological Society, 2019-10-01) Patidar, Kavish R.; Garimella, Pranav S.; Macedo, Etienne; Slaven, James E.; Ghabril, Marwan S.; Weber, Regina E.; Anderson, Melissa; Orman, Eric S.; Nephew, Lauren D.; Desai, Archita P.; Chalasani, Naga; El-Achkar, Tarek M.; Medicine, School of Medicine
Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis. Uromodulin, a protein uniquely produced by the kidney and released both in the urine and circulation, has been shown to regulate AKI and is linked to tubular reserve. Although low levels of urine uromodulin are associated with AKI after cardiac surgery, it is unclear whether circulating uromodulin can stratify the risk of AKI, particularly in a susceptible population such as hospitalized patients with cirrhosis. Thus, we investigated whether plasma uromodulin measured at the time of admission is associated with subsequent hospital-acquired AKI (defined by a rise in serum creatinine >0.3mg/dL within 48 h or ≥ 1.5 times baseline) in patients with cirrhosis. A total of 98 patients [mean age 54 yr, Model for Endstage Liver Disease Sodium (MELD-Na) score 19, and baseline creatinine of 0.95 mg/dL] were included, of which 13% (n = 13) developed AKI. Median uromodulin levels were significantly lower in patients who developed AKI compared with patients who did not (9.30 vs. 13.35 ng/mL, P = 0.02). After adjusting for age, sex, diabetes, hypertension, albumin, and MELD-Na score as covariates on multivariable logistic regression, uromodulin was independently associated with AKI [odd ratios of 1.19 (95% confidence interval 1.02, 1.37; P = 0.02)]. Lower uromodulin levels on admission are associated with increased odds of subsequent AKI in hospitalized patients with cirrhosis. Further studies are needed to better understand the role of uromodulin in the pathogenesis and as a predictive biomarker of AKI in this population. NEW & NOTEWORTHY In this study, we found that admission plasma uromodulin levels are significantly lower in patients who developed subsequent acute kidney injury (AKI) during their hospital stay compared with patients who did not. Additionally, uromodulin is independently associated with AKI development after adjusting for clinically relevant parameters such as age, sex, diabetes, hypertension, severity of cirrhosis, and kidney function. To our knowledge, this is the first study linking plasma uromodulin with AKI development in patients with cirrhosis.

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