Prospective validation of the EASL management algorithm for acute kidney injury in cirrhosis.

BACKGROUND AND AIMS: The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice. METHODS: Prospective cohort study of consecutive hospitalized patients with cirrhosis and AKI. EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥ stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). Primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy. RESULTS: A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in 1/3 of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with ATN being the most common phenotype. Response rate in patients not meeting criteria of HRS-AKI was 70%. Only 30 patients met the diagnostic criteria HRS-AKI, and response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While urinary neutrophil gelatinase-associated lipocalin (uNGAL) could differentiate acute tubular necrosis (ATN) vs other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema. CONCLUSIONS: The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy.

Patterns of kidney dysfunction in acute-on-chronic liver failure: Relationship with kidney and patients' outcome.

Impairment of kidney function is common in acute-on-chronic liver failure (ACLF). Patterns of kidney dysfunction and their impact on kidney and patient outcomes are ill-defined. Aims of the current study were to investigate patterns of kidney dysfunction and their impact on kidney and patient outcomes in patients with acute decompensation (AD) of cirrhosis, with or without ACLF. This prospective study includes 639 admissions for AD (232 with ACLF; 407 without) in 518 patients. Data were collected at admission and during hospitalization, and patients were followed up for 3 months. Urine samples were analyzed for kidney biomarkers. Most patients with ACLF (92%) had associated acute kidney injury (AKI), in most cases without previous chronic kidney disease (CKD), whereas some had AKI-on-CKD (70% and 22%, respectively). Prevalence of AKI in patients without ACLF was 35% (p < 0.001 vs. ACLF). Frequency of CKD alone was low and similar in both groups (4% and 3%, respectively); only a few patients with ACLF (4%) had no kidney dysfunction. AKI in ACLF was associated with poor kidney and patient outcomes compared with no ACLF (AKI resolution: 54% vs. 89%; 3-month survival: 51% vs. 86%, respectively; p < 0.001 for both). Independent predictive factors of 3-month survival were Model for End-Stage Liver Disease-Sodium score, ACLF status, and urine neutrophil gelatinase-associated lipocalin (NGAL). AKI is almost universal in patients with ACLF, sometimes associated with CKD, whereas CKD alone is uncommon. Prognosis of AKI depends on ACLF status. AKI without ACLF has good prognosis. Best predictors of 3-month survival are MELD-Na, ACLF status, and urine NGAL.

Stigmatization is common in patients with non-alcoholic fatty liver disease and correlates with quality of life.

BACKGROUND AND AIMS: Stigmatization is a well-documented problem of some diseases. Perceived stigma is common in alcohol-related liver disease and hepatitis C, but little information exists on stigma in patients with non-alcoholic fatty liver disease (NAFLD). Aim of the study was to investigate frequency and characteristics of perceived stigma among patients with NAFLD. METHODS: One-hundred and ninety-seven patients seen at the liver clinic were included: a study group of 144 patients with NAFLD, 50 with cirrhosis (34 compensated, 16 decompensated), and a control group of 53 patients with alcohol-related cirrhosis. Demographic, clinical, and laboratory data were collected. Quality-of-life was assessed by chronic liver disease questionnaire (CLDQ). Perceived stigma was assessed using a specific questionnaire for patients with liver diseases categorized in 4 domains: stereotypes, discrimination, shame, and social isolation. RESULTS: Perceived stigma was common in patients with NAFLD (99 patients, 69%) and affected all 4 domains assessed. The frequency was slightly higher, yet not significant, in patients with NAFLD cirrhosis vs those without (72% vs 67%, respectively; p = 0.576). In patients without cirrhosis perceived stigma was unrelated to stage of disease, since frequency was similar in patients with no or mild fibrosis compared to those with moderate/severe fibrosis (66% vs 68%, respectively). There were no differences in perceived stigma between patients with compensated cirrhosis and these with decompensated cirrhosis. Among patients with cirrhosis, stigmatization was more common in alcohol-related vs NAFLD-cirrhosis, yet differences were only significant in two domains. In patients with NAFLD, perceived stigma correlated with poor quality-of-life, but not with demographic or clinical variables. CONCLUSIONS: Perceived stigmatization is common among patients with NAFLD independently of disease stage, is associated with impaired quality-of-life, and may be responsible for stereotypes, discrimination, shame, and social isolation, which may affect human and social rights of affected patients.

Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC. METHODS: A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison. RESULTS: Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis. CONCLUSIONS: Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC. LAY SUMMARY: Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis.

