Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway.

BACKGROUNDS/AIMS: The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). METHODS: Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. RESULTS: Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. CONCLUSIONS: Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

A Treat-to-Target Concept to Guide the Medical Management of Hepatorenal Syndrome.

BACKGROUND: The principle of treating-to-target has been successfully applied to many diseases with significant improvement in patient care and as a useful guidance for healthcare providers. Appreciation of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin in patients with HRS. An appropriate target to guide such therapy, however, has not yet been established. AIMS: The purpose of the current study was to identify a suitable target that can predict clinical outcome and guide the medical management of type 1 HRS, a condition associated with very poor prognosis. METHODS: A total of 85 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled. A potential therapeutic target was identified by univariate and multivariate logistic regression analyses. The treat-to-target concept to guide the management of HRS was then tested via a retrospective cohort study. RESULTS: A change in mean arterial pressure (MAP) during treatment was identified as a sole independent predictor for patient survival. Compared with mild or no increase in MAP, achievement in a marked increase in MAP of more than 10 mmHg in these patients was associated with better overall survival and transplant-free survival. Increased MAP to higher than 15 mmHg did not result in further improvement in clinical outcome. CONCLUSIONS: A treat-to-target concept by the use of a specific goal of MAP is feasible and may potentially guide the medical management of type 1 HRS.

Effect of various drugs used in conservative therapy of hepatorenal syndrome: a retrospective drug utilization study.

OBJECTIVES: To analyze the impact of various drugs used in conservative therapy on renal failure and mortality in hepatorenal syndrome (HRS) at a tertiary care teaching hospital. MATERIALS AND METHODS: Retrospective review of hospital admission records was conducted for case records with HRS as diagnosis. Demographic and clinical data and drug utilization pattern were collected in a pre-designed patient information sheet. Impact of various drugs especially hepatoprotector antioxidant, silymarin, on survival benefits in terms of number of patients alive, change in mean arterial pressure (MAP) and change in serum creatinine at the end of treatment period were estimated by univariate and followed by multivariate analysis. RESULTS: Of the total 89 case records, 31 met the eligibility criteria and were included in the analysis. On multivariate analysis, a significant correlation between use of intravenous fluids (IVFs) and survival benefits was observed (P < 0.05); wherein patients treated with IVFs had an increase in log odds of survival by 2.42 (95% CI = 1.06 to 121.13) as compared to patient not treated with IVF. However, MAP was not affected by any of the treatment modalities. While change in serum creatinine level was not significantly (P = 0.06, regression correlation = -0.3) correlated with duration of treatment with IVFs. CONCLUSION: Use of IVFs may be associated with better short-term survival benefits and favor HRS reversal. Use of silymarin as hepatoprotector antioxidant has no beneficial effects on HRS reversal or survival benefits.

Alcoholic hepatitis: a clinician's guide.

Alcoholic hepatitis is a frequent reason for admission and a common consultation request for hepatologists and gastroenterologists. Although it seems to occur acutely, it is usually subacute and often superimposed on underlying alcoholic cirrhosis. Typically patients have a background of drinking on a daily basis, but, in response to a life crisis, patients have started drinking massively.

Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome.

UNLABELLED: Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05). CONCLUSION: An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.

Recent advances in the management of hepato-renal syndrome (HRS).

Hepato-renal syndrome (HRS) is a functional renal failure complicating end-stage liver disease. HRS is characterized by marked arterial vasodilation (mainly of the splanchnic bed) and severe renal vasoconstriction. HRS is classified into 2 types: type I HRS shows a rapid and progressive decline in renal function with a very poor prognosis (median survival of about 2 weeks); HRS type 2 has a more stable renal failure, with a median survival of about 6 months. The management of HRS is still a big challenge. The definitive therapy for HRS is liver transplantation (LT); however, the survival rate of HRS patients is poor, and important organ shortage exists. Various approaches have been used for HRS treatment including vasoconstrictor therapy. Recent evidence has shown that vasoconstrictor agents are effective and serve as a bridge to LT; the rationale for vasoconstrictors is to counteract the splanchnic arterial vasodilation and increase the effective arterial blood volume. Thus, renal perfusion and glomerular filtration rates improve. Terlipressin, a V1 vasopressin agonist, has been used frequently. A recent meta-analysis of clinical trials showed that the pooled rate of patients who reversed HRS after terlipressin therapy was 0.52 (95% CI, 0.42; 0.61; P = 0.0001, /2 = 24.6%). The pooled Odds Ratio (OR) for mortality rate in HRS patients who were not responders to terlipressin versus responders was 5.746 (95% CI, 1.5; 21.9; P = 0.0005). Prospective, controlled clinical trials are in progress to address the impact of vasoconstrictor use on survival in HRS patients. Alternative therapies such as transjugular intrahepatic portosystemic shunts (TIPS) and extracorporeal albumin dialysis (ECAD) have given encouraging results but experience is extremely limited.

[Effect of nephrophyte on the course of the hepatorenal syndrome caused by a complex of antituberculous drugs].

A complex of antituberculous drugs causes the hepatorenal syndrome in albino rats. The course administration of the plant agent nephrophyte in an experimental therapeutic dose during tuberculostatic therapy has a positive effect on the course of the hepatorenal syndrome.

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

BACKGROUND: Intravenous administration of a third-generation cephalosporin is optimal antibiotic treatment for spontaneous bacterial peritonitis. AIMS: To compare an intravenous-oral step-down schedule with ciprofloxacin (switch therapy) to intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis, and to evaluate the impact of terlipressin and albumin in the treatment of type 1 hepatorenal syndrome on mortality. METHODS: A total of 116 cirrhotic patients with spontaneous bacterial peritonitis, were randomly given switch therapy with ciprofloxacin (61 patients) or intravenous ceftazidime (55 patients). All patients who developed type 1 hepatorenal syndrome were treated with terlipressin (2-12 mg/day) and albumin (20-40 g/day). RESULTS: Resolution of infection was achieved in 46/55 patients treated with ceftazidime (84%) and in 49/61 patients treated with ciprofloxacin (80%, P = N.S.). An intravenous-oral step-down schedule was possible in 50/61 patients (82%) who received ciprofloxacin; 45/61 patients (74%) were discharged before the end of antibiotic treatment and completed it at home. The mean saving per patient due to the reduction of hospital stay in the ciprofloxacin group was 1150 . Type 1 hepatorenal syndrome was treated successfully in 12/19 patients (63%). As a consequence, the in-hospital mortality rate due to infection was 10%. CONCLUSIONS: Switch therapy with cephalosporin is more cost-effective than intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in cirrhotic patients who are not on prophylaxis with quinolones.