S. Fasolato

Renal failure and bacterial infections in patients with cirrhosis: Epidemiology and clinical features

The aim of the study was to investigate the prevalence and clinical course of renal failure that was induced by the various types of bacterial infections in patients with cirrhosis and ascites. Three hundred and nine patients, who were consecutively admitted to the 3 major hospitals of Padova, Italy, during the first 6 months of 2005, were studied prospectively. Of these, 233 patients (75.4%) had evidence of ascites. In 104 patients with cirrhosis and ascites (44.6%) a bacterial infection was diagnosed. A bacterial infection‐induced renal failure was observed in 35 of 104 patients (33.6%). The prevalence of renal failure was higher in biliary or gastrointestinal tract infections and in spontaneous bacterial peritonitis (SBP) and in than in other types of infections. In addition, the progressive form of renal failure was only precipitated by biliary or gastrointestinal tract infections, SBP, and urinary tract infections (UTI). In a multivariate analysis only MELD score (P = 0.001), the peak count of neutrophil leukocyte in blood (P = 0.04), and the lack of resolution of infection (P = 0.03) had an independent predictive value on the occurrence of renal failure. Conclusion: The results of the study show that the development of bacterial‐induced renal failure in patients with cirrhosis and ascites is related to the MELD score, and to both the severity and the lack of resolution of the infection. A progressive form of renal failure occurs only as a consequence of biliary or gastrointestinal tract infections, SBP, and UTI. (HEPATOLOGY 2007;45:223–229.)

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.

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial

Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty‐seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20‐40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End‐Stage Liver Disease score were associated with better survival. Conclusion: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS (Hepatology 2015;62:567–574

Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial

Objective: The aim of the study was to compare sequential versus combined diuretic therapy in patients with cirrhosis, moderate ascites and without renal failure. Design: One hundred patients were randomly assigned to the two diuretic treatments. The sequential treatment provided potassium canrenoate at the initial dose of 200 mg/day, then increased to 400 mg/day. Non-responders were treated with 400 mg/day of potassium canrenoate and furosemide at an initial dose of 50 mg/day, then increased to 150 mg/day. The combined treatment provided the initial dose of 200 mg/day of potassium canrenoate and 50 mg/day of furosemide, then increased to 400 mg/day and 150 mg/day, respectively. Results: Most patients who received sequential treatment responded to potassium canrenoate alone (19% to 200 mg/day and 52.63% to 400 mg/day, respectively). Most patients who received the combined treatment responded to the first two steps (40% to the first step and 50% to the second, ie, 400 mg/day of potassium canrenoate plus 100 mg/day of furosemide). Adverse effects (38% vs 20%, p<0.05), in particular, hyperkalaemia (18% vs 4%, p<0.05), were more frequent in patients who received sequential therapy. As a consequence, the per cent of patients who resolved ascites without changing the effective diuretic step was higher in those who received the combined treatment (56% vs 76%, p<0.05). Conclusions: The combined diuretic treatment is preferable to the sequential one in the treatment of moderate ascites in patients with cirrhosis and without renal failure. NCT00741663. This work is an open randomised clinical trial.

Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost

Intravenous administration of a third‐generation cephalosporin is optimal antibiotic treatment for spontaneous bacterial peritonitis.

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

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. (Hepatology 2016;63:1299–1309)

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

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. (Hepatology 2016;63:983–992)

Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms

The aim of this study was to evaluate the effect and molecular mechanism of albumin infusion on cardiac contractility in experimental cirrhosis with ascites. Cardiac contractility was recorded ex vivo in rats with cirrhosis and ascites and in control rats after the injection in the caudal vein of albumin, saline, or hydroxyethyl starch (HES). Gene and protein expression of β‐receptors and pathways involved in their intracellular signaling such as Gαi2 protein (Gαi2), adenylate cyclase 3 (Adcy3), protein expression of tumor necrosis factor alpha (TNF‐α) and inducible nitric oxide synthase (iNOS), were evaluated in cardiac tissue in both groups. Phosphorylation and membrane‐translocation of the cytosolic components of nicotinamide adenine dinucleotide phosphate (NAD(P)H)‐oxidase and translocation of nuclear factor kappa B (NF‐κB) were also evaluated. After saline intravenous injection, cardiac contractility was significantly reduced in rats with cirrhosis as compared to control rats (P < 0.01). This was associated with: (1) increased expression of protein Gαi2 (P < 0.05), TNF‐α (P < 0.05), iNOS (P < 0.05); (2) increased NAD(P)H‐oxidase activity (P < 0.05); (3) increased nuclear translocation of NF‐κB (P < 0.05); and (4) lower expression of Adcy 3 (P < 0.05) in cardiac tissue of rats with cirrhosis. After albumin injection cardiac contractility (P < 0.01), protein expression of TNF‐α, iNOS, Gαi2, and Adcy3, NAD(P)H‐oxidase activity and nuclear translocation of NF‐κB in cardiac tissue of rats with cirrhosis were reversed to control levels (P < 0.05). HES injection did not modify cardiac contractility and nuclear translocation of NF‐κB in cardiac tissue of rats with cirrhosis. Conclusion: Albumin exerts a positive cardiac inotropic effect in rats with cirrhosis and ascites counteracting the negative effects of oxidative stress‐ and TNF‐α‐induced activation of NF‐κB‐iNOS pathway and oxidative stress‐induced alteration of β‐receptor signaling. (HEPATOLOGY 2013)

Immunohistochemical reactivity of a monoclonal antibody prepared against human ovarian carcinoma on normal and pathological female genital tissues.

The reactivity profile of the monoclonal antibody (MAb) MOv18, raised against a poorly differentiated ovarian carcinoma specimen, was studied on normal tissues and tumors from the female reproductive system and on the kidney, which like the oviducts, vagina and uterus, also derives from the intermediate mesoderm. The obtained results indicate that MOv18 recognizes an epitope present on the normal epithelium of the oviducts, on 14-week old fetal kidney and, focally, on proximal and distal tubules of normal adult kidney. A strong reactivity was found on ovarian carcinomas, on invasive squamous carcinomas of the cervix and on endometrial carcinomas and hyperplasias. The antigen recognized by MOv18 (CaMOv18) therefore seems to be an epithelial cell marker associated with intermediate mesoderm differentiation, which can be derepressed during the neoplastic transformation of the ovary and the uterus.

SERPINB3 is associated with TGF-β1 and cytoplasmic β-catenin expression in hepatocellular carcinomas with poor prognosis.

Background:Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome.Methods:Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-β and β-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out.Results:High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-β at transcription and protein level was observed, whereas for β-catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis.Conclusions:SERPINB3 is overexpressed in the subset of the most aggressive HCCs.