Toll-like receptor 4 signaling pathway mediates both liver and kidney injuries in mice with hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a complication of cirrhosis with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the Toll-like receptor 4 (TLR4) signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney. Nevertheless, impaired liver and kidney functions, inflammatory response, and fibrosis were examined in mice after 2 wk of BDL. Compared with those of other groups, mice in the BDL + UUO group presented severer liver and kidney injuries, higher levels of inflammatory factors, and faster deposition of collagens, suggesting that kidney injuries accelerated the aggravation of HRS. Correlation analysis identified a positive correlation between expression levels of inflammatory factors and fibrotic levels. Meanwhile, TLR4 and its ligand MyD88 were upregulated during the process of liver and kidney injuries in HRS mice. Further animal experiments in transgenic TLR4-/- mice or in those treated with TAK242, a small molecule inhibitor of TLR4, showed that blocking the TLR4 signaling pathway significantly improved survival quality and survival rate in HRS mice by alleviating liver fibrosis and kidney injury. It is concluded that kidney dysfunction plays an important role in the aggravation of cirrhosis, which may be attributed to the TLR4 signaling pathway. Targeting TLR4 could be a promising therapeutic strategy for protecting both liver and kidneys in patients with HRS.NEW & NOTEWORTHY Our study established BDL, UUO, and BDL + UUO models, providing a novel idea for analyzing liver and kidney diseases. It is highlighted that the kidney injury accelerated the aggravation of HRS via inflammatory response, which could be protected by inhibiting the TLR4 signaling pathway. We believed that targeting TLR4 was a promising therapeutic strategy for protecting both liver and kidney functions in patients with HRS.

The Use of Rifaximin in Patients With Cirrhosis.

Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.

Hyponatremia in Cirrhosis: An Update.

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.

Application of the Molecular Adsorbent Recirculating System in Type 1 Hepatorenal Syndrome in the Course of Alcohol-Related Acute on Chronic Liver Failure.

BACKGROUND This study aimed to evaluate the Molecular Adsorbent Recirculating System (MARS) effectiveness in patients with alcohol-related acute-on-chronic liver failure (AoCLF) complicated with type 1 hepatorenal syndrome (HRS). So far, MARS efficacy and safety has been demonstrated in various acute liver failure scenarios. MATERIAL AND METHODS Data from 41 MARS procedures (10 patients with type 1 HRS, in the course of alcohol-related AoCLF were considered for this study. Biochemical tests of blood serum were performed before and after each procedure. The condition of patients was determined before and after the treatment with the use of the model for end-stage liver disease - sodium (MELD-Na) and the stage of encephalopathy severity based on the West Haven criteria. RESULTS During the observation period (20.5±13.9 days), 5 patients died, and the remaining 5 surviving patients were discharged from the hospital. In the group of 10, the 14-day survival, starting from the first MARS treatment, was 90%. The MARS procedure was associated with a 19% reduction in bilirubin (27.5±6.1 versus 22.3±4.0 mg/dL, P<0.001), 37% reduction in ammonia (44.1±22.5 versus 27.6±20.9 P<0.001), 27% reduction in creatinine (1.5±1.0 versus 1.1±0.6 mg/dL, P<0.001) and 14% reduction urea (83.8±36.1 versus 72.1±33.3, P<0.001) in blood serum samples, with stable hemodynamic parameters. In the group of patients discharged from the clinic (n=5), the MARS treatments resulted in an improvement in hepatic encephalopathy (West Haven; P=0.043), as well as a reduction in the MELD-Na score (P=0.015). CONCLUSIONS MARS is a hemodynamically safe method for supporting the function of the liver and the kidneys. Application of the MARS reduces the symptoms of encephalopathy in patients with alcohol-related type 1 HRS.

Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome.

STUDY RATIONALE: Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the cannabinoid-2 receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL). METHODS: Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys. KEY RESULTS: We found that liver injury triggered marked inflammation and oxidative stress in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both the liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice. CONCLUSIONS: Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.

