Natural history of acute kidney disease in patients with cirrhosis.

BACKGROUND & AIMS: In 2012, the KDIGO group proposed new definitions for acute kidney injury (AKI), acute kidney disease (AKD) and chronic kidney disease (CKD). According to the definition adapted by the International Club of Ascites, AKI has been extensively investigated in patients with cirrhosis. On the contrary, there are currently no data on the epidemiology and clinical outcomes associated with AKD. The aim of the study was to assess the prevalence and the impact of AKD on the clinical course and survival of patients with cirrhosis. METHODS: A total of 272 consecutive patients with cirrhosis attending our outpatient clinic were included in the study. Clinical and laboratory data were collected at inclusion. Patients were followed-up until death, liver transplant or the end of follow-up. RESULTS: During follow-up, 80 patients developed AKD (29.4%). Forty-two (52.5%) recovered from the first episode of AKD and 26 maintained a normal renal function up to the end of follow-up. Sixteen patients developed a second episode of AKD. Globally, 36 patients (45.0%) died with AKD. Finally, AKD progressed to CKD in 11 patients (13.8%). The 5-year survival rate was significantly lower in patients who developed AKD than in those who did not (34.8% vs. 88.8%, p <0.001). The 5-year rates of complications of cirrhosis and of hospitalizations were also higher in patients with AKD than in those without AKD. CONCLUSIONS: AKD is frequent in patients with cirrhosis. It can be reversible, but it may recur and progress to CKD. AKD has a very negative impact on morbidity and mortality in patients with cirrhosis. LAY SUMMARY: Renal impairment has a very negative impact on patients with cirrhosis. Renal impairment seems to be characterized by a very dynamic course, which is defined according to renal function and length of the impairment as acute kidney injury, acute kidney disease and chronic kidney disease. The role of acute kidney disease is currently unknown. Our study shows for the first time that acute kidney disease is frequent in patients with cirrhosis and has a very negative impact on survival.

Outcomes and Mortality of Grade 1 Ascites and Recurrent Ascites in Patients With Cirrhosis.

BACKGROUND & AIMS: Ascites has been classified according to quantity and response to medical therapy. Despite its precise definitions, little is known about the effects of grade 1 ascites or recurrent ascites (i.e. ascites that recurs at least on 3 occasions within a 12-month period despite dietary sodium restriction and adequate diuretic dosage) on patient outcome. We studied progression of grade 1 ascites and recurrent ascites in a large cohort of outpatients with cirrhosis. METHODS: We performed a post-hoc analysis of data from 547 outpatients with cirrhosis (259 without ascites, 54 patients with grade 1 ascites, 234 with grade 2 or 3 ascites) who participated a care management program study in Italy from March 2003 through September 2017. We collected demographic, clinical, and laboratory data and patients were evaluated at least every 6 months. Patients received abdominal ultrasound analysis at study inclusion and at least twice a year. Number and volume of paracentesis were collected, when available. Patients were followed until death, liver transplantation, or March 2018. The median follow-up time was 29 months. Primary outcomes were mortality and development of complications of cirrhosis. RESULTS: There was no significant difference in 60-month transplant-free survival between patients with grade 1 vs grade 2 or 3 ascites (36% vs 43%) but survival was significantly lower when both groups were compared with patients without ascites (68%; P < .001 for both comparisons). However, the grade of systemic inflammation and the rate of complications were significantly greater in patients with grade 1 ascites than in patients without ascites, but significantly lower than in patients with grade 2 or 3 ascites. Development of grade 2 or 3 ascites did not differ significantly between patients with no ascites vs grade 1 ascites (10% vs 14%). There was no significant difference in 36-month transplant-free survival between patients with ascites responsive to medical treatment vs recurrent ascites (78% vs 62%), whereas patients with refractory ascites had significantly lower survival than patients with responsive or recurrent ascites (23%; responsive vs refractory ascites P<.001; recurrent vs refractory ascites P = .022). CONCLUSIONS: In an analysis of data from a large cohort of outpatients with cirrhosis, we found that grade 1 ascites is associated with systemic inflammation, more complications, and increased mortality compared with no ascites. Mortality does not differ significantly between patients with recurrent ascites vs ascites responsive to medical treatment.

