Arun B. Jesudian

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common conditions among patients with cirrhosis whose development is associated with increased morbidity and mortality. Recurrent episodes of AKI within this population can ultimately lead to CKD, while patients with underlying CKD are in turn more likely to experience AKI. Determining the etiology of kidney dysfunction in the setting of cirrhosis is often challenging given the considerable limitations of currently available diagnostic tools. Ongoing research into the role of novel serum and urine biomarkers may allow for more timely diagnosis and treatment of kidney injury among patients with cirrhosis. This review provides an overview of kidney dysfunction in cirrhosis with a focus on the role of these emerging biomarkers for diagnosis of AKI and CKD.

Background: Rifaximin treatment is associated with reduced rates of overt hepatic encephalopathy (OHE) hospitalization relative to lactulose alone. This real-world study evaluated the impact of treatment on rehospitalizations following an initial OHE hospitalization among commercial, Medicare, and Medicaid patients treated with rifaximin±lactulose or lactulose only. Methods: Claims data from January 1, 2016, to September 30, 2023, were used to identify adults with an initial OHE hospitalization under commercial, Medicare, and/or Medicaid coverage (index date was the day following discharge). Patients were stratified into either the rifaximin cohort (±lactulose) or the lactulose-only cohort based on treatments received within 30 days following discharge. The 30-day OHE rehospitalization rate and OHE rehospitalization rate per-patient-per-year were compared between cohorts using adjusted logistic regression and negative binomial regressions, respectively. Subgroup analyses were conducted based on the timing of rifaximin treatment and adherence to treatment guidelines. Results: The study included 7880 patients with an OHE hospitalization with commercial insurance (rifaximin: 5997; lactulose only: 1883), 4131 patients with Medicare insurance (rifaximin: 2419; lactulose only: 1712), and 2924 patients with Medicaid insurance (rifaximin: 1854; lactulose only: 1070). After adjustment, rifaximin was associated with a lower risk of 30-day OHE rehospitalization and lower OHE rehospitalization rates per-patient-per-year than lactulose in commercial (OR=1.75, incidence rate ratio [IRR]=1.67, respectively), Medicare (OR=1.61, IRR=1.51), and Medicaid (OR=1.50, IRR=1.54; all p <0.05) populations. Patients immediately receiving rifaximin and those with AASLD guideline-adherent escalation to rifaximin had the fewest rehospitalizations. Conclusions: Timely treatment with rifaximin in adherence with clinical practice guidelines following an initial OHE hospitalization was associated with improved short-term and longer-term rehospitalization outcomes, regardless of insurance type.

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of global cancer mortality, with increasing incidence and persistently poor survival. Hepatitis C virus (HCV) is a major risk factor for HCC, and while the advent of direct-acting antivirals (DAAs) has significantly altered HCV-related hepatocellular cancer (HCC-HCV) risk, the global burden remains substantial. With the World Health Organization (WHO) aiming to reduce hepatitis-related deaths by 2030, we set out to evaluate global HCC-HCV trends from 1990 to 2021, stratified by sex, WHO region, and sociodemographic index (SDI), using data from the Global Burden of Disease (GBD) 2021 study. Methods: We analyzed age-standardized incidence (ASI), deaths, and disability-adjusted life years (DALYs) due to HCV-HCC from 1990 to 2021 using GBD 2021 data. Trends were stratified by WHO region, sociodemographic index (SDI), and sex. Joinpoint regression modeling was used to identify statistically significant temporal inflection points and calculate the annual percent change (APC) in unique time segments and average annual percent change (AAPC) over the entire study period (1990 to 2021). Results: Globally, deaths and DALYs attributable to HCV-HCC increased over the study period while ASI declined modestly. The region of the Americas exhibited the highest AAPC in all three metrics, potentially driven by an aging HCV-infected population, rising comorbidities (e.g., obesity, diabetes), and improved case detection. Nevertheless, on a global level, high-SDI regions showed the most favorable trends, particularly after 2016, likely reflecting the earlier adoption of DAAs and a differential success of WHO goals. Lower-SDI regions continued to exhibit increasing burden. Notably, ASI began to rise again between 2019 and 2021, suggesting an ongoing need to critically evaluate and restructure our approach to reducing HCV and HCV-HCC. Conclusions: Our findings underscore the urgent need for equity-driven, region-specific strategies to achieve better control of this highly morbid disease.

Background.: A major contributor to increased healthcare spending in the United States is drug pricing, as US drug prices are nearly 3× higher than those in other countries. This cross-sectional study aimed to investigate current global price differences in liver transplant medications and provide potential cost savings for Medicare Part D if international reference pricing was adopted. Methods.: Publicly available drug formularies for Canada, the United Kingdom, Japan, France, Germany, Italy, and Australia were used to collect 2024 prices for 8 commonly used liver transplant medications (mycophenolate mofetil, mycophenolate sodium, sirolimus, tacrolimus, Advagraf, Envarsus, everolimus, and cyclosporine). US prices were obtained from UptoDate’s 2024 listed representative average wholesale prices and Medicare Part D’s drug prices from 2022. Results.: The average US wholesale price and Medicare spend for originator liver transplant medications were 4.1× and 6.8×, respectively, the average originator prices in G7 countries and Australia. Adopting the average global originator drug price per dose may lead to an estimated $26 141 463 in cost savings per year to Medicare. The average US wholesale price and Medicare spend for generic liver transplant medications were 2.76× and 3.75×, respectively, the global average generic prices. Adopting the average global generic drug price per dose may lead to an estimated $363 538 474 in cost savings per year to Medicare. Conclusions.: This study demonstrates the significantly greater financial burden that liver transplant patients in the United States face compared with liver transplant patients in 7 other major industrial countries. Future adoption of international reference pricing may help bridge this pricing disparity.