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis.

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Effects of Albumin on Survival after a Hepatic Encephalopathy Episode: Randomized Double-Blind Trial and Meta-Analysis.

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. METHODS: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient's data for survival including two clinical trials (BETA and ALFAE) was performed. RESULTS: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21-0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). CONCLUSIONS: Repeated doses of albumin might be beneficial for patient's survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.

Sequential changes in urinary biomarker levels in patients with cirrhosis and severe hepatorenal syndrome.

Whether tubular injury develops in patients with acute kidney injury owing to hepatorenal syndrome (AKI-HRS) is controversial. We performed repeated measurements of biomarkers of tubular injury during a 14-day period in 60 patients with cirrhosis and AKI (34 with AKI-HRS meeting the classical definition of type 1 HRS and 26 with AKI owing to acute tubular necrosis, AKI-ATN). Nineteen of 34 patients had resolution of AKI-HRS, while the remainder had persistent AKI-HRS. The persistence of AKI-HRS was associated with remarkably high short-term mortality. There were no significant differences in urinary NGAL or IL-18 between patients with resolution vs those with persistent AKI-HRS throughout the 14-day period. By contrast, biomarker levels were significantly lower in AKI-HRS, even if persistent, compared to AKI-ATN. These findings are highly suggestive of lack of significant tubular injury in AKI-HRS and could be of value in the clinical decision between combined liver-kidney or liver transplantation alone in patients with cirrhosis and AKI candidates to transplantation.

Hyperkalemia influences the outcome of patients with cirrhosis with acute decompensation (AD) and acute-on-chronic liver failure (ACLF).

INTRODUCTION: The presence of hyperkalemia in different clinical scenarios has been described as a risk factor for mortality. Information about this electrolyte disorder in patients with cirrhosis is limited and there are no data in patients with acute-on-chronic liver failure (ACLF). AIM: The aim of this study was to investigate whether hyperkalemia is a risk factor for mortality in patients with cirrhosis and acute decompensation (AD) with and without ACLF. METHODS: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,314 consecutive patients admitted to 29 European centers with AD both with and without associated ACLF (294 and 1020 respectively). Hyperkalemia was defined as serum potassium ≥ 5.0 mEq/L. All patients had at least one valid measure of serum potassium from admission and/or through the whole hospitalization. RESULTS: 1314 patients were admitted with AD and 294 of them had ACLF at admission. Prevalence of hyperkalemia was significantly higher in ACLF versus AD (22.4% and 8.6% respectively, p<0.001). Hyperkalemia was associated with an increased 90, 180 and 360-day mortality risk in ACLF compared to AD (HR 10 vs 2.3 at 90-day p<0.001, 8.9 vs 3.1 at 180-day, p<0.001 and 5.8 vs 3.8 at 360-day, p<0.001). In a multivariate analysis, the presence of hyperkalemia during admission was independently associated with 90-day mortality [HR 2.4 (1.7 - 3.4)]. Variability of potassium between two valid measures ≥ 0.9 mg/dl was always also associated with a higher mortality rate. Addition of hyperkalemia to MELD score (MELD-K model) improved the accuracy to predict 90-day mortality risk. CONCLUSIONS: Hyperkalemia is an independent risk factor of mortality in patients with AD and ACLF. Addition of hyperkalemia to the MELD score improves diagnostic accuracy to predict 90-day mortality in patients with AD and ACLF.

Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship With Acute-on-Chronic Liver Failure and Prognosis.

BACKGROUND AND AIMS: Cirrhosis is associated with changes in gut microbiome composition. Although acute-on-chronic liver failure (ACLF) is the most severe clinical stage of cirrhosis, there is lack of information about gut microbiome alterations in ACLF using quantitative metagenomics. We investigated the gut microbiome in patients with cirrhosis encompassing the whole spectrum of disease (compensated, acutely decompensated without ACLF, and ACLF). A group of healthy subjects was used as control subjects. METHODS: Stool samples were collected prospectively in 182 patients with cirrhosis. DNA library construction and sequencing were performed using the Ion Proton Sequencer (ThermoFisher Scientific, Waltham, MA). Microbial genes were grouped into clusters, denoted as metagenomic species. RESULTS: Cirrhosis was associated with a remarkable reduction in gene and metagenomic species richness compared with healthy subjects. This loss of richness correlated with disease stages and was particularly marked in patients with ACLF and persisted after adjustment for antibiotic therapy. ACLF was associated with a significant increase of Enterococcus and Peptostreptococcus sp and a reduction of some autochthonous bacteria. Gut microbiome alterations correlated with model for end-stage liver disease and Child-Pugh scores and organ failure and was associated with some complications, particularly hepatic encephalopathy and infections. Interestingly, gut microbiome predicted 3-month survival with good stable predictors. Functional analysis showed that patients with cirrhosis had enriched pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis, among others. CONCLUSIONS: Cirrhosis is characterized by marked alterations in gut microbiome that parallel disease stages with maximal changes in ACLF. Altered gut microbiome was associated with complications of cirrhosis and survival. Gut microbiome may contribute to disease progression and poor prognosis. These results should be confirmed in future studies.

Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.

BACKGROUND & AIMS: Acute kidney injury (AKI) is common in cirrhosis and is associated with poor prognosis. In patients who survive after AKI, it is not known whether the acute injury leads to chronic impairment of kidney function (chronic kidney disease [CKD]). The aim of the study was to determine the frequency of CKD at 3 months after an AKI episode and its effects on patient outcomes. METHODS: Patients admitted for complications of cirrhosis during a 6.5-year period were evaluated using the same protocol, with assessment of kidney function at regular intervals during and after hospitalization. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 at 3 months after AKI. RESULTS: A total of 409 patients (168 with AKI and 241 without AKI) were included. After 3 months, 97 patients with AKI and 188 patients without AKI had survived. Of the 97 patients with AKI, 24 had developed CKD at 3 months compared to only 2 of the 188 patients without AKI (25% vs. 1%, odds ratio 31; p <0.0001). Risk factors independently associated with CKD were nosocomial AKI and severity of AKI (stage ≥1B). At diagnosis of CKD, all patients had stage 3A CKD and one-quarter of them progressed to stages 3B and 4 after 1 year. The transition from AKI to CKD was associated with an increased rate of 3-month hospital readmission, increased frequency of AKI, bacterial infections, ascites, and refractory ascites and a trend towards a higher need for liver transplantation. Transplant-free survival was not impaired. CONCLUSIONS: CKD frequently develops in patients with cirrhosis who survive AKI and has a negative impact on relevant clinical outcomes. The transition from AKI to CKD is common and should be considered a high-risk condition in patients with cirrhosis. LAY SUMMARY: Episodes of acute impairment of kidney function are common in patients with cirrhosis. This study shows that the development of chronic impairment of kidney function is frequent in patients surviving these acute episodes and that it is associated with a higher risk of developing other complications of cirrhosis and to a higher rate of 3-month hospital readmissions.

Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. METHODS: We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. FINDINGS: The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST -14 IU/L [-91 to 64; p=0·728] and for ALT -8 IU/L [-49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [-804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. INTERPRETATION: Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. FUNDING: Horizon 20/20 European programme.

Neutrophil Gelatinase-Associated Lipocalin for Assessment of Acute Kidney Injury in Cirrhosis: A Prospective Study.

Kidney biomarkers appear to be useful in differential diagnosis between acute tubular necrosis (ATN) and other types of acute kidney injury (AKI) in cirrhosis, particularly hepatorenal syndrome (HRS-AKI). Distinction is important because treatment is different. However, kidney biomarkers are still not used in clinical practice. The aim of the current study was to investigate the accuracy of several biomarkers in differential diagnosis of AKI and in predicting kidney outcome and patient survival. This was a prospective study of 320 consecutive cases of AKI in patients hospitalized for decompensated cirrhosis. Evaluation of AKI was made with a diagnostic algorithm that included identification and removal/treatment of precipitating factors and albumin administration (1 g/kg for 2 days) to patients with AKI stage 1B or greater. Urinary neutrophil gelatinase-associated lipocalin (NGAL), monomeric NGAL (mNGAL), interleukin-18, and standard biomarkers were measured at diagnosis and on days 3, 7, and 14. Of the 320 cases, 153 were hypovolemia-induced AKI (48%), 93 were HRS-AKI (29%), 39 were ATN (12%), and 35 were due to miscellaneous causes (11%). Among all biomarkers, urinary NGAL measured at day 3 had the greatest accuracy for differential diagnosis between ATN and other types of AKI (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.78-0.95). The cutoff with the best predictive accuracy for ATN diagnosis was 220 µg/g creatinine. Progression of AKI during hospitalization was associated with persistently high NGAL levels, and NGAL was an independent predictive factor of AKI progression. Likewise, NGAL was also an independent predictive factor of 28-day mortality together with Model for End-Stage Liver Disease score. Conclusion: These results support the use of NGAL in clinical practice within the context of a diagnostic algorithm for differential diagnosis of AKI and outcome prediction in cirrhosis.

