P. Ginès

Total paracentesis with dextran 40 vs diuretics in the treatment of ascites in cirrhosis: a randomized controlled study.

The aim of the current study was to compare total paracentesis associated with dextran-40 infusion with diuretics in the treatment of tense ascites in patients with cirrhosis. Eighty patients were randomly allocated to two groups: 40 patients were treated with paracentesis plus dextran-40 infusion (8 g per liter of ascitic fluid removed), and 40 patients with diuretics. After treatment patients were discharged with diuretics, and patients developing tense ascites during follow up (54 +/- 4 weeks) were treated according to their initial schedule. Paracentesis was more effective than diuretics in mobilizing the ascitic fluid. The incidence of complications was significantly higher (p < 0.05) in the diuretic group (38%) than in the paracentesis group (15%). This difference was mainly due to a higher incidence of hepatic encephalopathy in the former group (30% vs. 2.5%). A significantly higher incidence of hepatic encephalopathy was also observed in the diuretic group during the follow-up readmissions for ascites recurrence. There were no significant differences between the two treatment groups in the probability of survival after inclusion. Plasma renin activity and plasma aldosterone concentration measured before and 2 and 6 days after paracentesis in 20 randomly selected patients increased significantly (p < 0.05) (baseline values: 5.3 +/- 1.4 ng.ml-1.h-1 and 63 +/- 21 ng/dl; 48 h after paracentesis: 11.7 +/- 3.9 ng.ml-1.h-1 and 99 +/- 31 ng/dl; 6 days after paracentesis: 10.9 +/- 3 ng.ml-1.h-1 and 110 +/- 27 ng/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Oral misoprostol or intravenous prostaglandin E2 do not improve renal function in patients with cirrhosis and ascites with hyponatremia or renal failure

Prostaglandins play an important role in the maintenance of renal hemodynamics and water excretion in cirrhosis. To investigate whether the administration of prostaglandins improves renal function in cirrhotic patients with ascites, 16 patients with functional renal failure and/or dilutional hyponatremia were given oral misoprostol, a prostaglandin E1 analogue (200 micrograms/6 h for 4 days; n = 9) or intravenous prostaglandin E2 (0.5 microgram/min for 1 h followed by 1 microgram/min for another hour; n = 7). The administration of misoprostol did not induce significant changes in the glomerular filtration rate (59 +/- 11 vs. 54 +/- 11 ml/min), sodium excretion (4.0 +/- 1.3 vs. 4.1 +/- 2.1 microEq/min), and free water clearance (2.4 +/- 0.8 vs. 2.1 +/- 0.9 ml/min), nor did it improve the natriuretic response to an intravenous bolus of 40 mg of furosemide (486 +/- 124 vs. 406 +/- 88 microEq/min). Similarly, an infusion of prostaglandin E2 did not induce significant changes in the glomerular filtration rate (baseline: 33 +/- 6; 0.5 microgram/min: 31 +/- 5; 1 microgram/min: 31 +/- 6 ml/min) and sodium excretion (5.7 +/- 2.7; 3.2 +/- 1.4; and 1.5 +/- 0.7 microEq/min, respectively), whereas free water clearance decreased significantly (1.1 +/- 0.7; 0.5 +/- 0.5; and -0.1 +/- 0.2 ml/min, respectively, p < 0.05). These results indicate that oral misoprostol or the intravenous infusion of prostaglandin E2 do not improve renal function in cirrhosis with ascites.

49 OSTEOPONTIN IS A NOVEL THERAPEUTIC TARGET IN PATIENTS WITH ALCOHOLIC HEPATITIS

Background: Alcoholic hepatitis is a lifeand health-threatening disease covering a wide clinical spectrum. Accurate and representative data on its incidence and prognosis are scarce. Aim: To provide population based crude and adjusted (age, sex and cirrhosis) incidence and mortality rates for patients with alcoholic hepatitis, using a 10-year study period. Methods: Using administrative registers; we identified all patients with a first time diagnosis of alcoholic hepatitis in Denmark from 1999 to 2008, and their dates of death. A simultaneous diagnosis of cirrhosis was also registered. We computed the annual ageand sex-standardized incidence rate as well as 28-, 84-day and longterm mortality rates. Results: We identified 1951 patients, 63% men. During the study time, the annual incidence rate rose from 37 to 46 per 1.000.000 for men and from 24 to 34 per 1.000.000 for women. The 28day mortality rate rose from 12% to 15% over time (no gender difference). The 84-day mortality rate rose from 14% to 24%. The rise in short term mortality was dependable on a rise in patient mean age and cirrhotic comorbidity and there was no difference in short-term mortality after adjusting for these factors. Overall 5-year survival was 44%, 53% without cirrhosis and 31% with cirrhosis. Conclusions: This population-based study spanning 10 years describes an increasing incidence rate and short-term mortality of patients with alcoholic hepatitis. Patients with Alcoholic hepatitis have a high shortand long-term mortality, the latter highly dependable on the presence of cirrhosis. The increase in mortality can be explained by a higher frequency of cirrhosis on admission combined with increasing patient age. Our data does not support causal conclusions on the increase in incidence, age and cirrhosis, but we believe that changes in diagnostic approach or the observed increase in people who drink more than the recommended limit. 49 OSTEOPONTIN IS A NOVEL THERAPEUTIC TARGET IN PATIENTS WITH ALCOHOLIC HEPATITIS O. Morales, M. Dominguez, E. Juez, M. Moreno, R. Miquel, J.J. Lozano, J. Colmenero, J.C. Garcia-Pagan, V. Arroyo, P. Gines, J. Caballeria, R. Bataller. Liver Unit, Pathology Unit, Hospital Clinic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain E-mail: oriol.morales@ciberehd.org

