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Pere Ginès

Publications and source records attributed to Pere Ginès.

At least 19 recordsLinked to original sources
PubMed2006

Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells.

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through alpha1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-alpha1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-kappaB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed alpha(1A)-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed alpha(1A)-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (alpha1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific beta-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-alpha1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-kappaB activation. BAY 11-7082, a specific NF-kappaB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-kappaB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

Adenoviridae↗
PubMed2006

Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival.

Relative adrenal insufficiency is frequent in patients with severe sepsis and is associated with hemodynamic instability, renal failure, and increased mortality. This study prospectively evaluated the effects of steroids on shock resolution and hospital survival in a series of 25 consecutive patients with cirrhosis and septic shock (group 1). Adrenal function was evaluated by the short corticotropin test within the first 24 hours of admission. Patients with adrenal insufficiency were treated with stress doses of intravenous hydrocortisone (50 mg/6 h). Data were compared to those obtained from the last 50 consecutive patients with cirrhosis and septic shock admitted to the same intensive care unit in whom adrenal function was not investigated and who did not receive treatment with steroids (group 2). Incidence of adrenal insufficiency in group 1 was 68% (17 patients). Adrenal dysfunction was frequent in patients with advanced cirrhosis (Child C: 76% vs. Child B: 25%, P = .08). Resolution of septic shock (96% vs. 58%, P = .001), survival in the intensive care unit (68% vs. 38%, P = .03), and hospital survival (64% vs. 32%, P = .003) were significantly higher in group 1. The main causes of death in group 1 were hepatorenal syndrome or liver failure (7 of 9 patients). In contrast, refractory shock caused most of the deaths in group 2 (20 of 34 patients). In conclusion, relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock. Hydrocortisone administration in these patients is associated with a high frequency of shock resolution and high survival rate.

Adrenal Insufficiency↗
PubMed2006

Hyponatremia in cirrhosis: Results of a patient population survey.

Low serum sodium concentration is an independent predictor of mortality in patients with cirrhosis, but its prevalence and clinical significance is unclear. To evaluate prospectively the prevalence of low serum sodium concentration and the association between serum sodium levels and severity of ascites and complications of cirrhosis, prospective data were collected on 997 consecutive patients from 28 centers in Europe, North and South America, and Asia for a period of 28 days. The prevalence of low serum sodium concentration as defined by a serum sodium concentration < or =135 mmol/L, < or =130 mmol/L, < or =125 mmol/L, and < or =120 mmol/L was 49.4%, 21.6%, 5.7%, and 1.2%, respectively. The prevalence of low serum sodium levels (<135 mmol/L) was high in both inpatients and outpatients (57% and 40%, respectively). The existence of serum sodium <135 mmol/L was associated with severe ascites, as indicated by high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large-volume paracentesis, and impaired renal function, compared with normal serum sodium levels. Moreover, low serum sodium levels were also associated with greater frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome, but not gastrointestinal bleeding. Patients with serum sodium <130 mmol/L had the greatest frequency of these complications, but the frequency was also increased in patients with mild reduction in serum sodium levels (131-135 mmol/L). In conclusion, low serum sodium levels in cirrhosis are associated with severe ascites and high frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome.

Adolescent↗
PubMed2006

Aquaporin-1 and aquaporin-2 urinary excretion in cirrhosis: Relationship with ascites and hepatorenal syndrome.

