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We investigated the impact of the inclusion of kidney dysfunction type on the discrimination and calibration of the Model for End-Stage Liver Disease with sodium (MELD-Na-KT) score.We included all adults listed for ≥90 days without exception points from January 1, 2008, through December 31, 2018. We defined kidney dysfunction types as follows: acute kidney disease (AKD; an increase of ≥0.3 mg/dL or ≥50% in serum creatinine in the last 7 days or fewer than 72 days of hemodialysis), chronic kidney disease (CKD; an estimated glomerular filtration rate60 ml/min/1.73 mThis study demonstrates the feasibility and the potential for objectively defined kidney dysfunction types to enhance the prognostication of waitlist mortality provided by the MELD-Na score.

Acute kidney injury (AKI) and frailty are major drivers of outcomes among patients with cirrhosis. What is unknown is the impact of physical frailty on the development of AKI. We included adults with cirrhosis without hepatocellular carcinoma listed for liver transplantation at nine US centers (n=1,033). Frailty was assessed using the Liver Frailty Index (LFI); "frail" was defined by LFI≥4.2. Chronic kidney disease as a baseline estimated glomerular filtration rate

Simultaneous liver-kidney transplantation (SLKT) is increasingly common in the United States. However, little is known about the renal-related outcomes following SLKT, which are essential to maximize the health of these allografts. We examined the factors impacting renal function following SLKT. This is an observational multicenter cohort study from the US Multicenter SLKT Consortium consisting of recipients of SLKT aged ≥18years of transplantations performed between February 2002 and June 2017 at 6 large US centers in 6 different United Network for Organ Sharing regions. The primary outcome was incident post-SLKT stage 4-5 chronic kidney disease (CKD) defined as

AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions.

BACKGROUND: Women on the liver transplant waitlist are at greater risk of hospitalization compared with men, but whether this impacts length of stay (LOS) post-transplant is unknown. We aimed to evaluate gender disparities in post-transplant LOS, an important surrogate of health resource utilization post-transplant. METHODS: Using the UNOS/OPTN registry, we analyzed all non-Status 1 adult deceased donor liver transplant recipients without exception points from 2008–2017. Poisson regression associated female gender with post-transplant LOS. RESULTS: Of 27,294 transplant recipients, 36% were female. Women were more likely to be hospitalized pre-transplant than men (44% vs 39%, p

Risk scoring for patients with cirrhosis has evolved greatly over the past several decades. However, patients with low Model for End-Stage Liver Disease-Sodium scores still suffer from liver-related morbidity and mortality. Unfortunately, it is not clear which of these low Model for End-Stage Liver Disease-Sodium score patients would benefit from earlier consideration of liver transplantation. This article reviews the literature of risk prediction in patients with cirrhosis, identifies which patients may benefit from earlier interventions, such as transplantation, and proposes directions for future research.

The burden of early hospitalization (within 6 months) following simultaneous liver-kidney transplant (SLKT) is not known. We examined risk factors associated with early hospitalization after SLKT and their impact on patient mortality conditional on 6-month survival. We used data from the US Multicenter SLKT Consortium cohort study of all adult SLKT recipients between 2002 and 2017 who were discharged alive following SLKT. We used Poisson regression to model rates of early hospitalizations after SLKT. Cox regression was used to identify risk factors associated with mortality conditional on survival at 6 months after SLKT. Median age (N = 549) was 57.7 years (interquartile range [IQR], 50.6-63.9) with 63% males and 76% Whites; 33% had hepatitis C virus, 20% had non-alcohol-associated fatty liver disease, 23% alcohol-associated liver disease, and 24% other etiologies. Median body mass index (BMI) and Model for End-Stage Liver Disease-sodium scores were 27.2 kg/m

We sought to determine whether race/ethnicity is associated with hospitalization outcomes among patients admitted with acute cholangitis.Few studies have evaluated the association between race and outcomes in patients with acute cholangitis.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.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, P0.001). Black patients were also less likely to undergo ERCP, more likely to undergo delayed ERCP, and had longer LOS (P0.001 for all).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.