844 COMPARISON OF AKIN CRITERIA AND CONVENTIONAL CRITERIA FOR DEFINITION OF RENAL IMPAIRMENT IN CIRRHOSIS. PRELIMINARY RESULTS OF A PROSPECTIVE STUDY

25 patients (33.8%) in group I and 39 (55.7%) patients in group II, and in 25 patients (33.8%) versus 31 patients (44.3%) after the second session. 24 patients (32.4%) in group I achieved variceal eradication after the third session. Fever, chest pain and dysphagia were observed more frequently in group II than in group I, fatal bleeding from post sclerotherapy ulcer was seen in three patients in group II which never occurred in group I. Conclusion: Band ligation is a good alternative to cyanoacrylate injection in treatment of actively bleeding junctional varices.

1019 URINARY NGAL IS USEFUL TO PREDICT CAUSE AND SEVERITY OF KIDNEY FUNCTION IMPAIRMENT AND IS A PROGNOSTIC MARKER IN PATIENTS HOSPITALIZED FOR COMPLICATIONS OF CIRRHOSIS

1018 URINARY KIDNEY INJURY MOLECULE-1 (KIM-1) IN THE ASSESSMENT OF ACUTE KIDNEY INJURY IN PATIENTS WITH CIRRHOSIS R. Barreto, C. Fagundes, R. Moreira, E. Rodriguez, R. Cela, E. Sola, I. Graupera, X. Ariza, G. Pereira, M. Morales, W. Jimenez, M. Guevara, V. Arroyo, P. Gines. Liver Unit, Hospital Cĺinic, University de Barcelona, IDIBAPS, CIBERehd, Centro Diagnostico Biomedica, IDIBAPS, Insititud d’Investigacions Biomediques August Pi i Sunyer, Biochemistry and Molecular Genetics Dept, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEReHD), Biochemistry and Molecular Genetics Dept, Hospital Clinic, University of Barcelona, Barcelona, Spain E-mail: rbarreto@clinic.cat

952 MELD-SODIUM PREDICTS SURVIVAL AND DEVELOPMENT OF TYPE-1 HEPATORENAL SYNDROME IN PATIENTS WITH TYPE-2 HEPATORENAL SYNDROME

Patients with type 2 hepatorenal syndrome (HRS) may develop type-1 HRS; however, the frequency and risk factors associated with the occurrence of this complication are currently unknown. With the aim of studying the risk factors associated with the development of type-1 HRS, 164 consecutive patients with cirrhosis and type-2 HRS were evaluated. The mean age was 62±10 years, 70% were male and 47% had alcoholic cirrhosis. At diagnosis, serum creatinine value was 1.77±0.25mg/dL, 57% patients had refractory ascites and 40% hyponatremia (serum sodium 131±5 mEq/L). Patients showed a marked deterioration in systemic hemodynamics and liver function, as evidenced by low mean arterial pressure (78±11mmHg), an increase in endogenous vasoactive systems activity (plasma renin activity 10.7±9ng/ml*h) and high values for MELD and MELD-sodium (18±5 and 23±5, respectively). At one year, only 34 patients were still alive, 29 had been transplanted and 92 had died. Thirty-nine patients (24%) developed type-1 HRS within a median of 65 days (95%CI 15– 117). Mean serum creatinine value at the time of diagnosis was 3.77±1.17mg/dL, which corresponded to mean an increase of 117% respect to baseline (95%CI 100–137%). No precipitating event was identified in 22 patients (56%). Bacterial infections were the most common precipitating factor of type-1 HRS (observed in 14 patients (37%). On multivariate analysis, MELD-Sodium was the only factor independently associated with survival and development of type-1 HRS, and the best cut-off point was 22. At 6 months, the incidence of type 1 HRS was significantly higher in patients with MELD-Sodium greater than or equal to 22, when compared to patients with MELD-Sodium lower than 22 (29 vs. 9%, p = 0.002). In conclusion, development of type-1 HRS is a frequent event in patients with type-2 HRS and occurs in absence of any precipitating event in almost half of cases. MELD-Sodium is a useful tool to predict both survival and development of type-1 HRS in this population. These results should be accounted not only on prediction of prognosis of these patients, but also for design of possible future therapeutic strategies.

18 PROTEOMIC ANALYSIS IDENTIFIES P90RSK AS A NOVEL THERAPEUTIC TARGET IN PATIENTS WITH ALCOHOLIC HEPATITIS

18 PROTEOMIC ANALYSIS IDENTIFIES P90RSK AS A NOVEL THERAPEUTIC TARGET IN PATIENTSWITH ALCOHOLIC HEPATITIS O. Morales-Ibanez, M. Moreno, T. Knorpp, M. Templin, C. Millan, J.-C. Garcia-Pagan, V. Arroyo, P. Gines, J. Caballeria, R. Bataller. Liver Unit, Hospital Cĺinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz, CIBER de Enfermedades Hepaticas y Digestivas (CIBERehd), Barcelona, Spain; Natural and Medical Sciences Institute, University of Tuebingen, Tubingen, Germany E-mail: oriol.mibanez@gmail.com

Chapter 14 – Hepatorenal Syndrome

Patients with cirrhosis are prone to developing acute kidney injury (AKI), which is defined by an acute increase in the serum creatinine of >0.3 mg/dL within 48 hours or by ≥50% from a stable baseline serum creatinine (sCr) within 3 months. Prerenal AKI, the hepatorenal syndrome (HRS), also known as HRS type 1, a particular form of prerenal AKI in liver cirrhosis, and acute tubular necrosis (ATN) represent the most common causes of renal dysfunction in cirrhotic patients. Teasing these two entities apart is of key importance because treatment differs substantially. While prerenal AKI usually responds well to plasma volume expansion, a diagnosis of HRS or ATN requires specific treatment approaches and is associated with substantial mortality. HRS isxa0characterized mainlyxa0by functional renal failure due to renal vasoconstriction in the absence of underlying kidney pathology. Thexa0diagnosis of HRS is based on established diagnostic criteria aimed at excluding nonfunctional causes of renal failure.xa0The prognosis of patients with HRS is poor,xa0especially in those who have a rapidly progressive course. Liver transplantation is the best option in suitable candidates butxa0difficult to implement in all patients because of the poor prognosis. Pharmacologic therapies based on the use of vasoconstrictor drugsxa0plus intravenous albumin arexa0the standard first line of therapy. Other treatments such as transjugular intrahepatic portosystemic shunts and renal replacement therapy may be effective, but experience is limited.

P344 TRANSLATIONAL STUDY IDENTIFIES NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) AS A POTENTIAL MEDIATOR OF LIVER INJURY AND FIBROGENESIS IN ALCOHOLIC HEPATITIS

allows quantification and visualization of biochemical processes by monitoring the distribution of molecules labelled with positron imaging isotopes. We aimed to develop a methodology for noninvasive PET imaging of Kupffer cell status in liver. Methods: Our strategy was to target CD206 receptor that selectively takes up mannosylated albumin. Thus mannosylated albumin (mHSA) was synthesized and coupled to radionuclideF. Thereafter the pharmacological properties of this radiotracer were explored in a range of pre-clinical models including cells and wistar-rats. Whole-body PET images were acquired 30/60 minutes after injection of 5–15 MBq of radiotracer-[18F]B-mHSA. Results: Hepatic uptake at 30 and 60 min was high whereas accumulation in the kidney was even higher, due to metabolism in liver and renal clearance. Blocking studies with a 20 fold excess of unlabeled tracer revealed saturable tracer uptake. In immune-related organs such as the bone-marrow, spleen, and liver radio-tracer uptake was highest at 30 minutes post injection and decreased thereafter. Ex-vivo biodistribution indicated lowest tracer uptake in non-target organs. Tracer uptake reaches a plateau in 45 min for RAW cells and in 60 min for murine Kupffer cells. Conclusions: [F]B-mHSA is readily labelled, is stable in plasma and displays binding affinity for the CD206 receptors. This method allows quantitative and non-invasive imaging of liver function by using expression of the Kupffer cell specific CD206 receptor with special interest in liver toxicity and the early events leading to liver fibrosis.

1126 IDENTIFICATION OF p90RSK AS A NOVEL THERAPEUTIC TARGET FOR LIVER FIBROSIS

able to repress AKT phosphorylation after GAS6 exposure (30 min, 200ng/ml), and overnight treatment of LX2 cells was able to dosedependently decrease basal AKT levels and inhibit GAS6-dependent AKT activation. Conclusions: Our results point to Axl/AKT axis as a relevant mechanism in HSC activation and suggest that Axl targeting may be an interesting therapeutic strategy to reduce liver fibrosis.