Characterization of inflammatory response in hepatorenal syndrome: Relationship with kidney outcome and survival.

BACKGROUND: Several lines of evidence indicate that decompensated cirrhosis is characterized by the presence of systemic inflammation. Hepatorenal syndrome (HRS-AKI) is a unique type of renal failure that occurs at late stages of cirrhosis. However, confirmation of the presence and significance of such inflammatory response in HRS-AKI is lacking. AIM AND METHODS: To characterize the systemic inflammatory response, as estimated by measuring a large number of cytokines, in 161 patients hospitalized for an acute decompensation of cirrhosis: 44 patients without acute kidney injury (AKI), 63 patients with hypovolaemia-induced AKI and 58 patients with HRS-AKI. RESULTS: HRS-AKI was characterized by an altered cytokine profile compared to the other two groups, particularly IL-6, IL-8, TNF-α, VCAM-1, fractalkine and MIP-1α. The inflammatory response was not related to presence of bacterial infection, concomitant acute-on-chronic liver failure or severity of renal dysfunction. Patients who responded to terlipressin and albumin had only a decrease in TNF-α and RANTES after treatment without changes in other cytokines. Interestingly, patients with persistent HRS-AKI had higher levels of IP-10 and VCAM-1 compared to those with resolution of HRS-AKI. VCAM-1 was also an independent predictor of 3-month mortality. A systems biology analysis approach showed that the inflammatory status of HRS-AKI was similar to that of chronic nonhepatic inflammatory conditions, such as lupus erythematosus or inflammatory bowel disease. CONCLUSION: Hepatorenal syndrome is characterized by a marked systemic inflammatory state, reminiscent of that of nonhepatic inflammatory diseases, that correlates with patient outcomes.

Treatment and Response to Statins: Gender-related Differences.

Response to drug administration is a primary determinant for treatment success. Sex and gender disparities play a role in determining the efficacy and safety of the most commonly used medications suggesting the need for a sex-tailored approach in prescription. Statins are a cost-effective strategy for cardiovascular disease (CVD) prevention. While statins are similarly effective in secondary CVD prevention, some concerns raised by conflicting data reported in primary CVD prevention clinical trials. The small representation of women in clinical trials and the fewer rates of events due to the lower female baseline CVD risk may have conditioned contradictory meta-analysis findings. Specifically, benefits outweigh disadvantages of statin therapy in women with a high CVD risk, while several doubts exist for the primary prevention of women at low-intermediate CVD risk. Furthermore, disparities between women and men in medication adherence may influence statin efficacy in CVD prevention. The sex-dependent impact of adverse side effects is one of the reasons advocated for explaining the gender gap, but it is not evidence-proved. The present review summarizes the sex and gender differences in the use of statins, pointing out new perspectives and opening issues in sex-tailored CVD prevention strategy.

The 35-year odyssey of beta blockers in cirrhosis: any gender difference in sight?

Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended.

Low-grade endotoxemia and platelet activation in cirrhosis.

Patients with cirrhosis may display impaired or enhanced platelet activation, but the reasons for these equivocal findings are unclear. We investigated if bacterial lipopolysaccharide (LPS) is implicated in platelet activation. In a cross-sectional study, conducted in an ambulatory care clinic and hospital, comparing 69 cirrhosis patients and 30 controls matched for sex, age, and atherosclerotic risk factors, serum levels of LPS, soluble cluster of differentiation 40 ligand and p-selectin (two markers of platelet activation), and zonulin (a marker of gut permeability) were investigated. Ex vivo and in vitro studies were also performed to explore the effect of LPS on platelet activation. Compared to controls, cirrhosis patients displayed higher serum levels of LPS (6.0 [4.0-17.5] versus 57.4 [43.4-87.2] pg/mL, P < 0.0001), soluble cluster of differentiation 40 ligand (7.0 ± 2.2 versus 24.4 ± 13.3 ng/mL, P < 0.0001), soluble p-selectin (14.2 ± 4.05 versus 33.2 ± 15.2 ng/mL, P < 0.0001), and zonulin (1.87 ± 0.84 versus 2.54 ± 0.94 ng/mL, P < 0.006). LPS significantly correlated with zonulin (r = 0.45, P < 0.001). Ex vivo studies showed that platelets from cirrhosis patients were more responsive to the agonists independently from platelet count; this phenomenon was blunted by incubation with an inhibitor of Toll-like receptor 4. In vitro study by normal platelets showed that LPS alone (50-150 pg/mL) did not stimulate platelets but amplified platelet response to the agonists; Toll-like receptor 4 inhibitor blunted this effect. CONCLUSION: LPS may be responsible for platelet activation and potentially contributes to thrombotic complications occurring in cirrhosis. (Hepatology 2017;65:571-581).