Several experimental models of cirrhosis have shown dysregulation of renal aquaporins in different phases of liver disease. We investigated the urinary excretion of both aquaporin-1 and aquaporin-2 in patients with cirrhosis at different stages of the disease. Twenty-four-hour urine was collected from 11 healthy volunteers, 13 patients with compensated cirrhosis (without ascites), and 20 patients with decompensated cirrhosis (11 with ascites without renal failure and 9 with hepatorenal syndrome). Aquaporin-1 and aquaporin-2 excretion was analyzed by immunoblotting. Urinary aquaporin-2 excretion was reduced in patients with cirrhosis compared to healthy subjects. A progressive decrease in urinary aquaporin-2 excretion was observed as the severity of cirrhosis increased, from compensated cirrhosis to cirrhosis with ascites and hepatorenal syndrome. Patients with hyponatremia had lower urinary aquaporin-2 excretion than patients without hyponatremia. Vasopressin plasma level did not correlate with aquaporin-2 excretion. There were no differences between healthy subjects and patients with cirrhosis with or without ascites in urinary excretion of aquaporin-1, but urinary aquaporin-1 excretion of those with hepatorenal syndrome was extremely low. In conclusion, patients with cirrhosis appear to exhibit a decreased abundance of renal aquaporin-2 and therefore lower water permeability in the collecting tubules. This may represent an adaptive renal response to sodium retention, with expansion of extracellular fluid volume and dilutional hyponatremia observed in those who have cirrhosis with ascites. Finally, aquaporin-1 does not appear to play a role in the progressive dysregulation of extracellular fluid volume in cirrhosis.

Aquaporin 1↗
PubMed2006

Hyponatremia in cirrhosis: clinical features and management.

The presence of dilutional hyponatremia has a poor prognosis for survival in patients with cirrhosis and ascites. Effective and safe treatments are needed to improve prognosis in patients with cirrhosis and dilutional hyponatremia. The initial approach to management includes fluid restriction, low sodium diet, and minimizing the use of diuretics. In addition, the use of hypertonic saline should be avoided in patients with cirrhosis and dilutional hyponatremia. Furthermore, patients should be placed on the top of the list for liver transplantation if they are appropriate candidates. Although V2 arginine vasopressin receptor antagonists that selectively enhance solute-free water excretion in patients with cirrhosis seem very promising, two points must be considered in relation to the available data. First, although the results of phase-2 studies are encouraging, the efficacy and safety of these compounds should be further evaluated. Second, the clinical utility of these agents in cirrhosis has only been assessed in short-term studies. The long-term effects of these drugs remain unknown. Future research with these compounds should not only focus on the effects on serum sodium, but also on treatment and prevention of recurrence of ascites. In addition, the possible beneficial effects of these drugs in the prevention of hepatic encephalopathy would be worth studying.

Antidiuretic Hormone Receptor Antagonists↗
PubMed2006

Therapy insight: Management of hepatorenal syndrome.

Hepatorenal syndrome (HRS), a feared complication of advanced cirrhosis, is characterized by functional renal failure, secondary to renal vasoconstriction in the absence of underlying kidney pathology. Extreme underfilling of the arterial circulation, caused by arterial vasodilation of the splanchnic circulation, activates vasoconstrictor systems, which lead to intense renal vasoconstriction and HRS. Factors predictive for the development of HRS include intense urinary sodium retention, dilutional hyponatremia, low blood pressure, decreased cardiac output, and increased activity of systemic vasoconstrictors. The prognosis for patients with HRS is extremely poor, especially for those with the acute, progressive (type 1) form. Liver transplantation is the best treatment for suitable candidates and should always be the management option considered first. Pharmacologic therapies are aimed at improving renal function to enable patients to survive until transplantation is possible. These therapies are based on plasma expansion with albumin, combined with the use of either vasopressin analogs or alpha-adrenergic agonists. Other nonpharmacologic therapies, such as transjugular intrahepatic portosystemic shunts and albumin dialysis show promise, but experience with these treatments is limited. For prevention of HRS, albumin infusion is recommended in patients with spontaneous bacterial peritonitis, and pentoxifylline treatment is recommended in patients with acute alcoholic hepatitis.

Adrenergic alpha-Agonists↗
PubMed2006

Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation.