Prophylactic or therapeutic doses of heparins for COVID-19 infection? A retrospective study.

BACKGROUND: Coronavirus disease 19 (COVID-19) is a global outbreak. COVID-19 patients seem to have relevant coagulative abnormalities, even if they are not typical of disseminated intravascular coagulopathy (DIC) of the kind seen in septicaemia. Therefore, anticoagulant therapy with heparins is increasing in interest for a clinical approach to these patients, particularly if older. Studies comparing if prophylactic doses are more effective than therapeutic ones are still missing. METHODS: Data were collected in the Geriatric Section of the Dolo Hospital, ULSS 3 "Serenissima", Venice from 31st March to 01st May 2020. Heparins (calciparin, fondaparinux, enoxaparine) were divided into prophylactic or therapeutic doses. People previously treated with oral anticoagulants were removed. Vital status was assessed using administrative data. Cox's regression analysis, adjusted for potential confounders, was used for assessing the strength of the association between heparins and mortality. The data were reported as hazard ratio (HR) with 95% confidence intervals (CIs). RESULTS: 81 older people (mean age 84.1 years; females = 61.9%) were included. No significant differences in terms of demographic and clinical characteristics emerged between people treated with prophylactic or therapeutic doses, including age, gender, X-rays findings or severity of disease. Therapeutic doses were not associated to a better survival rate (HR 1.06; 95% CI 0.47-2.60; p = 0.89), even after adjusting for 15 confounders related to mortality (HR 0.89; 95% CI 0.30-2.71; p = 0.84). CONCLUSIONS: Our paper indicates that in older people affected by COVID-19 there is no justification for using therapeutic doses instead of prophylactic ones, having a similar impact on mortality risk.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

BACKGROUND & AIMS: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. METHODS: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. RESULTS: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). CONCLUSIONS: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. LAY SUMMARY: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections.

INTRODUCTION: Patients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) ≥2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure ≤100 mm Hg or respiratory rate ≥22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis-3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections. METHODS: 259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients). RESULTS: Sepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (p<0.01 for both). Similar results were observed in the validation cohort. Sepsis-3 (subdistribution HR (sHR)=5.47; p=0.006), qSOFA (sHR=1.99; p=0.020), Chronic Liver Failure Consortium Acute Decompensation score (sHR=1.05; p=0.001) and C reactive protein (sHR=1.01;p=0.034) were found to be independent predictors of in-hospital mortality. Patients with Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3. CONCLUSIONS: Sepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

BACKGROUND & AIMS: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. METHODS: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ±â€¯197.6 days. RESULTS: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. CONCLUSIONS: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. LAY SUMMARY: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome.

BACKGROUND & AIMS: Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality). METHODS: We performed a retrospective analysis of 4 different cohorts of consecutive patients with HRS treated with terlipressin and albumin from February 2007 through January 2016 at medical centers in Europe (total, 298 patients). We analyzed demographic, clinical, and laboratory data collected before and during treatment; patients were followed until death, liver transplantation, or 90 days after HRS diagnosis. RESULTS: Response to treatment was observed in 53% of patients. Of patients with grade 1 ACLF, 60% responded to treatment; among those with grade 2 ACLF, 48% responded, and among those with grade 3 ACLF, 29% responded (P < .001 for comparison between grades). In multivariate analysis, baseline serum level of creatinine (odds ratio, 0.23; P = .001) and ACLF grade (odds ratio, 0.63; P = .01) were independently associated with response to treatment. Patient age (hazard ratio [HR], 1.05; P < .001), white blood cell count (HR, 1.51; P = .006), ACLF grade (HR, 2.06; P < .001), and no response to treatment (HR, 0.41; P < .001) associated with 90-day mortality. CONCLUSION: In a retrospective analysis of data from 4 cohorts of patients treated for type 1 HRS, we found ACLF grade to be the largest determinant of response to terlipressin and albumin. ACLF grade affects survival independently of response to treatment. New therapeutic strategies should be developed for patients with type 1 HRS and extrarenal organ failure.

Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is the most life-threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. METHODS: A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45±44months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. RESULTS: During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1year, 5years, and 10years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p=0.012), ascites (HR 2.53; p=0.019), model of end-stage liver disease score (HR 1.26; p<0.001) and baseline hemoglobin (HR 0.07; p=0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. CONCLUSIONS: Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients. LAY SUMMARY: There is a need to identify predictors of acute-on-chronic liver failure (ACLF) in patients with cirrhosis in order to identify patients at high risk of developing ACLF and to plan strategies of prevention. In this study, we identified four simple predictors of ACLF: model of end-stage liver disease (MELD) score, ascites, mean arterial pressure and hemoglobin. These variables may help to identify patients with cirrhosis, at a high risk of developing ACLF, that are candidates for new strategies of surveillance and prevention. Anemia is a potential new target for treating these patients.

Validation of a Staging System for Acute Kidney Injury in Patients With Cirrhosis and Association With Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: In patients with cirrhosis of the liver, acute kidney injury (AKI) is classified into 3 stages. Recent studies indicate that there are 2 subgroups of stage 1 disease, associated with different outcomes and serum levels of creatinine (SCr): stage 1A (SCr <1.5 mg/dL) and stage 1B (SCr ≥1.5 mg/dL). We performed a prospective study to validate, in a large series of patients with cirrhosis, the association between this new description and patient outcomes, and assess the relationship between AKI stage and the presence of acute-on-chronic liver failure. METHODS: We collected data from 547 consecutive patients admitted for cirrhosis with acute decompensation to 2 tertiary hospitals (Italy and Spain), from February 2011 through June 2015. A total of 290 patients had AKI (53%; 197 had stage 1 disease); AKI stages were determined based on levels of SCr at diagnosis. Patients were followed up until death, liver transplantation, or for 90 days. The primary outcome was 90-day survival; secondary outcomes were progression and resolution of AKI and association with acute-on-chronic liver failure. RESULTS: Based on level of sCr at diagnosis, 58 patients had stage 1A disease and 139 had stage 1B disease. Of patients with stage 1A disease, 82% survived for 90 days; of patients with stage 1B disease, 55% survived for 90 days (P = .001). Hepatorenal syndrome and acute tubular necrosis were the most common causes of stage 1B AKI, and hypovolemia was the most common cause of stage 1A AKI. AKI progressed in a higher proportion of patients with 1B than 1A AKI (31% vs 15%; P = .017) and resolved in a higher proportion of patients with 1A disease (90% vs 52% of patients with stage 1B; P < .001). Stage 1B disease, but not 1A, was an independent predictor of AKI progression and mortality. ACLF developed in a significantly greater proportion of patients with stage 1B disease (76%) than stage 1A disease (22%; P < .001), which could account for the poor outcomes of patients with stage 1B disease. CONCLUSIONS: In a large group of patients with decompensated cirrhosis, we validated the association between AKI stages IA and IB (based on level of sCR) with survival times and AKI progression. We also associated these subgroups of AKI with development of acute-on-chronic liver failure. These findings are important for management of patients with decompensated cirrhosis.

Predictors of Early Readmission in Patients With Cirrhosis After the Resolution of Bacterial Infections.

OBJECTIVES: In patients with cirrhosis, infections represent a frequent trigger for complications, increasing frequency of hospitalizations and mortality rate. This study aimed to identify predictors of early readmission (30 days) and of mid-term mortality (6 months) in patients with liver cirrhosis discharged after a hospitalization for bacterial and/or fungal infection. METHODS: A total of 199 patients with cirrhosis discharged after an admission for a bacterial and/or fungal infection were included in the study and followed up for a least 6 months. RESULTS: During follow-up, 69 patients (35%) were readmitted within 30 days from discharge. C-reactive protein (CRP) value at discharge (odds ratio (OR)=1.91; P=0.022), diagnosis of acute-on-chronic liver failure during the hospital stay (OR=2.48; P=0.008), and the hospitalization in the last 30 days previous to the admission/inclusion in the study (OR=1.50; P=0.042) were found to be independent predictors of readmission. During the 6-month follow-up, 47 patients (23%) died. Age (hazard ratio (HR)=1.05; P=0.001), model of end-stage liver disease (MELD) score (HR=1.13; P<0.001), CRP (HR=1.85; P=0.001), refractory ascites (HR=2.22; P=0.007), and diabetes (HR=2.41; P=0.010) were found to be independent predictors of 6-month mortality. Patients with a CRP >10 mg/l at discharge had a significantly higher probability of being readmitted within 30 days (44% vs. 24%; P=0.007) and a significantly lower probability of 6-month survival (62% vs. 88%; P<0.001) than those with a CRP ≤10 mg/l. CONCLUSIONS: CRP showed to be a strong predictor of early hospital readmission and 6-month mortality in patients with cirrhosis after hospitalization for bacterial and/or fungal infection. CRP values could be used both in the stewardship of antibiotic treatment and to identify fragile patients who deserve a strict surveillance program.

Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals.

Concerns about an increased hepatocellular carcinoma (HCC) recurrence rate following direct-acting antiviral (DAA) therapy in patients with cirrhosis with a prior complete oncological response have been raised. Data regarding the impact of HCV treatment with DAAs on wait-list dropout rates in patients with active HCC and HCV-related cirrhosis awaiting liver transplantation (LT) are lacking. HCV-HCC patients listed for LT between January 2015 and May 2016 at Padua Liver Transplant Center were considered eligible for the study. After enrollment, patients were divided into 2 groups, depending on whether they underwent DAA treatment while awaiting LT or not. For each patient clinical, serological, and virological data were collected. HCC characteristics were radiologically evaluated at baseline and during follow-up (FU). For transplanted patients, pathological assessment of the explants was performed and recurrence rates were calculated. A total of 23 patients treated with DAAs and 23 controls were enrolled. HCC characteristics at time of LT listing were comparable between the 2 groups. Median FU was 10 and 7 months, respectively, during which 2/23 (8.7%) and 1/23 (4.3%) dropout events due to HCC progression were registered (P = 0.90). No significant differences in terms of radiological progression were highlighted (P = 0.16). A total of 9 out of 23 (39%) patients and 14 out of 23 (61%) controls underwent LT, and histopathological analysis showed no differences in terms of median number and total tumor volume of HCC nodules, tumor differentiation, or microvascular invasion. During post-LT FU, 1/8 (12.5%) DAA-treated patient and 1/12 (8.3%) control patient experienced HCC recurrence (P = 0.60). In conclusion, viral eradication does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV-HCC patients awaiting LT. Liver Transplantation 23 1103-1112 2017 AASLD.

Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.

UNLABELLED: In patients with cirrhosis and hepatorenal syndrome (HRS), terlipressin has been used either as continuous intravenous infusion or as intravenous boluses. To date, these two approaches have never been compared. The goal of this study was to compare the administration of terlipressin as continuous intravenous infusion versus intravenous boluses in the treatment of type 1 HRS. Seventy-eight patients were randomly assigned to receive either continuous intravenous infusion (TERLI-INF group) at the initial dose of 2 mg/day or intravenous boluses of terlipressin (TERLI-BOL group) at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups (1 g/kg of body weight at the first day followed by 20-40 g/day). Complete response was defined by decrease of serum creatinine (sCr) from baseline to a final value ≤133 µmol/L, partial response by a decrease ≥50% of sCr from baseline to a final value >133 µmol/L. The rate of adverse events was lower in the TERLI-INF group (35.29%) than in the TERLI-BOL group (62.16%, P < 0.025). The rate of response to treatment, including both complete and partial response, was not significantly different between the two groups (76.47% versus 64.85%; P value not significant). The mean daily effective dose of terlipressin was lower in the TERLI-INF group than in the TERLI-BOL group (2.23 ± 0.65 versus 3.51 ± 1.77 mg/day; P < 0.05). CONCLUSION: Terlipressin given by continuous intravenous infusion is better tolerated than intravenous boluses in the treatment of type 1 HRS. Moreover, it is effective at doses lower than those required for intravenous bolus administration.

The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a randomized, controlled clinical trial.

UNLABELLED: Spontaneous bacterial peritonitis (SBP) is a common, life-threatening complication of liver cirrhosis. Third-generation cephalosporins have been considered the first-line treatment of SBP. In 2014, a panel of experts suggested a broader spectrum antibiotic regimen for nosocomial SBP, according to the high rate of bacteria resistant to third-generation cephalosporins found in these patients. However, a broader-spectrum antibiotic regimen has never been compared to third-generation cephalosporins in the treatment of nosocomial SBP. The aim of our study was to compare meropenem plus daptomycin versus ceftazidime in the treatment of nosocomial SBP. Patients with cirrhosis and nosocomial SBP were randomized to receive meropenem (1 g/8 hours) plus daptomycin (6 mg/kg/day) or ceftazidime (2 g/8 hours). A paracentesis was performed after 48 hours of treatment. A reduction in ascitic fluid neutrophil count <25% of pretreatment value was considered a treatment failure. The primary outcome was the efficacy of treatment defined by the resolution of SBP after 7 days of treatment. Thirty-two patients were randomized and 31 were analyzed. The combination of meropenem plus daptomycin was significantly more effective than ceftazidime in the treatment of nosocomial SBP (86.7 vs. 25%; P < 0.001). Ninety-day transplant-free survival (TFS) was not significantly different between the two groups. In the multivariate analysis, ineffective response to first-line treatment (hazard ratio [HR]: 20.6; P = 0.01), development of acute kidney injury during hospitalization (HR: 23.2; P = 0.01), and baseline mean arterial pressure (HR: 0.92; P = 0.01) were found to be independent predictors of 90-day TFS. CONCLUSION: The combination of meropenem plus daptomycin is more effective than ceftazidime as empirical antibiotic treatment of nosocomial SBP. Efficacy of the empirical antibiotic treatment is a strong predictor of 90-day survival in patients with nosocomial SBP.

Why and how to measure renal function in patients with liver disease.

Patients with advanced liver disease frequently have impaired renal function. Both acute kidney injury (AKI) and chronic kidney disease (CKD) are quite common in patients with cirrhosis and both are associated with a worse prognosis in these patients. A careful assessment of renal function is highly important in these patients to help physicians determine their diagnosis, prognosis and therapeutic management and to define transplantation strategies (liver transplantation alone vs simultaneous liver and kidney transplantation). Although they are still widely used in clinical practice, conventional biomarkers of renal function such as serum creatinine have several limitations in these patients. Recent progress has been made in the evaluation of renal function and new diagnostic criteria for AKI have been proposed. However, certain issues such as the noninvasive assessment of the glomerular filtration rate and/or improvement in the differential diagnosis between hepatorenal syndrome and acute tubular necrosis must still be addressed. The purposes of this paper are: (i) to highlight the importance of the evaluation of renal function in patients with cirrhosis; (ii) to review the state of the art in the assessment of renal function in these patients as well as advances that we expect will be made to improve the accuracy of available tools.

The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.

Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis.

OBJECTIVE: Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). DESIGN: The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. RESULTS: 240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment. CONCLUSIONS: ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

New ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients: can we use an imputed value of serum creatinine?

BACKGROUND & AIMS: The new International Club of Ascites diagnostic criteria to diagnose acute kidney injury at hospital admission suggests the possibility of using a presumed baseline serum creatinine, defined as the last of at least two stable creatinine values during the last 3 months. Nevertheless, the possibility of the lack of such a value still remains. In these patients, the KDIGO criteria suggest to use an inverse application of MDRD equation assuming that baseline glomerular filtration rate is 75 ml/min per 1.73 m(2) (imputed baseline creatinine). We tested the accuracy of this approach to detect acute kidney injury at admission in patients with decompensated cirrhosis and creatinine <1.5 mg/dl. METHODS: We analysed 213 patients hospitalized for acute decompensation of cirrhosis. At admission, glomerular filtration rate was estimated using creatinine-based equations and measured by inulin clearance. A diagnosis of acute kidney injury was made using an imputed value of serum creatinine as baseline. RESULTS: The diagnosis of AKI based on an imputed baseline creatinine identified only 20.1% of patients with measured glomerular filtration rate ≤60 ml/min/1.73 m(2) without any predictive value on 90-day survival. CONCLUSIONS: In patients with cirrhosis and ascites with a creatinine <1.5 mg/dl without a baseline value on their records, the diagnosis of acute kidney injury at admission based on an imputed baseline creatinine is not accurate.

Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and ascites: a real-life cross-sectional study.

BACKGROUND & AIMS: A moderate sodium restriction diet should be indicated in patients with cirrhosis and ascites. Nevertheless, there is a lack of specific investigation on its correct application. To evaluate the adherence of patients with cirrhosis and ascites to a moderately low-salt diet and the impact on intake of total calories and serum sodium concentration. METHODS: A total of 120 outpatients with cirrhosis and ascites were interviewed with a pre-established questionnaire. A quantitative assessment of nutrient and salt intake was performed. RESULT: A moderately low-salt diet was followed by 37 patients (Group A). Of the 83 patients who did not follow the diet (Group B), 54 thought that they were following it. The mean daily sodium intake was 79.5 ± 5.5 mmol/day (Group A) and 205.9 ± 14.1 mmol/day (Group B), P < 0.0001. The adherence to diet was related to the severity of cirrhosis, and was higher among candidates for liver transplantation and in patients followed through the Care Management Program. Patients of Group A had reduced the mean daily calorie intake by 20% compared with Group B patients (P < 0.0005), while there was no difference on the occurrence of hyponatraemia. CONCLUSIONS: This study shows a poor adherence of patients with cirrhosis and ascites to a moderate dietary sodium restriction. Adherence to a diet seems to increase with the worsening of liver disease, probably because of the reduction of alternative therapeutic options. In addition, a deficiency in the educational process can lead the patient to follow a sodium-reduced diet by means of dangerous tools, such as reducing the overall daily food intake.

Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.

BACKGROUND & AIMS: For several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) ≥ 50% to a final value of sCr>1.5mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3mg/dl or a percentage increase in sCr ≥ 50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr ≥ 0.3mg/dl or increase in sCr ≥ 1.5-fold to 2-fold from baseline. AKI diagnosed with the two different criteria was evaluated for the prediction of in-hospital mortality. METHODS: Consecutive hospitalized patients with cirrhosis and ascites were included in the study and evaluated for the development of AKI. RESULTS: Conventional criterion was found to be more accurate than AKIN criteria in improving the prediction of in-hospital mortality in a model including age and Child-Turcotte-Pugh score. The addition of either progression of AKIN stage or a threshold value for sCr of 1.5mg/dl further improves the value of AKIN criteria in this model. More in detail, patients with AKIN stage 1 and sCr<1.5mg/dl had a lower mortality rate (p=0.03), a lower progression rate (p=0.01), and a higher improvement rate (p=0.025) than patients with AKIN stage 1 and sCr ≥ 1.5mg/dl. CONCLUSIONS: Conventional criterion is more accurate than AKIN criteria in the prediction of in-hospital mortality in patients with cirrhosis and ascites. The addition of either the progression of AKIN stage or the cut-off of sCr ≥ 1.5mg/dl to the AKIN criteria improves their prognostic accuracy.

How to improve care in outpatients with cirrhosis and ascites: a new model of care coordination by consultant hepatologists.

BACKGROUND & AIMS: The development of ascites in patients with cirrhosis is associated with a high rate of health care utilization. New models of specialized caregiving support are necessary to optimize its management. The aim of the study was to evaluate the efficacy and financial sustainability of the "Care management check-up" as a new model of specialized caregiving support based on a series of diagnostic facilities performed in real time and on the integrated activity of consultant hepatologists at the hospital unit for outpatients, dedicated nurses, physicians in training and primary physicians, compared to standard care in outpatients with cirrhosis and ascites. METHODS: 100 cirrhotic patients admitted to our hospital were allocated, after discharge, to the "Care management check-up" group (group 1), or to the "Standard outpatient care" group (group 2), and followed prospectively as outpatients up to death or for at least 12 months. Patients of the two groups could also access to a "Day hospital" when an invasive procedure was required. In group 1, the "Care management check-up" and the "Day hospital" taken together defined the "Care management program". RESULTS: Twelve-month mortality was higher in group 2 than in group 1 (45.7% vs. 23.1%, p<0.025). The rate of 30-day readmission was also higher in group 2 (42.4% vs. 15.4%, p<0.01). The global cost attributable to the management per patient-month of life was lower (1479.19 ± 2184.43 €) in group 1 than (2816.13 ± 3893.03 €) in group 2 (p<0.05). CONCLUSIONS: The study suggests that this new model of specialized caregiving reduces 12-month mortality in patients with cirrhosis and ascites as well as the global health care costs for their management.