Introduction Continuous treatment with rifaximin 550 mg (hereafter rifaximin) is associated with lower hospitalization rates in patients with hepatic encephalopathy (HE); however, access barriers may exist. This study assessed gaps in rifaximin access and the impact of treatment gaps, particularly those resulting from claim rejections, on hospitalizations and healthcare costs among patients with HE in the United States. Methods The IQVIA PharMetrics^® Plus database linked with Longitudinal Access and Adjudicated Data (2015–2022) were used to identify adults with HE who had ≥ 1 paid rifaximin prescription fill. Rifaximin treatment gaps were assessed during the 12-month period from the first observed attempt at receiving rifaximin (index date). Adjusted number of overt HE (OHE) hospitalizations and healthcare costs were compared over the 6 months following the index date between Cohort 1, who had no gap due to claim rejection and had < 7 days of treatment gap due to other reasons, and Cohort 2, who had ≥ 1 rejection gap or had ≥ 7 days of non-rejection gap. Results During the year following the index date, 94.7% of the 1711 patients experienced a treatment gap, including 34.8% with initiation gaps from first attempt at receiving rifaximin to first paid claim (77.7% of initiation gaps due to rejected claims) and 72.0% with gaps in access during active treatment (14.8% of active treatment gaps due to rejected claims). Compared with Cohort 1 (n = 432; mean age 56.3 years), Cohort 2 (n = 679; mean age 54.8 years) had 1.55 times the incidence rate of OHE hospitalizations [adjusted incidence rate ratio: 1.55 (95% confidence interval: 1.10–2.20)] and incurred US$1579 more in healthcare-associated costs per-patient-per-month (all p < 0.05). Conclusion Prescription claim rejections frequently led to delays in rifaximin initiation and gaps in access during active treatment. Access barriers to rifaximin were associated with increased hospitalizations and healthcare costs in patients with HE.

Background: Acute kidney injury (AKI) is one of the common complications of liver cirrhosis. It occurs in nearly 20% of patients with cirrhosis who are hospitalized. Prior literature demonstrated that the AKI occurrence in patients with cirrhosis is independently associated with higher mortality. However, there are data assessing predictors and outcomes of AKI resolution in hospitalized patients with cirrhosis. Therefore, the aim of the current study was to identify clinical predictors of AKI resolution among inpatients with cirrhosis that are easily obtained and to evaluate the clinical outcomes of those patients. Methods: The current study is a retrospective cohort of patients with cirrhosis who were hospitalized and had AKI between 2012 and 2020 at a tertiary referral center. Patients included in this study were identified using the International Classification of Diseases 9 codes and then they were manually verified by two independent chart reviewers. AKI was classified according to the AKI Network (AKIN) serum creatinine (Cr) criteria, with AKIN resolution defined as AKIN stage 1 or lower at the time of discharge, while unresolved AKIN was defined as AKIN stage 2 or 3 at the time of discharge. For univariate analysis, Fisher’s exact and the two-sample T-test were utilized. For multivariable analysis, stepwise logistic regression was performed to evaluate variables associated with AKIN resolution. Survival curves were estimated and compared using the Kaplan–Meier method and Log-Rank Test. A p-value cutoff of 0.05 was used for statistical significance. Results: Between 2012 and 2020, there were 140 patients who were included (59% males). The majority of patients had viral hepatitis (54%) as the cirrhosis etiology with 80% of them having hepatitis C virus. Most patients had fluid-responsive AKI (49%), and stage 1 AKIN (69%). In terms of outcomes, the majority of patients (117 patients; 84%) had AKIN resolution at the time of discharge. In the multivariable analysis, after adjusting for clinical meaningful variables, our study shows that higher albumin value at the time of admission (adjusted Odds Ratio “aOR” = 3.28; p = 0.01) and non-metabolic dysfunction-associated steatotic liver disease (non-MASLD) cirrhosis (aOR = 9.43; p < 0.01) were variables associated with higher odds of AKIN resolution at the time of discharge. Conversely, we show that a higher Cr value at the time of admission was associated with lower odds of AKIN resolution at the time of discharge (aOR = 0.31; p < 0.01). When evaluating mortality, patients with unresolved AKIN at the time of discharge had higher rates of in-hospital mortality (p < 0.01) compared to those with resolved AKIN. Survival curve analyses using the Kaplan–Meier method indicated that patients with resolved AKIN experienced higher 90-day survival rates (p < 0.01). Additionally, those with resolved AKIN demonstrated greater transplant-free survival compared to patients with unresolved AKIN at both the 1-year (p = 0.04) and 3-year (p < 0.01) follow-ups. Conclusions: When evaluating clinical predictors of AKIN resolution in admitted patients with cirrhosis, our study showed that a higher admission albumin value and non-MASLD etiology of cirrhosis were associated with higher odds of AKIN resolution at the time of discharge. Conversely, a higher admission Cr value was associated with lower odds of AKIN resolution at the time of discharge. We also demonstrate that AKIN resolution during index admission was associated with improved short- and long-term transplant-free survival (up to 3 years). Our findings warrant external validation in larger cohorts to further evaluate the impact of inpatient AKI resolution on cirrhosis outcomes. Our findings can help clinicians predict AKIN outcomes and encourage more aggressive management of AKI, especially in high-risk patients, which can improve mortality.