BACKGROUND & AIMS: Hyponatremia is associated with reduced survival in patients with cirrhosis awaiting liver transplantation. However, it is not known whether hyponatremia also represents a risk factor of poor outcome after transplantation. We aimed to assess the effects of hyponatremia at the time of transplantation on posttransplantation outcome in patients with cirrhosis. METHODS: Two-hundred forty-one consecutive patients with cirrhosis submitted to liver transplantation during a 4-year period (January 2000-December 2003) were included in the study. The main end point was survival at 3 months after transplantation. Secondary end points were complications within the first month after transplantation. RESULTS: Patients with hyponatremia (serum sodium lower than 130 mEq/L) had a greater incidence of neurologic disorders, renal failure, and infectious complications than patients without hyponatremia (odds ratio; 4.6, 3.4 and 2.7, respectively) within the first month after transplantation. By contrast, hyponatremia was not associated with an increased incidence of severe intra-abdominal bleeding, acute rejection, or vascular and biliary complications. Hyponatremia was an independent predictive factor of early posttransplantation survival. Three-month survival of patients with hyponatremia was 84% compared with 95% of patients without hyponatremia (P < .05). Survival was similar after 3 months. CONCLUSIONS: In patients with cirrhosis, the presence of hyponatremia is associated with a high rate of neurologic disorders, infectious complications, and renal failure during the first month after transplantation and reduced 3-month survival. In cirrhosis, hyponatremia should be considered not only a risk factor of death before transplantation but also a risk factor of impaired early posttransplantation outcome.

Adult↗
PubMed2006

New treatments of hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis, characterized by renal failure and major abnormalities in the systemic circulatory function. Renal failure is caused by intense vasoconstriction of the renal circulation. The syndrome is probably the final consequence of an extreme underfilling of the arterial circulation, secondary to vasodilatation in the splanchninc vascular bed and a decrease in cardiac output due to central hypovolemia. The diagnosis of HRS is based on the exclusion of other causes of renal failure. The survival of patients with HRS is very short, particularly when there is rapidly progressive renal failure (type-1 HRS). Liver transplantation is the best therapeutic option but its applicability is low. During the past few years effective treatment for HRS, such as vasoconstrictor drugs (vasopressin analogues, proportional variant-adrenergic agonists) associated with intravenous albumin infusion and transjugular intrahepatic portosystemic shunts (TIPS), have been introduced. They improve circulatory function, normalize serum creatinine, and may improve survival. Sequential treatment with vasoconstrictors plus albumin and TIPS is an attractive therapeutic possibility. Plasma volume expansion with albumin at infection diagnosis in patients with spontaneous bacterial peritonitis and the administration of pentoxiphilline in patients with severe alcoholic hepatitis significantly reduce the development of type-1 HRS.

Albumins↗
PubMed2005

Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites.

Nonselective inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs frequently induces renal failure in decompensated cirrhosis. Studies in experimental cirrhosis suggest that selective inhibitors of the inducible isoform COX-2 do not adversely affect renal function. However, very limited information is available on the effects of these compounds on renal function in human cirrhosis. This investigation consists of a double-blind, randomized, placebo-controlled trial aimed at comparing the effects of the selective COX-2 inhibitor celecoxib (200 mg every 12 hours for a total of 5 doses) on platelet and renal function and the renal response to furosemide (40 mg intravenously) with those of naproxen (500 mg every 12 hours for a total of 5 doses) and placebo in 28 patients with cirrhosis and ascites. A significant reduction (P < .05) in glomerular filtration rate (113 +/- 27 to 84 +/- 22 mL/min), renal plasma flow (592 +/- 158 to 429 +/- 106 mL/min) and urinary prostaglandin E(2) excretion (3430 +/- 430 to 2068 +/- 549 pg/min) and suppression of the diuretic (urine volume: 561 +/- 128 to 414 +/- 107 mL/h) and natriuretic (urine sodium: 53 +/- 13 to 34 +/- 10 mEq/h) responses to furosemide were observed in the group of patients treated with naproxen but not in the other two groups. Naproxen, but not celecoxib or placebo, significantly inhibited platelet aggregation (72% +/- 8% to 47% +/- 8%, P < .05) and thromboxane B(2) production (41 +/- 12 to 14 +/- 5 pg/mL, P < .05). In conclusion, our results indicate that short-term administration of celecoxib does not impair platelet and renal function and the response to diuretics in decompensated cirrhosis. Further studies are needed to evaluate the long-term safety of this drug in cirrhosis.

Ascites↗
PubMed2005

MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation.