Kidney function in patients with cirrhosis is dynamic. After controlling for the presence of chronic kidney disease (CKD) and acute kidney injury (AKI), we investigated the impact of variation in clinical function on pre-liver transplantation (LT) and post-LT outcomes.We included adults listed for LT from 2011 through 2018. We excluded those with any exceptions, those on hemodialysis at listing, and those with fewer than three clinical updates in the United Network for Organ Sharing database. Our primary exposure was the serum creatinine coefficient of variation (sCr CoV). Logistic regression determined the associations between our exposures and higher sCr CoV. Competing risk regression determined the associations between our exposures and waitlist mortality, accounting for LT as a competing risk. Cox regression determined the associations between our exposures and either listing for kidney transplant or death. We divided our cohort into tertiles of sCr CoV: low variability, 8.8% (interquartile range [IQR], 6.6%-10.8%); intermediate variability, 17.4% (IQR, 14.8%-20.4%); high variability, 36.8% (IQR, 29.5%-48.8%). We demonstrate that women, those with CKD, and those with advanced liver disease were more likely to have a greater sCr CoV. Compared to those with low variability, those with high variability had significantly higher waitlist mortality (34.7% vs. 19.6% vs. 11.7%, p 0.001). We highlight that the sCr CoV was associated with higher waitlist and post-LT mortality-an association independent of baseline sCr, the degree of underlying liver disease, the presence of AKI, or the presence of CKD.This study informs the long-term impact of the variation in kidney function we all see in clinical practice. These data highlight that all fluctuations in sCr are associated with worse pre-LT and post-LT outcomes.

BACKGROUND & AIMS: Studies regarding acute-on-chronic liver failure (ACLF) among liver transplant (LT) candidates from the United Network for Organ Sharing (UNOS) database are being used to inform LT policy changes worldwide. We assessed the validity of identifying ACLF in UNOS. METHODS: We performed stratified random sampling among 3 US LT centers between 2013–2019 to obtain a representative patient sample across ACLF grades. We compared the concordance of ACLF classification by UNOS vs. blinded manual chart review, according to EASL-CLIF. RESULTS: Among 481 sampled LT registrants, 250 (52%) had no ACLF, 75 (16%) had ACLF grade 1, 79 (16%) had ACLF Grade 2, and 77 (16%) had ACLF Grade 3 per UNOS categorization. Concordance of ACLF grade by UNOS vs. chart review was: 72%, 64%, 56%, and 64% for no ACLF, Grade 1, Grade 2, and Grade 3, respectively, with overall Cohen’s kappa coefficient 0.48 (95%CI 0.42–0.54). Absence of acute decompensation was the most common reason for overestimation, and discordant brain and respiratory failure categorization were the most common reasons for underestimation of ACLF by UNOS. CONCLUSIONS: In this retrospective multi-center study, ACLF categorization by UNOS showed weak agreement with manual chart review. These findings are informative for ongoing allocation policy discussions, highlight the importance of prospective studies regarding ACLF in LT and should encourage UNOS reform. LAY SUMMARY: Acute-on-chronic-liver-failure (ACLF) is a specific and common form of liver failure with high death rates. Studies have been published using the United States transplant registry (UNOS) to identify and describe outcomes of transplant candidates and recipients with ACLF, and these data are driving policy changes for transplant allocation around the world, but nobody has shown whether these data are reliable. We found that UNOS was not categorizing ACLF in concordance or accurately when compared to chart review, which shows the need for UNOS reform and non-UNOS studies to appropriately inform policies in transplant with ACLF.

We aimed to understand the contemporary changes in the characteristics and the determinants of outcomes among simultaneous liver-kidney transplantation (SLKT) recipients at 6 liver transplantation centers in the United States. We retrospectively enrolled SLKT recipients between 2002 and 2017 in the US Multicenter SLKT Consortium. We analyzed time-related trends in recipient characteristics and outcomes with linear regression and nonparametric methods. Clustered Cox regression determined the factors associated with 1-year and overall survival. We enrolled 572 patients. We found significant changes in the clinical characteristics of SLKT recipients: as compared with 2002, recipients in 2017 were older (59 versus 52years; P&nbsp