Adherence to antithrombotic therapy guidelines improves mortality among elderly patients with atrial fibrillation: insights from the REPOSI study.

BACKGROUND: Atrial fibrillation (AF) is associated with a substantial risk of thromboembolism and mortality, significantly reduced by oral anticoagulation. Adherence to guidelines may lower the risks for both all cause and cardiovascular (CV) deaths. METHODS: Our objective was to evaluate if antithrombotic prophylaxis according to the 2012 European Society of Cardiology (ESC) guidelines is associated to a lower rate of adverse outcomes. Data were obtained from REPOSI; a prospective observational study enrolling inpatients aged ≥65 years. Patients enrolled in 2012 and 2014 discharged with an AF diagnosis were analysed. RESULTS: Among 2535 patients, 558 (22.0 %) were discharged with a diagnosis of AF. Based on ESC guidelines, 40.9 % of patients were on guideline-adherent thromboprophylaxis, 6.8 % were overtreated, and 52.3 % were undertreated. Logistic analysis showed that increasing age (p = 0.01), heart failure (p = 0.04), coronary artery disease (p = 0.013), peripheral arterial disease (p = 0.03) and concomitant cancer (p = 0.003) were associated with non-adherence to guidelines. Specifically, undertreatment was significantly associated with increasing age (p = 0.001) and cancer (p < 0.001), and inversely associated with HF (p = 0.023). AF patients who were guideline adherent had a lower rate of both all-cause death (p = 0.007) and CV death (p = 0.024) compared to those non-adherent. Kaplan-Meier analysis showed that guideline-adherent patients had a lower cumulative risk for both all-cause (p = 0.002) and CV deaths (p = 0.011). On Cox regression analysis, guideline adherence was independently associated with a lower risk of all-cause and CV deaths (p = 0.019 and p = 0.006). CONCLUSIONS: Non-adherence to guidelines is highly prevalent among elderly AF patients, despite guideline-adherent treatment being independently associated with lower risk of all-cause and CV deaths. Efforts to improve guideline adherence would lead to better outcomes for elderly AF patients.

Portal vein thrombosis relevance on liver cirrhosis: Italian Venous Thrombotic Events Registry.

Portal vein thrombosis may occur in cirrhosis; nevertheless, its prevalence, and predictors are still elusive. To investigate this issue, the Italian Society of Internal Medicine undertook the "Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry" (PRO-LIVER). This prospective multicenter study includes consecutive cirrhotic patients undergoing Doppler ultrasound examination of the portal area to evaluate the prevalence and incidence of portal vein thrombosis over a 2-year scheduled follow-up. Seven hundred and fifty-three (68 % men; 64 ± 12 years) patients were included in the present analysis. Fifty percent of the cases were cirrhotic outpatients. Viral (44 %) etiology was predominant. Around half of the patients had a mild-severity disease according to the Child-Pugh score; hepatocellular carcinoma was present in 20 %. The prevalence of ultrasound-detected portal vein thrombosis was 17 % (n = 126); it was asymptomatic in 43 % of the cases. Notably, more than half of the portal vein thrombosis patients (n = 81) were not treated with anticoagulant therapy. Logistic step-forward multivariate analysis demonstrated that previous portal vein thrombosis (p < 0.001), Child-Pugh Class B + C (p < 0.001), hepatocellular carcinoma (p = 0.01), previous upper gastrointestinal bleeding (p = 0.030) and older age (p = 0.012) were independently associated with portal vein thrombosis. Portal vein thrombosis is a frequent complication of cirrhosis, particularly in patients with moderate-severe liver failure. The apparent undertreatment of patients with portal vein thrombosis is a matter of concern and debate, which should be addressed by planning interventional trials especially with newer oral anticoagulants. Clinicaltrials.gov identifier NCT01470547.