Role of Probiotic Mixture with and Without Green Tea Extract in Prevention of Hepatorenal Syndrome in Rat Model.

BACKGROUND AND OBJECTIVE: Hepatorenal syndrome (HRS) is a major public health problem in which both liver and kidney dysfunctions are encountered. The present research aimed to investigate the beneficial use of micro-encapsulated probiotic alone (Bifidobacterium bifidum, Lactobacillus delbrueckii and Streptococcus thermophilus mixture) or with green tea alcohol extract in HRS model in rats. MATERIALS AND METHODS: Flavonoids content and in vitro antioxidant activity of the extract were assessed. The animal experiment consisted of 4 groups; control healthy, control with HRS and two test groups with HRS and treated with either the encapsulated probiotic mixture alone or with green tea extract. After 3 weeks; urinary creatinine was determined in 24 h rat urine samples. Colonic microbiota was assessed in faeces. Plasma malondialdehyde, nitrite, C-reactive protein, creatinine, uric acid, urea and the activity of transaminases, catalase (CAT) and angiotensin-1 converting enzyme (ACE-1) were determined with calculation of creatinine clearance. RESULTS: Results showed significant increase in all biochemical parameters of HRS control except for ACE-1, CAT and creatinine clearance that experienced significant reduction along with dysbiosis compared to healthy control. Test groups showed improvement in all biochemical parameters with superiority to probiotic-green tea extract combination. Both treatments produced significant increase in fecal B. bifidum, S. thermophilus and L. bulgaricus and reduction of Staphylococci and Coliform. The effect of probiotic-green tea extract combination was more pronounced concerning the last three. Flavonoids and antioxidant activity of the extract were 1.325±0.01 mg quercetin/g and 98±1.66%, respectively. CONCLUSION: Administration of micro-encapsulated probiotic with or without alcohol green tea extract exerted significant prevention of HRS in rat with superiority to probiotic-green tea extract combination.

Clinical utility of urinary neutrophil gelatinase-associated lipocalin and serum cystatin C in a cohort of liver cirrhosis patients with renal dysfunction: a challenge in the diagnosis of hepatorenal syndrome.

OBJECTIVES: This study aimed to assess urinary neutrophil gelatinase-associated lipocalin (uNGAL) and serum cystatin C (sCys C) in liver cirrhosis patients with renal dysfunction and to evaluate their role in the diagnosis of the hepatorenal syndrome (HRS). PATIENTS AND METHODS: Forty-five liver cirrhosis patients were enrolled in the study and they were divided into three groups; the first group included 15 patients with normal renal function, the second group included 15 patients with HRS; and the third group included 15 patients with chronic kidney disease (CKD). There was a fourth group, which included 15 healthy controls. Liver and renal function tests, as well as the estimated glomerular filtration rate were determined. uNGAL was measured using the enzyme-linked immunosorbent assay, and the uNGAL/urinary creatinine concentration (UCC) ratio was calculated. sCys C was measured using the particle-enhanced immunoturbidimetric assay. RESULTS: The ratios of uNGAL and uNGAL/UCC were the highest among HRS patients. The combined uNGAL/UCC ratio and sCys C improved the sensitivity of diagnosis to 93.33% and specificity to 76.67%, with the highest area under the curve of 0.944, 95% confidence interval of 0.879-1.0 (P<0.001). The three biomarkers could successfully identify HRS at the following cutoffs: 84.94 ng/ml, 0.6 ng/mg, and 1.6 mg/l, respectively. Significant positive correlations were found between uNGAL, uNGAL/UCC ratios as well as sCys C and KDIGO stage in liver cirrhosis patients with CKD. CONCLUSION: uNGAL and a better uNGAL/UCC ratio can be used alone or together with serum cystatin C as early biomarkers for HRS among patients with decompensated liver cirrhosis. Moreover, uNGAL, uNGAL/UCC as well as serum cystatin C could aid the prognostic assessment of cirrhotic patients with CKD.

Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats.

Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response to generalized systemic arterial vasodilatation. Nevertheless, the mechanisms have been barely investigated. Cumulative studies demonstrated renal vasodilatation in portal hypertensive and compensated cirrhotic rats. Previously, we identified that blunted renal vascular reactivity of portal hypertensive rats was reversed after lipopolysaccharide (LPS). This study was therefore conducted to delineate the sequence of renal vascular alternation and underlying mechanisms in LPS-treated cirrhotic rats. Sprague-Dawley rats were randomly allocated to receive sham surgery (Sham) or common bile duct ligation (CBDL). LPS was induced on the 28th day after surgery. Kidney perfusion was performed at 0.5 or 3 h after LPS to evaluate renal vascular response to endothelin-1 (ET-1). Endotoxemia increased serum ET-1 levels ( P < 0.0001) and renal arterial blood flow ( P < 0.05) in both Sham and CBDL rats. CBDL rats showed enhanced renal vascular reactivity to ET-1 at 3 h after LPS ( P = 0.026). Pretreatment with endothelin receptor type A (ETA) antagonist abrogated the LPS-enhanced renal vascular response in CBDL rats ( P < 0.001). There were significantly lower inducible nitric oxide synthase (iNOS) expression but higher ETA and phosphorylated extracellular signal-regulated kinase (p-ERK) expressions in renal medulla of endotoxemic CBDL rats ( P < 0.05). We concluded that LPS-induced renal iNOS inhibition, ETA upregulation, and subsequent ERK signaling activation may participate in renal vascular hyperreactivity in cirrhosis. ET-1-targeted therapy may be feasible in the control of HRS. NEW & NOTEWORTHY Hepatorenal syndrome (HRS) occurred in advanced cirrhosis after large-volume paracentesis or bacterial peritonitis. We demonstrated that intraperitoneal lipopolysaccharide (LPS) enhanced renal vascular reactivity to endothelin-1 (ET-1) in cirrhotic rats, accompanied by inducible nitric oxide synthase inhibition, endothelin receptor type A (ETA) upregulation, and subsequent extracellular signal-regulated kinase activation in renal medulla. Pretreatment with ETA antagonist abrogated the LPS-enhanced renal vascular response in common bile duct ligation rats. These findings suggest that further clinical investigation of ET-1-targeted therapy may be feasible in the control of HRS.

Renin angiotensin system in liver diseases: Friend or foe?

In the last three decades, the understanding of the renin angiotensin system (RAS) has been changed by the discoveries of functional local systems, novel biologically active peptides, additional specific receptors, alternative pathways of angiotensin (Ang) II generation, and new roles for enzymes and precursor components other than those in Ang II synthesis. In this regard, the discovery that Ang-(1-7) opposes the pressor, proliferative, pro-fibrotic, and pro-inflammatory effects mediated by Ang II has contributed to the realization that the RAS is composed of two axes. The first axis consists of the angiotensin-converting enzyme (ACE), with Ang II as the end product, and the angiotensin type 1 (AT1) receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to the production of Ang-(1-7), with the Mas receptor as the main effector conveying the vasodilatory, anti-proliferative, anti-fibrotic, and anti-inflammatory effects of Ang-(1-7). Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases. In this manuscript, we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications, including hemodynamic changes and hepatorenal syndrome. The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.

Association of arginine vasopressin receptor 1a gene polymorphisms with hepatorenal syndrome.

OBJECTIVE: To assess the association of arginine vasopressin receptor 1a gene single nucleotide polymorphisms with type I hepatorenal syndrome. METHODS: The case-control study was conducted at the Hangzhou City Xixi Hospital, Hangzhou, China, from January 2012 to June 2014, and comprised patients with type I hepatorenal syndrome and individuals with cirrhosis who acted as the control group. Arginine vasopressin receptor 1a gene rs113481894 locus single nucleotide polymorphisms were analysed by high-resolution melting methods. Statistical analysis was performed using SPSS 17. RESULTS: Of the 60 participants, 28(46.7%) were in the hepatorenal syndrome group and 32(53.3%) were controls. The mean age was 42.21±11.30years in the hepatorenal syndrome group and 43.69±12.60in the control group (p=0.64). Mean total bilirubin, albumin and prothrombin activity levels were 154.76±51.58, 49.30±24.67 and 33.42±3.69 in the hepatorenal syndrome group compared to 181.26±64.46, 41.78±17.52 and32.98±4.81among controls (p=0.09, p=0.18 and p=0.70). Statistically significant differences were found in the distributions of arginine vasopressin receptor 1a gene rs113481894 locus T allele between type I hepatorenal syndrome patients and the control group (odds ratio= 2.230; p= 0.040). CONCLUSIONS: T allele located at arginine vasopressin receptor 1a receptor promoter rs113481894 locus may be associated with the pathogenesis of type I hepatorenal syndrome.