Cardiovascular disease is a leading complication after both liver and kidney transplantation. Factors associated with and rates of cardiovascular events (CVEs) after simultaneous liver-kidney transplant (SLKT) are unknown. This was a retrospective cohort study of adult SLKT recipients between 2002 and 2017 at six centers in six United Network for Organ Sharing regions in the US Multicenter SLKT Consortium. The primary outcome was a CVE defined as hospitalization due to acute coronary syndrome, arrhythmia, congestive heart failure, or other CV causes (stroke or peripheral vascular disease) within 1 year of SLKT. Among 515 SLKT subjects (mean age ± SD, 55.4 ± 10.6 years; 35.5% women; 68.1% White), 8.7% had a CVE within 1 year of SLKT. The prevalence of a CVE increased from 3.3% in 2002-2008 to 8.9% in 2009-2011 to 14.0% in 2012-2017 (p = 0.0005). SLKT recipients with a CVE were older (59.9 vs. 54.9 years, p 0.0001) and more likely to have coronary artery disease (CAD) (37.8% vs. 18.4%, p = 0.002) and atrial fibrillation (AF) (27.7% vs. 7.9%, p = 0.003) than those without a CVE. There was a trend toward older age by era of SLKT (p = 0.054). In multivariate analysis adjusted for cardiac risk factors at transplant, age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02, 1.11), CAD (OR, 3.62; 95% CI, 1.60, 8.18), and AF (OR, 2.36; 95% CI, 1.14, 4.89) were associated with a 1-year CVE after SLKT. Conclusion: Among SLKT recipients, we observed a 4-fold increase in the prevalence of 1-year CVEs over time. Increasing age, CAD, and AF were the main potential explanatory factors for this trend independent of other risk factors. These findings suggest that CV risk protocols may need to be tailored to this high-risk population.

BackgroundWith the implementation of the "Safety Net," we aimed to determine the impact of simultaneous liver-kidney transplantation (SLKT), as compared to kidney transplant after liver transplant (KALT), on kidney allograft failure (KF).MethodsAn analysis of the UNOS database for all adult patients who received either an SLKT or KALT from 2002 to 2017. The outcomes were 90-day KF and 1-year KF (as reported to UNOS, at 90- and 365-day postkidney transplant, respectively). We compared the following groups of patients: SLKT

BACKGROUND Women with chronic liver disease have lower rates of hepatocellular carcinoma (HCC) as compared to men; it is unknown if there are sex-based differences in HCC recurrence postliver transplant. METHODS We conducted an analysis of patients who underwent liver transplant for HCC in the United Network for Organ Sharing/Organ Procurement and Transplantation Network from January 1, 2012 through December 31, 2017. RESULTS A total of 12 711 patients underwent liver transplant for HCC: 2909 (23%) women and 9802 (73%) men. Women had significantly lower rates of postliver transplant HCC recurrence than men (4.0% versus 5.4%, P = 0.002). A cox-regression analysis for postliver transplant HCC recurrence highlighted that even after accounting for etiology of cirrhosis, alpha-fetoprotein at liver transplant, tumor diameter, tumor pathology, and vascular invasion, female sex was associated with a 25% lower risk of postliver transplant HCC recurrence (95% confidence interval: 0.57-0.99). There were no interactions between female sex and the following variables: age, type of locoregional therapy, alpha-fetoprotein, donor sex, body mass index, or nonalcoholic steatohepatitis etiology (P > 0.05 for each). CONCLUSIONS This study demonstrates an independent effect of sex on risk for HCC recurrence postliver transplant. Our data highlight an opportunity to better understand HCC tumor biology by investigating the drivers of this sex-based difference in HCC recurrence.