Important progress has been made recently regarding the pathogenesis and treatment of hepatorenal syndrome (HRS). However, scant information exists about factors predicting outcome in patients with cirrhosis and HRS. Moreover, the prognostic value of the model of end-stage liver disease (MELD) score has not been validated in the setting of HRS. The current study was designed to assess the prognostic factors and outcome of patients with cirrhosis and HRS. The study included 105 consecutive patients with HRS. Forty-one patients had type 1 HRS, while 64 patients had type 2 HRS. Patients with type 1 HRS not only had more severe liver and renal failure than type 2 patients, they also had greater impairment of circulatory function, as indicated by lower arterial pressure and higher activation of vasoconstrictor factors. In the whole series, the median survival was 3.3 months. In a multivariate analysis of survival, only HRS type and MELD score were associated with an independent prognostic value. All patients with type 1 HRS had a high MELD score (> or =20) and showed an extremely poor outcome (median survival: 1 mo). By contrast, the survival of patients with type 2 HRS was longer and dependent on MELD score (> or =20, median survival 3 mo; <20, median survival 11 mo; P < .002). In conclusion, the outcome of patients with cirrhosis and HRS can be estimated by using two easily available variables, HRS type and MELD score. These data can be useful in the management of patients with HRS, particularly for patients who are candidates for liver transplantation.

Decision Support Techniques↗
PubMed2005

Circulatory function and hepatorenal syndrome in cirrhosis.

The pathogenic mechanism of hepatorenal syndrome is not well established. We investigated the circulatory function in cirrhosis before and after the development of hepatorenal syndrome. Systemic and hepatic hemodynamics and the activity of endogenous vasoactive systems were measured in 66 patients who had cirrhosis with tense ascites and normal serum creatinine levels; measurements were repeated at follow-up in 27 cases in whom hepatorenal syndrome had developed. At baseline, mean arterial pressure and cardiac output were significantly higher, and hepatic venous pressure gradient, plasma renin activity, and norepinephrine concentration were significantly lower in patients who did not develop hepatorenal syndrome compared with those presenting with this complication. Peripheral vascular resistance was decreased to the same extent in the two groups. Plasma renin activity and cardiac output were the only independent predictors of hepatorenal syndrome. Hepatorenal syndrome occurred in the setting of a significant reduction in mean arterial pressure (83 +/- 9 to 75 +/- 7 mmHg; P < .001), cardiac output (6.0 +/- 1.2 to 5.4 +/- 1.5 L/min; P < .01), and wedged pulmonary pressure (9.2 +/- 2.6 to 7.5 +/- 2.6 mmHg; P < .001) and an increase in plasma renin activity (9.9 +/- 5.2 to 17.5 +/- 11.4 ng/mL . hr; P < .001), norepinephrine concentration (571 +/- 241 to 965 +/- 502 pg/mL; P < .001), and hepatic venous pressure gradient. No changes were observed in peripheral vascular resistance. In conclusion, these data indicate that hepatorenal syndrome is the result of a decrease in cardiac output in the setting of a severe arterial vasodilation.

Aged↗
PubMed2005

Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice.

BACKGROUND/AIMS: Pharmacological blockade of the renin-angiotensin system (RAS) attenuates liver fibrogenesis in rats. Here, we provide genetic evidence implicating angiotensin type 1 (AT1) receptors in liver fibrogenesis. METHODS: Wild type (WT) and AT1a knockout [AT1a (-/-)] mice were subjected to either sham operation or bile-duct ligation. Fibrosis was assessed by Sirius Red staining and hydroxyproline hepatic content. Fibrogenic and inflammatory cytokines were measured by ELISA. RESULTS: Bile duct ligation-induced elevation of serum liver enzymes was similar in WT and AT1a (-/-) mice. Bile duct ligated WT mice showed inflammatory changes and severe septal fibrosis. In contrast, AT1a (-/-) mice showed minor fibrotic lesions. Collagen accumulation was lower in AT1a (-/-) mice compared to WT mice. The increase in hepatic concentration of TGFbeta1 and pro-inflammatory cytokines was attenuated in AT1a (-/-) mice compared to WT mice. Immunohistochemistry analysis revealed decreased infiltration by inflammatory cells, lipid peroxidation products as well as decreased phosphorylation of c-Jun and p42/44 MAPK in AT1a (-/-) mice compared to AT1 (+/+) mice. CONCLUSIONS: AT1 receptors play an important role in the development of fibrosis. Pharmacological blockade of AT1 receptors appears to be a promising approach to treat liver fibrosis.

Animals↗
PubMed2005

Genomic and functional characterization of stellate cells isolated from human cirrhotic livers.

BACKGROUND/AIMS: Hepatic stellate cells (HSCs) are believed to participate in liver fibrogenesis and portal hypertension. Knowledge on human HSCs is based on studies using HSCs isolated from normal livers. We investigated the phenotypic, genomic and functional characteristics of HSCs from human cirrhotic livers. METHODS: HSC were obtained from normal and cirrhotic human livers. Cells were characterized by immunocytochemistry and gene microarray analysis. Cell proliferation, Ca(2+) changes and cell contraction were assessed by 3H-thymidine incorporation and by using an epifluorescence microscope. RESULTS: HSCs freshly isolated from human cirrhotic livers showed phenotypical features of myofibroblasts. These features were absent in HSCs freshly isolated from normal human livers and become prominent after prolonged culture. HSCs from cirrhotic human livers markedly express genes involved in fibrogensis, inflammation and apoptosis. HSCs from normal livers after prolonged culture preferntially expressed genes related to fibrogenesis and contractility. Agonists induced proliferation, Ca(2+) increase and cell contraction in HSCs isolated from human cirrhotic livers. Response to agonists was more marked in culture-activated HSCs and was not observed in HSCs freshly isolated from normal livers. CONCLUSIONS: HSCs from human cirrhotic livers show fibrogenic and contractile features. However, the current model of HSCs activated in culture does not exactly reproduce the activated phenotype found in cirrhotic human livers.

Calcium↗
PubMed2005

Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.

BACKGROUND & AIMS: Although renal failure is a common complication of sepsis and patients with cirrhosis frequently develop sepsis, there have been no studies specifically assessing renal function in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. The aim of this study was to investigate prospectively the frequency, characteristics, and outcome of renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. METHODS: One hundred six consecutive patients with cirrhosis and sepsis were studied prospectively. Patients with spontaneous bacterial peritonitis were excluded. RESULTS: Twenty-nine out of 106 patients (27%) with cirrhosis and sepsis developed acute renal failure as compared with only 8 of 100 patients (8%) from a control group of cirrhotic patients without infection (P < .0001). Renal failure in the sepsis group was reversible in 22 (76%; 21% of all patients) patients and nonreversible in 7 (24%; 6% of all patients) patients. Renal failure was associated with impairment of effective arterial blood volume, without evidence of tubular damage. The occurrence and type of renal failure correlated strongly with mortality (mortality at 3 months: nonreversible renal failure, 100%; reversible renal failure, 55%; no renal failure, 13%). Among variables obtained at diagnosis of sepsis, the Model for End-Stage Liver Disease (MELD) score was the only independent predictive factor of mortality. CONCLUSIONS: Renal failure is common in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis and is associated with arterial underfilling and renal vasoconstriction. Outcome is poor, even in the setting of reversible renal failure. The MELD score is the best prognostic marker of patients with cirrhosis and sepsis.

Adult↗
PubMed2005

Hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a serious event during the course of decompensated cirrhosis. Although the most characteristic feature of the syndrome is a functional renal failure due to intense renal vasoconstriction, it is a more generalized process affecting the heart, brain and splanchnic organs. There are two types of HRS. Type 1 HRS is characterized by a rapidly progressive impairment of the circulatory and renal functions associated with a very poor prognosis (median survival rate lower than 2 weeks). Type 2 HRS is characterized by a steady impairment of the circulatory and renal functions with a median survival of 6 months. The pathogenesis of HRS is a deterioration of the effective arterial blood volume due to splanchnic arterial vasodilation and a reduction in venous return and cardiac output. It is therefore not surprising that the syndrome can be reversed by the simultaneous administration of intravenous albumin and arterial vasoconstrictors. Intrarenal mechanisms are important as well and require prolonged improvement of the circulatory function to be deactivated. Long-term administration of intravenous albumin and vasoconstrictors or correction of portal hypertension with a transjugular intrahepatic portacaval shunt are effective treatments of HRS, and many serve as a bridge to liver transplantation, the treatment of choice in these patients.

Albumins↗