Terlipressin, a vasoactive prodrug recommended in hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its safety profile.

Terlipressin is recommended as a gold standard to treat hepatorenal syndrome complicating liver cirrhosis. It is presented as a specific V1A receptor agonist, beyond its enzymatic conversion into lysine8-Vasopressin (LVP), able to counteract the splanchnic vasodilation. However, the complete pharmacological characterization of this drug with respect to the different vasopressin receptor subtypes is missing. We studied terlipressin intrinsic properties, focusing not only on V1A, but also on other vasopressin receptor subtypes. The experimental studies were conducted on rat and human cellular models. Binding experiments were performed on rat liver membranes and CHO cells transfected with the different human vasopressin receptor subtypes. Agonist status was assessed from inositol phosphate or cyclic AMP assays, and measurement of intracellular calcium variations, performed on cultured vascular smooth muscle cells from rat aorta and human uterine artery and CHO cells. Terlipressin binds to the rat and human V1A receptors with an affinity in the micromolar range, a value 120 fold lower than that of LVP. It induces a rapid and transient intracellular calcium increase, a robust stimulation of phospholipase C but with reduced maximal efficiencies as compared to LVP, indicating a partial V1A agonist property. In addition, terlipressin is also a full agonist of human V2 and V1B receptors, with also a micromomolar affinity. CONCLUSIONS: Terlipressin is a non-selective vasopressin analogue, exhibiting intrinsic agonist properties. Its full V2 receptor agonism may result in renal effects potentially aggravating water retention and hyponatremia of cirrhosis.

Abnormal Expression of Urea Transporter Protein in a Rat Model of Hepatorenal Syndrome Induced by Succinylated Gelatin.

BACKGROUND: Hepatorenal syndrome (HRS) is a serious complication of advanced chronic liver disease. Abdominal compartment syndrome (ACS) occurs with dysfunction of multiple organs when abdominal pressure increases. Here, we report on a novel model of ACS with ascites and a model of HRS in rats to observe the urea transporter protein (UT) expression in the 2 models. MATERIAL AND METHODS: A liver cirrhosis model was induced by CCl4. After changes of liver histopathology were observed, rats were injected intraperitoneally with succinylated gelatin to establish a model of ACS and HRS. Then, changes in BUN, Cr, and renal histopathology were detected. Moreover, the UT in ACS and HRS were also quantified. RESULTS: The surfaces of liver in the cirrhotic group became coarse, with visible small nodules and became yellow and greasy. The normal structure of the hepatic lobules were destroyed, and hyperplasia of fibrotic tissue and pseudo-lobe was observed. The levels of BUN and Cr were significantly increased in rats suffering from ACS and HRS, respectively, compared to their control groups. In addition, the mRNA levels of UT-A2 and UT-A3 decreased in rats with HRS compared to cirrhotic rats. However, there was no significant difference between the mRNA levels of UT-A2, UT-A3, and UT-B in rats with ACS vs. normal rats. CONCLUSIONS: It is feasible to model ACS in rats by injecting succinylated gelatin into the abdominal cavity. Increasing the intra-abdominal pressure by succinylated gelatin is also a novel approach for modeling HRS in cirrhotic rats. Compared with control rats, there is an abnormal mRNA expression of UT in ACS rats and HRS rats.

A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.

BACKGROUND: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics. METHODS: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites). RESULTS: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and ß2-microglobulin performed better compared to Cr in estimating RPF, ß-trace protein, ß2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index. CONCLUSION: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.

[Pain management in patients with liver cirrhosis]. / Tratamiento del dolor en el paciente con cirrosis hepática.

Pain management in patients with liver cirrhosis is a real challenge and is often inadequate due to a lack of therapeutic efficacy or the high incidence of adverse effects. The focus of treatment differs depending on whether the pain is acute or chronic and involves understanding the causative pathophysiological mechanism. Analgesics should be started with the minimum effective dose and should be titrated slowly with avoidance of polypharmacy. Adverse effects must be monitored, especially sedation and constipation, which predispose the patient to the development of hepatic encephalopathy. The first-line drug is paracetamol, which is safe at doses of 2-3g/day. Non-steroidal anti-inflammatory agents are contraindicated because they can cause acute renal failure and/or gastrointestinal bleeding. Tramadol is a safe option for moderate-severe pain. The opioids with the best safety profile are fentanyl and hydromorphone, with methadone as an alternative. Topical treatment can reduce oral drug consumption. In neuropathic pain the first-line therapeutic option is gabapentin. The use of antidepressants such as amitriptyline can be considered in some patients. Interventional techniques are a valuable tool in moderate to severe pain, since they allow a reduction in drug therapy and consequently its adverse effects. Psychological treatment, physical therapy and rehabilitation should be considered as part of multimodality therapy in the management of chronic pain.

Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study.

BACKGROUND: Various vasoconstrictors have shown promising results in the management of type 1 hepatorenal syndrome (HRS). However, there are very few studies on vasopressors in the management of type 2 HRS. Terlipressin has been used commonly; however, it is costly and not available in some countries. In this study, we evaluated the safety and efficacy of terlipressin and noradrenaline in the treatment of type 2 HRS. METHODS: Forty-six patients with type 2 HRS were managed with terlipressin (group A, N = 23) or noradrenaline (Group B, N = 23) with albumin in a randomized controlled trial at a tertiary centre. RESULTS: HRS reversal could be achieved in 17(73.9%) patients in group A as well as in group B (P = 1.0). Univariate analysis showed that the baseline model of end-stage liver disease score, urine output, urinary sodium, serum creatinine and mean arterial pressure were associated with response. However, in multivariate analysis only baseline serum creatinine, urine output and urinary sodium were associated with the response. Eight patients in group A and 9 in group B died within 90 days of follow-up (P > 0.05). Noradrenaline was less expensive than terlipressin (P < 0.05). No major adverse effects were seen. CONCLUSIONS: The results of this randomized study suggest that terlipressin and noradrenaline are safe and effective in the treatment of type 2 HRS and baseline serum creatinine, urine output and urinary sodium are predictive of response. Noradrenaline is less expensive than terlipressin in the treatment of type 2 HRS (ClinicalTrials.gov, Number NCT01637454).

Protective effect of nitric oxide on hepatopulmonary syndrome from ischemia-reperfusion injury.

AIM: To evaluate immunological protection of nitric oxide (NO) in hepatopulmonary syndrome and probable mechanisms of ischemia-reperfusion (IR) injury in rat liver transplantation. METHODS: Sixty-six healthy male Wistar rats were randomly divided into three groups (11 donor/recipient pairs). In group II, organ preservation solution was lactated Ringer's solution with heparin 10, 000/µL at 4 °C. In groups I and III, the preservation solution added, respectively, L-arginine or N(G)-L-arginine methyl ester (L-NAME) (1 mmol/L) based on group II, and recipients were injected with L-arginine or L-NAME (50 mg/kg) in the anhepatic phase. Grafted livers in each group were stored for 6 h and implanted into recipients. Five rats were used for observation of postoperative survival in each group. The other six rats in each group were used to obtain tissue samples, and executed at 3 h and 24 h after transplantation. The levels of alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α and NO metabolites (NOx) were detected, and expression of NO synthase, TNF-α and intercellular adhesion molecule 1 (ICAM-1) was examined by triphosphopyridine nucleotide diaphorase histochemical and immunohistochemical staining. RESULTS: By supplementing L-arginine to strengthen the NO pathway, a high survival rate was achieved and hepatic function was improved. One-week survival rate of grafted liver recipients in group I was significantly increased (28.8 ± 36.6 d vs 4 ± 1.7 d, P < 0.01) as compared with groups II and III. Serum levels of ALT in group I were 2-7 times less than those in groups II and III (P < 0.01). The cyclic guanosine monophosphate (cGMP) levels in liver tissue and NOx in group I were 3-4 times higher than those of group II after 3 h and 24 h reperfusion, while in group III, they were significantly reduced as compared with those in group II (P < 0.01). The levels of TNF-α in group I were significantly lower than in group II after 3 h and 24 h reperfusion (P < 0.01), while being significantly higher in group III than group II (P < 0.01). Histopathology revealed more severe tissue damage in graft liver and lung tissues, and a more severe inflammatory response of the recipient after using NO synthase inhibitor, while the pathological damage to grafted liver and the recipient's lung tissues was significantly reduced in group I after 3 h and 24 h reperfusion. A small amount of constitutive NO synthase (cNOS) was expressed in liver endothelial cells after 6 h cold storage, but there was no expression of inducible NO synthase (iNOS). Expression of cNOS was particularly significant in vascular endothelial cells and liver cells at 3 h and 24 h after reperfusion in group II, but expression of iNOS and ICAM-1 was low in group I. There was diffuse strong expression of ICAM-1 and TNF-α in group III at 3 h after reperfusion. CONCLUSION: The NO/cGMP pathway may be critical in successful organ transplantation, especially in treating hepatopulmonary syndrome during cold IR injury in rat orthotopic liver transplantation.

Treatment of the hepatorenal syndrome and hyponatremia in cirrhosis - part II.

National guidelines for treatment of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hyponatremia have been approved by the Danish Society of Gastroenterology and Hepatology. Ascites develops in approximately 60% of patients with cirrhosis during a 10 year period and is frequently associated with complications that determine the course of the disease and the prognosis. These evidence-based guidelines are divided in two parts and consider definitions, pathophysiology, diagnostic aspects, treatment, and prophylaxis.

Hepatorenal syndrome: are we missing some prognostic factors?

BACKGROUND: Hepatorenal syndrome (HRS) is the functional renal failure associated with advanced cirrhosis and has also been described in fulminant hepatic failure. Without liver transplantation its prognosis is dismal. Our study included patients with type 1 HRS associated with cirrhosis, who were not liver transplant candidates. AIM: To identify variables associated with improved survival. METHODS: Sixty-eight patients fulfilled the revised Ascites Club Criteria for type 1 HRS. None of them was suitable for liver transplantation. All the patients were treated with combinations of: albumin, midodrine and octreotide, pressors, and hemodialysis. RESULTS: Median survival was 13 days for the whole group. Survival varied with the end-stage liver disease (ESLD) etiology: autoimmune, 49 days, cardiac cirrhosis, 22 days, idiopathic, 15.5 days, viral, 15 days, hepatitis C and alcohol, 14.5 days, alcohol 8 days, and neoplasia 4 days (p = 0.048). Survival of HRS associated with alcoholic liver disease versus other etiologies was not statistically significant (p = 0.1). Increased serum creatinine (p = 0.02) and urinary sodium 6-10 mEq/l (p = 0.027) at the initiation of therapy were prognostic factors for mortality. HRS treatment modalities (p = 0.73), use of dialysis (p = 0.56), dialysis modality (p = 0.35), use of vasopressors (p = 0.26), pre-existing renal disease (p = 0.49), gender (p = 0.90), and age (p = 0.57) were not associated with survival. CONCLUSIONS: We report for the first time ESLD etiology as a prognostic factor for survival. The renal function (expressed as serum creatinine) and urinary Na (<5 mEq/l) at the time of diagnosis were found to be associated with survival, suggesting that early treatment might increase survival.