BACKGROUND AND AIMS: Kidney dysfunction is associated with increased mortality among patients with cirrhosis. We investigated whether kidney dysfunction types [e.g., acute kidney injury (AKI), chronic kidney disease (CKD), and AKI on CKD] were differentially associated with inpatient mortality. METHODS: We utilized the nationwide inpatient sample, a nationally representative database, from 2007 to 2014. We included all hospitalizations with previously validated codes for cirrhosis or associated decompensated cirrhosis diagnoses. We defined kidney dysfunction types also from previously validated codes, and we grouped hospitalizations into the following diagnoses: normal, AKI, CKD, and AKI on CKD. Our primary outcome was inpatient mortality. RESULTS: There were 1,293,779 hospitalizations with cirrhosis sampled in this study. Of these hospitalizations, 849,193 (66%) had normal kidney function, 176,418 (14%) had AKI, 157,600 (12%) had CKD, and 110,568 (9%) had AKI on CKD. We found that the proportion of hospitalizations with AKI, CKD, and AKI on CKD increased significantly throughout the study period (p < 0.001, test for trend for all). Kidney dysfunction type was differentially associated with inpatient mortality, even after adjustment: as compared to those with CKD, normal kidney function: OR 0.75 [95 CI 0.73–0.78], AKI: OR 2.40 [95 CI 2.32–2.48], and AKI on CKD: OR 1.66 [95 CI 1.60–1.72]. DISCUSSION: Using a nationally representative cohort of all hospitalizations with cirrhosis, our study highlights that the burden of kidney dysfunction, especially AKI, among hospitalizations with cirrhosis is rising, and the inclusion of kidney dysfunction type may be an opportunity to improve prognostication.

Patients with end-stage renal disease (ESRD) have impaired functional status compared with the general population. We sought to explore the association between Karnofsky Performance Status (KPS) and death/delisting from the kidney transplantation waitlist and whether this association differed by age. Patients listed for single-organ kidney transplantation in the United Network for Organ Sharing/Organ Procurement and Transplantation Network from January 1, 2015, to January 1, 2018, were included. We performed competing-risk regression analyses to determine the association between KPS ("Severely impaired", "Moderately impaired", "Non-impaired") and death/delisting, with deceased-donor kidney transplantation as a competing risk. We tested for interactions between age and KPS on death/delisting. Of the 89,819 patients analyzed, 39% were impaired (KPS&nbsp

The burden of chronic kidney disease (CKD) is rising among patients with cirrhosis, though it is not known what impact this has had on outcomes after liver transplantation (LT). All patients listed for LT in the United States between 2002 and 2017 were analyzed, excluding those listed with Model for End-Stage Liver Disease (MELD) exceptions. The primary outcome was post-LT mortality. We defined pre-LT CKD as an estimated glomerular filtration rate 0.05). Therefore, pre-LT CKD has a deleterious impact on post-LT outcomes, which is an impact that is not mediated through SLKT. These findings highlight the need for the identification of CKD when preventative measures are possible.

Neutrophil gelatinase-associated lipocalin (NGAL) is a marker of both tissue injury and infection. Urine NGAL levels strongly predict acute kidney injury and mortality in patients with cirrhosis, but ascites NGAL is not well characterized. We hypothesized that ascites NGAL level is a marker of spontaneous bacterial peritonitis (SBP) and mortality risk in patients with cirrhosis. Hospitalized patients with cirrhosis and ascites undergoing diagnostic paracentesis were prospectively enrolled and followed until death or discharge. Patients with secondary peritonitis, prior transplantation, or active colitis were excluded. NGAL was measured in the ascites and serum. Ascites NGAL level was evaluated as a marker of SBP (defined as ascites absolute neutrophil count > 250 cells/mm3) and predictor of in-patient mortality. A total of 146 patients were enrolled, and of these, 29 patients (20%) had SBP. Baseline characteristics were similar between subjects with and without SBP. Median (IQR) ascites NGAL was significantly higher in patients with SBP compared to those without SBP (221.3 [145.9–392.9] vs. 139.2 [73.9–237.2], p < 0.01). Sixteen (11%) patients died in the hospital. In the final multivariable model, ascites NGAL (OR 1.02 per 10 units, p < 0.01) remained predictive of in-hospital mortality, controlling for SBP (OR 9.76, p < 0.01) and MELD (OR 1.11, p = 0.01). In ROC analysis, ascites NGAL had an AUC of 0.79 for inhospital mortality, and the final model including ascites NGAL, MELD, and SBP had an AUC of 0.94. Ascites NGAL level may be a biomarker of peritonitis in hospitalized patient with cirrhosis and an independent predictor of short-term in-hospital mortality, even controlling for SBP and MELD.

Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related mortality in the United States and is a leading indication for liver transplantation (LT). Changes have been noted in the age of the population with chronic liver disease, but how this change affects patients with HCC is unknown. This study aims to characterize trends and transplant-associated outcomes among patients ≥65years old listed for LT with HCC. Using the United Network for Organ Sharing database, we analyzed all patients ≥18years old listed for LT during 2003-2017 in the United States in 2 groups (

BackgroundPrevious simultaneous liver-kidney (SLK) transplant allocation was based on serum creatinine, a metric that disadvantaged women relative to men. A recent SLK transplant policy change uses estimated glomerular filtration rate (eGFR), which accounts for sex-based differences in creatinine.MethodsTo understand the impact of this new policy, we analyzed nonstatus 1 adults listed for liver transplantation (LT) from May 2007 to July 2014, excluding those with exceptions. We defined patients who met the new SLK policy as having an eGFR

IMPORTANCE: Alcohol-associated liver disease (ALD) has emerged as the most common indication for liver transplant in the United States, but data on the reasons for this increase and long-term post-liver transplant outcomes among liver transplant recipients are sparse. OBJECTIVE: To characterize trends and long-term outcomes of liver transplant for ALD in the United States between 2002 and 2016. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective, national cohort study used data from the United Network for Organ Sharing database to evaluate all liver transplants performed in the United States between January 1, 2002, and December 31, 2016. MAIN OUTCOMES AND MEASURES: National and regional trends in liver transplant for ALD, with a sensitivity analysis with hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) included, and early (≤90 days after liver transplant) and late (>90 days after liver transplant) patient and graft survival. RESULTS: The cohort consisted of 32 913 patients, including 9438 with ALD and 23 475 without ALD (patients who had HCV infection and HCC indications were excluded). Median age of patients with ALD was 54 years (interquartile range, 47–60 years) and of patients without ALD was 54 years (interquartile range, 44–61 years). Patients with ALD (vs non-ALD) were more frequently male (7197 of 9438 [76.2%] vs 11767 of 23 475 [50.1%]; P < .001) and white (7544 [80.0%] vs 17 251 [73.5%]; P < .001). The proportion of liver transplants for ALD increased from 24.2% (433 of 1791) in 2002 to 27.2% (556 of 2044) in 2010 and 36.7% (1253 of 3419) in 2016. With HCV infection included, the proportions of liver transplant for ALD were 15.3% in 2002,18.6% in 2010, and 30.6% in 2016, representing a 100% increase in liver transplant for ALD, of which 48% was associated with a decrease in HCV infection as an indication for liver transplant. The magnitude of increase in ALD was regionally heterogeneous and associated with changes in patient characteristics suggestive of alcoholic hepatitis: decreasing age (χ(2) = 36.5; P = .005) and increasing model for end-stage liver disease score (χ(2) = 69.1; P < .001). Cumulative unadjusted 5-year posttransplant survival was 79% (95% CI, 78%−80%) for ALD vs 80% (95% CI, 79%−80%) for non-ALD; cumulative unadjusted 10-year posttransplant survival was 63% (95% CI, 61%−64%) for ALD vs 68% (95% CI, 67%−69%) for non-ALD (P = .006). In multivariable analysis, ALD was associated with increased risk of late death after liver transplant (adjusted hazard ratio, 1.11; 95% CI, 1.03–1.20; P = .006). CONCLUSIONS AND RELEVANCE: The findings suggest that early liver transplant for alcoholic hepatitis may be leading to broader acceptance of ALD for liver transplant. Late survival among liver transplant recipients with ALD was inferior to that among recipients with non-ALD indications, suggesting a need for future studies to identify patient profiles associated with best outcomes. Regional differences suggest heterogeneity in policies toward liver transplant for ALD.

Acute-on-chronic liver failure (ACLF) is a feared complication that can develop at any stage of chronic liver disease. The incidence of ACLF is increasing, leading to a significant burden to both the affected individual and health care systems. To date, our understanding of ACLF suggests that it may be initiated by precipitants such as systemic infection, alcohol use, or viral hepatitis. The prevalence of these vary significantly by geography and underlying liver disease, and these precipitants have a varying impact on patient prognosis. Herein, we present a review of our current understanding of the precipitants of ACLF, including gaps in current data and opportunities for meaningful intervention and areas of future research.

Background Urinary neutrophil gelatinase-associated lipocalin (uNGAL)-associated acute kidney injury is common after liver transplantation (LT), but whether early acute kidney injury predicts chronic kidney disease (CKD) and mortality remains uncertain. Methods Adults with LT from 2008 to 2010 in a previously published prospective cohort evaluating serial uNGAL pre- and post-LT were retrospectively assessed to evaluate uNGAL as a predictor of long-term outcomes post-LT. The primary outcomes were post-LT CKD, defined as Modification of Diet in Renal Disease estimated glomerular filtration rate less than 60 mL/min per 1.73 m for 3 continuous months, and death. Results uNGAL at 24 hours postreperfusion was significantly higher among patients who developed CKD. Multivariable modeling for the development of CKD demonstrated that uNGAL at 24-hours postreperfusion, 24 hours post-LT renal function, initial calcineurin inhibitor, and age were independent predictors of the development of CKD at in this cohort with long-term follow-up post-LT. Further, this association was stronger in those with preserved pre-LT renal function, a population where renal outcomes are often difficult to predict. Conclusions We propose that perioperative uNGAL may identify patients at risk for CKD and allow for targeted early implementation of renal-sparing strategies.

Acute kidney injury (AKI) is a critical determinant of outcomes in hospitalized patients with cirrhosis, but little is known of the impact of AKI in the outpatient setting. We analyzed 385 adult outpatients with cirrhosis listed for liver transplant at a single center; excluded were those with severe hepatic encephalopathy, with hepatocellular carcinoma, or on hemodialysis. Baseline serum creatinine (bCr) was defined as the lowest value recorded, peak Cr as the highest value, ΔCr as peak Cr minus bCr, AKI as a rise in serum Cr (sCr) by ≥0.3 mg/dL from bCr, persistent kidney injury as elevation of sCR by ≥0.3 mg/dL from bCr on each subsequent clinical assessment. Among 385 outpatients with cirrhosis, bCr was ≤0.70, 0.70-0.97, and ≥0.97 mg/dL in 28%, 38%, and 34%, respectively. At a median follow-up of 16 (range 8-28) months, 143 (37%) had one or more AKI episode, which increased significantly by bCr group (24% versus 37% versus 48%, P = 0.001). Of these 143 with AKI, 13% developed persistent kidney injury. A multivariable Cox regression analysis highlighted that bCr (hazard ratio [HR], 2.96) and ΔCr (HR, 2.05) were the only factors independently associated with the development of persistent kidney injury (P

Heme oxygenase (HO) represents an intrinsic cytoprotective system based on its anti-oxidative and anti-inflammatory properties mediated via its products biliverdin/bilirubin and carbon monoxide (CO). We showed that deletion of HO-2 results in impaired corneal wound healing with associated chronic inflammatory complications. This study was undertaken to examine the role of HO activity and the contribution of HO-1 and HO-2 to corneal wound healing in an in vitro epithelial scratch injury model. A scratch wound model was established using human corneal epithelial (HCE) cells. These cells expressed both HO-1 and HO-2 proteins. Injury elicited a rapid and transient increase in HO-1 and HO activity; HO-2 expression was unchanged. Treatment with biliverdin or CORM-A1, a CO donor, accelerated wound closure by 10% at 24 h. Inhibition of HO activity impaired wound closure by more than 50%. However, addition of biliverdin or CORM-A1 reversed the effect of HO inhibition on wound healing. Moreover, knockdown of HO-2 expression, but not HO-1, significantly impaired wound healing. These results indicate that HO activity is required for corneal epithelial cell migration. Inhibition of HO activity impairs wound healing while amplification of its activity restores and accelerates healing. Importantly, HO-2, which is highly expressed in the corneal epithelium, appears to be critical for the wound healing process in the cornea. The mechanisms by which it contributes to cell migration in response to injury may reside in the cytoprotective properties of CO and biliverdin.

Background and Aims Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a mini-chromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA. Methods Among 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined. Results At the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88logIU/ml, 0.03copies/cell, and 0.01copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54log (71.46%), ihHBV DNA levels by 2.81log (99.84%), and cccDNA levels by 2.94log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021copies/cell, with 40% of patients having undetectable pgRNA. Conclusions Long-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study. Lay summary It is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment.