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Renal and circulatory dysfunction in cirrhosis: Current management and future perspectives

Open AccessPublished:August 20, 2010DOI:https://doi.org/10.1016/j.jhep.2010.08.001
      Chronic liver diseases are amongst the top leading causes of death in Europe as well as in other areas of the world [
      • Dalmau-Bueno A.
      • Garcia-Altes A.
      • Marí-Dell’olmo M.
      • Pérez K.
      • Espelt A.
      • Kunst A.E.
      • et al.
      Trends in socio-economic inequalities in cirrhosis mortality in an urban area of Southern Europe: a multilevel approach.
      ,
      • Heron M.
      • Hoyert D.L.
      • Murphy S.L.
      • Xu J.
      • Kochanek K.D.
      • Tejada-Vera B.
      Deaths: final data for 2006.
      ,
      • Everhart J.E.
      • Ruhl C.E.
      Burden of digestive diseases in the United States. Part III: Liver, biliary tract, and pancreas.
      ]. Chronic liver diseases are characterized by unrelenting progression of liver inflammation and fibrosis over a prolonged period of time, usually more than 20 years, which may eventually lead to cirrhosis [
      • Schuppan D.
      • Afdhal N.H.
      Liver cirrhosis.
      ]. Advanced cirrhosis leads to a complex syndrome of chronic liver failure which involves many different organs besides the liver, including the brain, heart and systemic circulation, adrenal glands, lungs, and kidneys [
      • Sen S.
      • Williams R.
      • Jalan R.
      The pathophysiological basis of acute-on-chronic liver failure.
      ]. The high morbidity and mortality secondary to chronic liver failure is due to complications related to the dysfunction of these organs, either alone or, more frequently, in combination. Understanding the mechanisms leading to organ dysfunction is crucial to the development of strategies for treatment and prevention of complications of cirrhosis. This article reviews our current knowledge, as well as future perspectives, on the management of circulatory and renal dysfunction in chronic liver failure.

      A brief review of the current understanding of renal and circulatory dysfunction in cirrhosis

      A wealth of evidence indicates that impairment in circulatory function is the main cause of renal dysfunction in cirrhosis. The dysfunction in the systemic arterial circulation is largely characterized by a reduction in systemic vascular resistance due to primary arterial vasodilation of the splanchnic circulation triggered by portal hypertension [
      • Ginès P.
      • Cárdenas A.
      • Schrier R.W.
      Liver disease and the kidney.
      ,
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ,
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ,
      • Martin P.Y.
      • Ginès P.
      • Schrier R.W.
      Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis.
      ]. The relationship between liver disease, portal hypertension, and abnormalities in splanchnic circulation is discussed in detail in several recent reviews [
      • Schuppan D.
      • Afdhal N.H.
      Liver cirrhosis.
      ,
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      Portal hypertension and gastrointestinal bleeding.
      ,
      • Iwakiri Y.
      • Groszmann R.J.
      The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
      ]. The vasodilation of the splanchnic arterial circulation is due to an increased production/activity of vasodilator factors, particularly nitric oxide, carbon monoxide, and endogenous cannabinoids [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ,
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ,
      • Martin P.Y.
      • Ginès P.
      • Schrier R.W.
      Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis.
      ,
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      Portal hypertension and gastrointestinal bleeding.
      ,
      • Iwakiri Y.
      • Groszmann R.J.
      The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
      ,
      • Ros J.
      • Clària J.
      • To-Figueras J.
      • et al.
      Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.
      ,
      • MacAllister R.J.
      • Calver A.L.
      • Collier J.
      • Edwards C.M.
      • Herreros B.
      • Nussey S.S.
      • et al.
      Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect?.
      ].
      At the early stages of cirrhosis, when patients are usually asymptomatic and with normal physical status, the increase in hepatic vascular resistance, mainly due to fibrosis, is moderate and therefore the increase in portal pressure is also moderate. In this context, there is a slight reduction in systemic vascular resistance due to moderate splanchnic arterial vasodilation which is compensated by an increase in cardiac output, thus permitting arterial pressure and effective arterial blood volume to remain within normal limits [
      • Ginès P.
      • Cárdenas A.
      • Schrier R.W.
      Liver disease and the kidney.
      ,
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ]. In advanced stages of cirrhosis, when patients are usually symptomatic and have already developed some complications of the disease, the reduction in systemic vascular resistance is marked and cannot be compensated by further increases in cardiac output; therefore, underfilling of the arterial circulation develops, there being a disarrangement between the intravascular blood volume and a very enlarged intravascular arterial circulation [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ]. Moreover, evidence indicates that at this stage of the disease there is a reduction in the cardiac output that contributes to the arterial underfilling [
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Arocena C.
      • et al.
      Circulatory function and hepatorenal syndrome in cirrhosis.
      ]. In this context of marked underfilling of the arterial circulation, arterial pressure must be maintained by the activation of vasoconstrictor systems, including the renin–angiotensin-system, the sympathetic nervous system, and, at late stages, a non-osmotic hypersecretion of arginine vasopressin (the antidiuretic hormone) [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ]. These systems help maintain effective arterial blood volume and arterial pressure but have important effects on kidney function, particularly sodium and solute-free water retention with accumulation of ascites and edema. If the activation of these systems is extreme, renal vasoconstriction leading to markedly reduced glomerular filtration rate may occur, a condition known as hepatorenal syndrome (HRS) [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ,
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ]. Other factors that may contribute to the development of HRS are vasoactive mediators acting on the intrarenal circulation. An increased synthesis of several vasoactive factors in the intrarenal circulation, which may affect renal blood flow or glomerular filtration rate, such as cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1, has been reported, yet the role of these factors in the pathogenesis of HRS remains poorly understood [
      • Ginès P.
      • Cárdenas A.
      • Schrier R.W.
      Liver disease and the kidney.
      ]. Nonetheless, a role for endothelin-1 is unlikely since the administration of the endothelin antagonist tazosentan does not improve renal function in patients with type 2 HRS [
      • Wong F.
      • Moore K.
      • Dingemanse J.
      • Jalan R.
      Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome.
      ]. Recent data indicate that impairment in the cardiac function, likely due to cirrhotic cardiomyopathy, is a risk factor for the development of HRS and likely further contributes to the impairment of the arterial blood volume that is related to splanchnic vasodilation [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ,
      • Moller S.
      • Henriksen J.H.
      Cirrhotic cardiomyopathy.
      ]. A summary of the pathogenesis of ascites and functional renal abnormalities with possible therapeutic interventions are shown in Fig. 1, Fig. 2, Fig. 3.
      Figure thumbnail gr1
      Fig. 1Schematic representation of the proposed pathogenesis of ascites and edema formation in cirrhosis. Established therapies are given on the left side and potential new therapies on the right. TIPS, transjugular intrahepatic portosystemic shunt.
      Figure thumbnail gr2
      Fig. 2Schematic representation of the proposed pathogenesis of hypervolemic hyponatremia in cirrhosis. Established therapies are given on the left side and potential new therapies on the right. ∗Vaptans are approved for the management of hypervolemic hyponatremia in cirrhosis in United States and Japan, but not in Europe.
      Figure thumbnail gr3
      Fig. 3Schematic representation of the proposed pathogenesis of hepatorenal syndrome in cirrhosis. Established therapies are given on the left side and potential new therapies on the right. ∗The use of TIPS, transjugular intrahepatic portosystemic shunt, has been reported in some studies but the information is very limited. ∗∗Vasoconstrictors include vasopressin analogues such as terlipressin and α-adrenergic agonists, such as norepinephrine or midodrine. ∗∗∗Albumin is given in combination with vasoconstrictors. Albumin alone is seldom effective.
      A wealth of evidence indicates that altered splanchnic hemodynamics is related to the development of portal hypertension [
      • Iwakiri Y.
      • Groszmann R.J.
      The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
      ]. On the other hand, studies in both experimental animals and patients with cirrhosis suggest that bacterial translocation, the passage of bacteria from the intestinal lumen to mesenteric lymph nodes, may play an important role in circulatory dysfunction in advanced cirrhosis [
      • Wiest R.
      • Das S.
      • Cadelina G.
      • Garcia-Tsao G.
      • Milstien S.
      • Groszmann R.J.
      Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility.
      ,
      • Wiest R.
      • Garcia-Tsao G.
      Bacterial translocation (BT) in cirrhosis.
      ]. Bacterial translocation may elicit an inflammatory response with increased production of proinflammatory cytokines in the splanchnic area, which may in turn lead to vasodilatation of the splanchnic arterial vessels. Patients with cirrhosis and increased levels of lipopolysaccharide-binding protein or circulating levels of bacterial DNA, which are considered surrogate markers of bacterial translocation, have higher serum levels of cytokines, lower systemic vascular resistance, and higher cardiac output when compared to those who do not [
      • Albillos A.
      • de la Hera A.
      • González M.
      • et al.
      Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.
      ,
      • Francés R.
      • Zapater P.
      • González Navajas J.M.
      • et al.
      Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis.
      ]. The important role of bacterial translocation in circulatory dysfunction is further supported by the observation that the administration of norfloxacin, an antibiotic that causes selective intestinal decontamination, improves circulatory function [
      • Chin-Dusting J.P.
      • Rasaratnam B.
      • Jennings G.L.
      • Dudley F.J.
      Effect of fluoroquinolone on the enhanced nitric oxide-induced peripheral vasodilation seen in cirrhosis.
      ,
      • Rasaratnam B.
      • Kaye D.
      • Jennings G.
      • Dudley F.
      • Chin-Dusting J.
      The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis: a randomized trial.
      ].

      The expanded extracellular fluid volume: ascites and edema

      Sodium is the main determinant of the volume of the extracellular fluid (ECF). In healthy subjects the amount of sodium is maintained constant through a very precise equilibrium between sodium intake and sodium excretion by the kidneys [
      • Schrier R.W.
      Body fluid volume regulation in health and disease: a unifying hypothesis.
      ,
      • Poole B.D.
      • Abraham W.T.
      • Schrier R.W.
      Extracellular fluid volume homeostasis.
      ]. In advanced cirrhosis, this equilibrium is lost because of an increased retention of sodium in the kidneys and positive sodium balance develops leading to expansion of the ECF [
      • Fernandez de la Llama P.
      • Ginès P.
      • Schrier R.W.
      Pathogenesis of sodium retention in cirrhosis: the arterial vasodilation hypothesis of ascites formation.
      ,
      • Kashani A.
      • Landaverde C.
      • Medici V.
      • Rossaro L.
      Fluid retention in cirrhosis: pathophysiology and management.
      ]. The excess of ECF is mainly stored in the peritoneal cavity (because of the high pressure of the splanchnic capillaries due to portal hypertension) and in the interstitial tissue of the legs (because of the high pressure of the capillaries of the lower extremities), causing ascites and edema, respectively. Excessive ECF may also be stored in other locations, such as the pleural space, causing pleural effusion. Ascites and edema are the most frequent complication of patients with advanced chronic liver diseases.

      Current management

      Figure thumbnail fx3
      Table 1Treatment of ascites: current management and potential future options.
      ∗TIPS, transjugular intrahepatic portosystemic shunt.
      The problems with diuretic therapy gave rise to another approach for management of ascites which is large-volume paracentesis (LVP, i.e. removal of large amounts of ascitic fluid) [
      • Ginès P.
      • Arroyo V.
      • Quintero E.
      • Planas R.
      • Bory F.
      • Cabrera J.
      • et al.
      Comparison of paracentesis and diuretics in the management of tense ascites. Results of a randomized, study.
      ]. LVP is very effective and is the treatment of choice for both patients with large ascites and those with recurrent ascites due to lack of response to diuretics (i.e. refractory ascites) [

      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrosis. J Hepatol 2010;53:397–417.

      ,
      • Runyon B.A.
      AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update.
      ,
      • Moore K.P.
      • Aithal G.P.
      Guidelines on the management of ascites in cirrhosis.
      ,
      • Garcia-Tsao G.
      • Lim J.K.
      Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Program and the National Hepatitis C Program.
      ]. LVP requires the associated administration of albumin to prevent an impairment of circulatory function that may occur with the removal of large amounts of ascitic fluid [
      • Ginès P.
      • Titó L.
      • Arroyo V.
      • Planas R.
      • Panés J.
      • Viver J.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      ]. The main disadvantages of LVP are that it is time consuming, involves the administration of albumin, which is not easily available in all settings, and does not prevent the recurrence of ascites because it does not interfere with the main mechanisms of ascites formation. An alternative approach to treatment with LVP and albumin for patients with an unresponsive ascites (refractory ascites) is the use of transjugular intrahepatic portosystemic shunts (TIPS). TIPS consist of an autoexpandable stent inserted through a transjugular approach which causes a remarkable reduction in portal pressure and decreases renal sodium retention. Although effective in the management of ascites, the use of TIPS has significant disadvantages over LVP plus albumin, including its limited applicability (it cannot be used in patients with severe liver failure or recurrent hepatic encephalopathy), high cost, increased risk of hepatic encephalopathy, and need of expertise for its insertion [
      • Ginès P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • Kamath P.S.
      • Del Arbol L.R.
      • et al.
      Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.
      ,
      • Salerno F.
      • Merli M.
      • Riggio O.
      • Cazzaniga M.
      • Valeriano V.
      • Pozzi M.
      • et al.
      Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.
      ,
      • D’Amico G.
      • Luca A.
      • Morabito A.
      • Miraglia R.
      • D’Amico M.
      Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis.
      ,
      • Albillos A.
      • Bañares R.
      • González M.
      • Catalina M.V.
      • Molinero L.M.
      A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites.
      ]. On this basis, TIPS is considered a second-line therapy for refractory ascites in all recent guidelines [

      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrosis. J Hepatol 2010;53:397–417.

      ,
      • Runyon B.A.
      AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update.
      ,
      • Moore K.P.
      • Aithal G.P.
      Guidelines on the management of ascites in cirrhosis.
      ,
      • Garcia-Tsao G.
      • Lim J.K.
      Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Program and the National Hepatitis C Program.
      ].
      Besides their efficacy in preventing variceal bleeding, non-selective ß-blockers could have beneficial effects on the prevention of other complications of cirrhosis by reducing portal pressure, including development of ascites. Patients demonstrating a positive response to ß-blockers, that is characterized by marked reduction in hepatic venous pressure gradient, afterwards show a decreased risk of ascites development during follow-up compared to patients who display no response [
      • Abraldes J.G.
      • Tarantino I.
      • Turnes J.
      • García-Pagán J.C.
      • Rodés J.
      • Bosch J.
      Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis in cirrhosis.
      ,
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • Hernández-Gea V.
      • López-Balaguer J.M.
      • Alvarez-Urturi C.
      • et al.
      Acute hemodynamic response to β-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      ]. In apparent contradiction with these findings, a recent study showed that in patients with refractory ascites, treatment with ß-blockers was an independent risk factor for mortality, suggesting that these drugs may have deleterious effects in patients with advanced cirrhosis [

      Sersté T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010 in press.

      ]. The results of this study indicate that the issue of benefit vs. risk of treatment with ß-blockers in patients with cirrhosis deserves an extensive investigation.

      Future therapeutic options

      The ideal therapeutic approach to management of ascites and edema in cirrhosis would consist of a drug able to reverse the circulatory dysfunction present in cirrhosis (which would suppress the mechanisms responsible for sodium retention) with or without combination with diuretics to enhance the excretion of the sodium retained together with the fluid. Although this ideal drug does not exist at present, several methods to improve the management of ascites have been attempted or are currently under investigation (Table 1).
      Two different approaches have been investigated using drugs that interact with the activity of the sympathetic nervous system. In the first approach, the administration of clonidine, a drug that causes a suppression of the sympathetic nervous outflow from the central nervous system, in patients with cirrhosis and ascites was associated with lower ascites recurrence and reduced need for diuretic administration compared to a control group of patients receiving standard therapy without clonidine [
      • Lenaerts A.
      • Codden T.
      • Meunier J.C.
      • Henry J.P.
      • Ligny G.
      Effects of clonidine on diuretic response in ascitic patients with cirrhosis and activation of sympathetic nervous system.
      ]. The beneficial effects of this approach are probably related to suppression of the afferent sympathetic activity to the renal nerves which has been shown to participate in renal sodium retention [
      • Veelken R.
      • Hilgers K.F.
      • Porst M.
      • Krause H.
      • Hartner A.
      • Schmieder R.E.
      Effects of sympathetic nerves and angiotensin II on renal sodium and water handling in rats with common bile duct ligature.
      ,
      • Esler M.
      • Dudley F.
      • Jennings G.
      • Debinski H.
      • Lambert G.
      • Jones P.
      • et al.
      Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis.
      ]. In a second approach, that appears contradictory with the previous one, the administration of midodrine, an orally active α-adrenergic agonist, in patients with cirrhosis and ascites improved circulatory function, as indicated by an increase in arterial pressure and suppression of the activity of the renin–angiotensin and sympathetic nervous systems [
      • Angeli P.
      • Volpin R.
      • Piovan D.
      • Bortoluzzi A.
      • Craighero R.
      • Bottaro S.
      • et al.
      Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites.
      ,
      • Kalambokis G.
      • Fotopoulos A.
      • Economou M.
      • Pappas K.
      • Tsianos E.V.
      Effects of a 7-day treatment with midodrine in non-azotemic cirrhotic patients with and without ascites.
      ]. This improvement in circulatory function was associated with increases in renal plasma flow, glomerular filtration rate, and urinary sodium excretion. However, in these studies, midodrine was given for a short period of time and its potentially beneficial effects in the management of ascites and edema have not yet been assessed. No significant side effects were reported in these two short-term studies, but the long-term safety is unknown. It would be worthwhile to perform studies in a large series of patients to assess the usefulness of both approaches in the long-term management of ascites.
      The administration of albumin has potentially beneficial effects on circulatory function in patients with cirrhosis [
      • Fernández J.
      • Navasa M.
      • Garcia-Pagan J.C.
      • G-Abraldes J.
      • Jiménez W.
      • Bosch J.
      • et al.
      Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis.
      ]. Moreover, a prospective study in patients with cirrhosis and ascites showed that the long-term administration of albumin increased survival compared to a control group of patients not receiving albumin [
      • Romanelli R.G.
      • La Villa G.
      • Barletta G.
      • Vizzutti F.
      • Lanini F.
      • Arena U.
      • et al.
      Long-term albumin infusion improves survival in patients with cirrhosis and ascites: an unblinded randomized trial.
      ]. Nevertheless, the usefulness of this approach requires validation in other studies before it becomes a standard of treatment for patients with cirrhosis. An interesting approach to improve circulatory and renal function in cirrhosis is to combine the administration of albumin together with clonidine or midodrine. This approach is currently being tested in patients in the waiting list for liver transplantation (www.clinicaltrials.gov).
      In contrast to these approaches that show promising results, there have been a number of other approaches that have failed in recent years. An increased production of the vasodilator factor nitric oxide likely plays a major role in the development and maintenance of splanchnic arterial vasodilation in cirrhosis [
      • Martin P.Y.
      • Ginès P.
      • Schrier R.W.
      Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis.
      ,
      • Sieber C.C.
      • Lopez-Talavera J.C.
      • Groszmann R.J.
      Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats.
      ]. Moreover, in experimental cirrhosis the normalization of the overproduction of nitric oxide is associated with an improvement of renal and circulatory function and reduction/disappearance of ascites [
      • Martin P.Y.
      • Ohara M.
      • Ginès P.
      • Xu D.L.
      • St. John J.
      • Niederberger M.
      • et al.
      Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites.
      ]. Unfortunately, the inhibitors of the nitric oxide system were withdrawn from development because of important side effects in patients with septic shock [
      • López A.
      • Lorente J.A.
      • Steingrub J.
      • Bakker J.
      • McLuckie A.
      • Willatts S.
      • et al.
      Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.
      ].
      In contrast to the splanchnic and systemic circulation in which there is overproduction of nitric oxide, in the intrahepatic circulation the production of nitric oxide is markedly decreased, which may be a factor contributing to an increased intrahepatic vascular resistance and portal hypertension [
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      Portal hypertension and gastrointestinal bleeding.
      ,
      • Wiest R.
      • Groszmann R.J.
      The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.
      ]. Therefore, the hypothesis was raised that increasing NO in the intrahepatic circulation could have beneficial effects in portal pressure. Attempts to decrease portal hypertension by the selective delivery of nitric oxide to the liver were promising in experimental portal hypertension but have so far failed in human cirrhosis [
      • Loureiro-Silva M.R.
      • Cadelina G.W.
      • Iwakiri Y.
      • Groszmann R.J.
      A liver-specific nitric oxide donor improves the intra-hepatic vascular response to both portal blood flow increase and methoxamine in cirrhotic rats.
      ,
      • Berzigotti A.
      • Bellot P.
      • De Gottardi A.
      • Garcia-Pagan J.C.
      • Gagnon C.
      • Spéndard J.
      • et al.
      NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study.
      ].
      Recent studies in experimental animals with cirrhosis suggest that the endocannabinoid system plays a role in the splanchnic vasodilation of cirrhosis and that inhibition of the endocannabinoid system with the use of CB1 endocannabinoid antagonists improves renal function and sodium excretion in experimental cirrhosis [
      • Garcia Jr., N.
      • Járai Z.
      • Mirshahi F.
      • Kunos G.
      • Danyal A.J.
      Systemic and portal hemodynamic effects of anandamide.
      ,
      • Bátkais S.
      • Járai Z.
      • Wagner J.A.
      • Goparaju S.K.
      • Varga K.
      • Liu J.
      • et al.
      Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis.
      ,
      • Domenicali M.
      • Caraceni P.
      • Giannone F.
      • Pertosa A.M.
      • Principe A.
      • Zambruni A.
      • et al.
      Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis.
      ]. Unfortunately, rimonabant, a drug that antagonizes both central and peripheral CB1 receptors, was recently withdrawn from the market in Europe (the drug was not approved in the USA) due to an increased risk of depression in patients treated for obesity. This approach to management of ascites will have to be re-explored if selective antagonists of the peripheral CB1 receptors become available.
      A final approach that has been tested in recent years is whether the combination of diuretics with satavaptan, a drug that selectively antagonizes the renal V2 receptors of vasopressin, the antidiuretic hormone, could improve the management of ascites [
      • Decaux G.
      • Soupart A.
      • Vassart G.
      Non-peptide arginine–vasopressin antagonists: the vaptans.
      ]. In phase 2 studies, the combination of satavaptan with diuretics for a short period of time was associated with a decrease in ascites volume and reduced the need for large-volume paracentesis in patients with difficult-to-treat ascites [
      • Ginès P.
      • Wong F.
      • Watson H.
      • Milutinovic S.
      • del Arbol L.R.
      • Olteanu D.
      • et al.
      Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial.
      ,
      • Ginès P.
      • Wong F.
      • Watson H.
      • Terg R.
      • Bruha R.
      • Zarski J.P.
      • et al.
      Clinical trial: short-term effects of combination of satavaptan, a selective vasopressin V2 receptor antagonist, and diuretics on ascites in patients with cirrhosis without hyponatremia – a randomized, double-blind, placebo-controlled study.
      ,
      • Wong F.
      • Ginès P.
      • Watson H.
      • Horsmans Y.
      • Angeli P.
      • Gow P.
      • et al.
      Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis.
      ]. Nevertheless, phase 3 double-blind studies showed that when this combination was used for prolonged periods of time, the effectiveness in the control of ascites was very limited and treatment was associated with an increased mortality compared to a control group of patients receiving placebo plus standard therapy with diuretics alone [
      • Wong F.
      • Bernardi M.
      • Horsmans Y.
      • Cabrijan Z.
      • Watson H.
      • Ginès P.
      Effects of satavaptan, an oral vasopressin V2 receptor antagonist, on management of ascites and morbidity in liver cirrosis in a long-term, placebo-controlled study.
      ,
      • Wong F.
      • Ginès P.
      • Nevens F.
      • Van Vlierberghe H.
      • Gerbes A.L.
      • Zarski J.P.
      • et al.
      Double-blind, placebo-controlled study of satavaptan in the management of recurrent ascites: the SPARE-1 study.
      ]. The reason for this increased risk of death in patients receiving satavaptan in combination with diuretics for the long-term treatment of ascites is currently unknown.

      The disturbed renal water homeostasis: hypervolemic hyponatremia

      Hypervolemic hyponatremia is a frequent complication of patients with advanced cirrhosis that consists of a decreased serum sodium concentration in the setting of an expanded extracellular fluid volume with ascites and edema [
      • Ginès P.
      • Guevara M.
      Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management.
      ]. It is generally accepted that the main pathogenic factor of hypervolemic hyponatremia is an impairment of renal solute-free water excretion secondary to an excessive production of vasopressin stimulated by circulatory dysfunction, yet other factors may also participate [
      • Ginès P.
      • Guevara M.
      Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management.
      ]. Some patients develop hypervolemic hyponatremia in the setting of a preserved renal capacity to eliminate solute-free water [
      • Arroyo V.
      • Rodés J.
      • Gutiérrez-Lizárraga M.A.
      • Revert L.
      Prognostic value of spontaneous hyponatremia in cirrhosis with ascites.
      ]. The pathogenesis of this latter disorder is unknown and deserves investigation. The interest in hypervolemic hyponatremia has been fostered by the observation that hyponatremia is a risk factor of hepatic encephalopathy and death [
      • Guevara M.
      • Baccaro M.E.
      • Torre A.
      • Gómez-Ansón B.
      • Ríos J.
      • Torres F.
      • et al.
      Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis.
      ,
      • Häussinger D.
      • Schliess F.
      Pathogenetic mechanisms of hepatic encephalopathy.
      ,
      • Dawwas M.F.
      • Lewsey J.D.
      • Neuberger J.M.
      • Gimson A.E.
      The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study.
      ,
      • Heuman D.M.
      • Abou_Assi S.G.
      • Habib A.
      • Williams L.M.
      • Stravitz R.T.
      • Sanyal A.J.
      • et al.
      Persistent ascites and low serum sodium identify patients at high risk for early death.
      ,
      • Biggins S.W.
      • Rodriguez H.J.
      • Bacchetti P.
      • Bass N.M.
      • Roberts J.P.
      • Terrault N.A.
      Serum sodium predicts mortality in patients listed for liver transplantation.
      ,
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.W.K.
      • Wiesner R.H.
      • Kamath P.S.
      • Benson J.T.
      Hyponatremia and mortality among patients on the liver transplantation waiting list.
      ].
      Hypervolemic hyponatremia should be differentiated from hypovolemic hyponatremia, a less common condition characterized by low sodium levels in the setting of contraction of the extracellular fluid volume and plasma volume due to marked and prolonged loss of sodium. This condition is managed by withdrawing the cause of sodium loss (usually diuretics) and administration of saline solutions and will not be discussed further in this review.

      Current management

      For many years there has been no effective pharmacological therapy for the management of hypervolemic hyponatremia. Several drugs, including demeclocycline and κ-opioid agonists, were found to increase serum sodium concentration in pilot studies, but were abandoned due to side effects [
      • Pérez-Ayuso R.M.
      • Arroyo V.
      • Camps J.
      • Jiménez W.
      • Rodamilans M.
      • Rimola A.
      • et al.
      Effect of demeclocycline on renal function and urinary prostaglandin E2 and kallikrein in hyponatremic cirrhotics.
      ,
      • Gadano A.
      • Moreau R.
      • Pessione F.
      • Trombino C.
      • Giuily N.
      • Sinnassamy P.
      • et al.
      Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis.
      ]. Because of the absence of effective drugs, treatment has relied on fluid restriction (to approximately 1 L/day) with the aim of causing a negative fluid balance. However, since urine volume is low in these patients, a negative fluid balance is infrequently achieved. This is the reason why fluid restriction is seldom effective in increasing serum sodium concentration in these patients. Hypertonic saline has been used but it is usually not effective and markedly increases ascites and edema due to the intense sodium retention present in these patients. Therefore, its use is not currently recommended [

      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrosis. J Hepatol 2010;53:397–417.

      ].
      In recent years, a new generation of drugs, known as vaptans, which selectively antagonize the vasopressin V2 receptors present in the renal tubules, has come into play [
      • Decaux G.
      • Soupart A.
      • Vassart G.
      Non-peptide arginine–vasopressin antagonists: the vaptans.
      ]. Some of these drugs are currently licensed for hyponatremia associated with high vasopressin levels. In the US, conivaptan (a dual V1/V2 antagonist) was approved few years ago for short-term (5 days) intravenous use. More recently, tolvaptan (a selective oral V2 antagonist) was approved by the FDA for severe hyponatremia (<125 mmol/L) associated with cirrhosis, cardiac failure, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In Europe, conivaptan is not available and tolvaptan is approved only for SIADH. There is very little information on conivaptan use in patients with cirrhosis [
      • O’Leary J.G.
      • Davis G.L.
      Conivaptan increases serum sodium in hyponatremic patients with end-stage liver disease.
      ]. In randomized studies, the administration of tolvaptan to patients with cirrhosis and hypervolemic hyponatremia induced a marked increase in urine volume and solute-free water excretion and a significant increase (normalization in some patients) in serum sodium levels [
      • Schrier R.W.
      • Gross P.
      • Gheorghiade M.
      • Berl T.
      • Verbalis J.G.
      • Czerwiec F.S.
      • et al.
      Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
      ,
      • Cardenas A.
      • Ginès P.
      • Marotta P.
      • Czerwiec F.S.
      • Ouyang J.
      • Sexton A.
      • et al.
      The effects of a vasopressin V2 receptor antagonist in the management of patients with cirrhosis and hyponatremia. Safety and efficacy of oral tolvaptan in the SALT trials.
      ]. Reversal of hyponatremia was associated with an improvement of the mental component of a quality of life score, suggesting a beneficial effect of the enhanced serum sodium levels on cerebral function. No adverse effects were noticed in these studies, except for thirst and a remarkable increase in urine volume in some patients. Unfortunately, however, the duration of tolvaptan therapy in these studies was of only one month. The Clinical Practice Guidelines of the European Association for the Study of the Liver (EASL) recommend tolvaptan for short-term management of patients with severe hypervolemic hyponatremia (<125 mmol/L) [

      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrosis. J Hepatol 2010;53:397–417.

      ]. Treatment should be initiated in the hospital at low doses (15 mg/day) with frequent monitoring of serum sodium to avoid a rapid increase in serum sodium concentration (<8–10 mmol/day) and the dose increased stepwise until a normalization of serum sodium levels has been achieved. Neither fluid restriction nor hypertonic saline should be used concomitantly with tolvaptan to avoid a too rapid increase in serum sodium concentration. Treatment may be particularly useful in patients with hyponatremia who have to undergo surgery, particularly liver transplantation, to reduce the increased risk of complications after transplantation in patients with hyponatremia [
      • Londoño M.C.
      • Guevara M.
      • Rimola A.
      • Navasa M.
      • Taurà P.
      • Mas A.
      • et al.
      Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation.
      ]. It is likely that the improvement/normalization of serum sodium concentration may reduce the risk of severe neurological complications in these patients, particularly central pontine myelinolysis. Nonetheless, more information is needed on the use of vaptans in the management of hypervolemic hyponatremia in cirrhosis, particularly with respect to its long-term safety. This is important because, as mentioned before, the development of one of these drugs, satavaptan, was stopped because of the finding of increased frequency of complications and reduced survival compared to placebo in a phase 3 study assessing the efficacy of this drug in the management of ascites in patients with cirrhosis [
      • Wong F.
      • Ginès P.
      • Nevens F.
      • Van Vlierberghe H.
      • Gerbes A.L.
      • Zarski J.P.
      • et al.
      Double-blind, placebo-controlled study of satavaptan in the management of recurrent ascites: the SPARE-1 study.
      ].

      Future therapeutic options

      The future of management of hypervolemic hyponatremia in cirrhosis is likely linked to the use of vaptans. However, there are several aspects of the use of vaptans that are worth of comment. First, the cautious use of vaptans cannot be overemphasized. Treatment should be started in the hospital and patients monitored closely during the treatment, and serum sodium levels measured at regular intervals, particularly at the beginning of the treatment, when the dose is increased or whenever there is a change in the clinical status of patients. Second, there is increasing evidence that patients with hyponatremia represent a heterogeneous population; therefore, it is of major importance to understand which patients are to benefit from treatment with vaptans. Finally, there is a need for data on long-term safety and efficacy of treatment with vaptans in patients with cirrhosis and hypervolemic hyponatremia. Another approach, besides vaptans, that would be of interest for the future, is the administration of albumin since some studies have shown that repeated albumin administration improves serum sodium concentration in patients with cirrhosis and severe hyponatremia [
      • McCormick P.A.
      • Mistry P.
      • Kaye G.
      • Burroughs A.K.
      • McIntyre N.
      Intravenous albumin infusion is an effective therapy for hyponatremia in cirrhotic patients with ascites.
      ,
      • Jalan R.
      • Mookerjee R.
      • Cheshire L.
      • Williams R.
      • Davies N.
      Albumin infusion for severe hyponatremia in patients with refractory ascites: a randomized clinical trial.
      ].

      The fascinating concept of functional renal vasoconstriction: hepatorenal syndrome

      Hepatorenal syndrome (HRS) is a unique form of renal failure that develops in patients with cirrhosis, in the absence of significant histological abnormalities in the kidneys [
      • Ginès P.
      • Guevara M.
      • Arroyo V.
      • Rodés J.
      Hepatorenal syndrome.
      ]. Until recent years, the only therapeutic method capable of reversing HRS was liver transplantation. Currently, reversal of HRS is achieved with treatment with vasoconstrictor drugs associated with albumin [
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ,
      • Gluud L.L.
      • Christensen K.
      • Christensen E.
      • Krag A.
      Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.
      ,
      • Sanyal A.J.
      • Boyer T.
      • Garcia-Tsao G.
      • Regenstein F.
      • Rossaro L.
      • Appenrodt B.
      • et al.
      A randomized, prospective, double-blind, placebo-controlled trial of terlipressina for type 1 hepatorenal syndrome.
      ]. As mentioned before, it is generally accepted that HRS is of circulatory origin and occurs as a consequence of reduction in renal blood flow and glomerular filtration rate secondary to marked arterial vasodilation in the splanchnic circulation. This leads to a reduction in effective arterial blood volume and arterial pressure with compensatory activation of vasoconstrictor systems, particularly sympathetic nervous system and renin–angiotensin–aldosterone system. An extended discussion of the pathophysiology of HRS can be found elsewhere [
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ,
      • Dagher L.
      • Moore K.
      The hepatorenal syndrome.
      ,
      • Angeli P.
      • Merkel C.
      Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis.
      ]. HRS characteristically develops after a precipitating factor, particularly a bacterial infection, most frequently spontaneous bacterial peritonitis, although in some cases it may develop without an identifiable precipitating factor. HRS occurs in two different forms: type-1 HRS, characterized by rapidly progressive renal failure usually in the setting of multiorgan failure, and type 2 HRS characterized by less severe and stable renal failure, which is clinically apparent by ascites refractory to diuretic therapy. The former is associated with a 1 month mortality rate greater than 50%, whereas the latter shows a better survival [
      • Alessandria C.
      • Ozdogan O.
      • Guevara M.
      • Restuccia T.
      • Jiménez W.
      • Arroyo V.
      • et al.
      MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation.
      ].

      Current management

      The most effective method currently available for the management of HRS is the administration of vasoconstrictor drugs (Table 2). The vasoconstrictor of choice is the vasopressin analogue terlipressin [

      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrosis. J Hepatol 2010;53:397–417.

      ]. The rationale for the use of terlipressin in HRS is to improve the markedly impaired circulatory function by causing vasoconstriction of the extremely dilated splanchnic vascular bed, increasing arterial pressure, and suppressing the activity of the endogenous vasoconstrictor factors acting on the kidney [
      • Moreau R.
      • Lebrec D.
      The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond.
      ,
      • Ginès P.
      • Guevara M.
      Therapy with vasoconstrictor drugs in cirrhosis: the time has arrived.
      ]. Terlipressin is effective in 40% to 50% of patients with type-1 HRS [
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ,
      • Gluud L.L.
      • Christensen K.
      • Christensen E.
      • Krag A.
      Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.
      ,
      • Moreau R.
      • Lebrec D.
      The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond.
      ]. Treatment is usually started at a dose of 1 mg/4–6 h (iv bolus) and increased to a maximum of 2 mg/4–6 h if there is no reduction in serum creatinine of at least 25% compared to the baseline value at day 3 of therapy. Responder patients usually show a progressive reduction in serum creatinine over several days and up to 1–2 weeks, together with an increase in arterial pressure, urine volume, and serum sodium concentration. Treatment is maintained until serum creatinine decreases to 1–1.2 mg/dl (88–106 μmol/L). Predictive factors of response are, pretreatment serum bilirubin levels lower than 10 mg/dl and an increase in mean arterial pressure greater than 5 mm Hg after 3 days of treatment [
      • Nazar A.
      • Pereira G.H.
      • Guevara M.
      • Martín-Llahi M.
      • Pepin M.N.
      • Marinelli M.
      • et al.
      Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome.
      ]. Recurrence of HRS after withdrawal of therapy occurs in less than 15% of patients and retreatment with terlipressin is generally effective. The most frequent side effects of treatment are cardiovascular or ischemic complications, which have been reported in 12% of patients, yet most studies excluded patients with known severe cardiovascular or ischemic conditions [
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ,
      • Moreau R.
      • Lebrec D.
      The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond.
      ]. Terlipressin is given in combination with albumin (1 g/kg on day 1 followed by 40 g/day) to improve the effect of treatment on circulatory function [
      • Ortega R.
      • Ginès P.
      • Uriz J.
      • et al.
      Terlipressin therapy with and without albúmina for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
      ]. Whether terlipressin improves survival in patients with HRS is not known, but a recent systematic review of randomized studies using terlipressin as well as other vasoconstrictors showed an increased short-term survival compared with control patients [
      • Gluud L.L.
      • Christensen K.
      • Christensen E.
      • Krag A.
      Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.
      ]. The effectiveness of terlipressin in the treatment of HRS with active bacterial infection is unknown, because all clinical trials have excluded patients with ongoing infections. Finally, treatment with terlipressin in patients with type 2 HRS is also associated with an improvement of renal function [
      • Alessandria C.
      • Venon W.D.
      • Marzano A.
      • Barletti C.
      • Fadda M.
      • Rizzetto M.
      Renal Failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2.
      ,
      • Martin LLahi M.
      • Pepin M.N.
      • Guevara M.
      • et al.
      Terlipressin and albúmina vs albúmina in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      ]. Nevertheless, there is still limited information on the use of terlipressin in type 2 HRS.
      Table 2Treatment of hepatorenal syndrome: current management and potential future options.
      ∗TIPS, transjugular intrahepatic portosystemic shunt.
      Figure thumbnail fx4
      Although TIPS may reverse HRS in some patients, the applicability of TIPS in patients with type-1 HRS is low because TIPS is contraindicated in patients with severe liver failure and hepatic encephalopathy, which are common findings in the setting of type-1 HRS [
      • Guevara M.
      • Ginès P.
      • Bandi J.C.
      • Gilabert R.
      • Sort P.
      • Jiménez W.
      • et al.
      Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems.
      ]. Due to the paucity of data, more studies are needed for assessing the use of TIPS in patients with HRS. Renal replacement therapy (RRT) has been used in the management of patients with type-1 HRS, especially in patient candidates for liver transplantation, in an attempt to maintain patients alive until liver transplantation is performed [
      • Meltzer J.
      • Brentjens T.E.
      Renal failure in patients with cirrhosis: hepatorenal syndrome and renal support strategies.
      ,
      • Kiser T.H.
      • Maclaren R.
      • Fish D.N.
      Treatment of hepatorenal syndrome.
      ]. Although RRT is not the first line therapy, it is a temporary option in patients not responding to vasoconstrictors or in those who develop severe volume overload, metabolic acidosis and/or refractory hyperkalemia. Most patients develop important side effects during hemodialysis including severe arterial hypotension, bleeding, and infections that may contribute to death during treatment.
      All patients with HRS should be considered for liver transplantation, unless they have contraindications [
      • Charlton M.R.
      • Wall W.J.
      • Ojo A.O.
      • Ginès P.
      • Textor S.
      • Shihab F.S.
      • et al.
      International Liver Transplantation Society Expert Panel. Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation.
      ]. The main problems of liver transplantation for HRS are the high waiting list mortality rate and an increased morbidity and mortality after transplantation. Nevertheless, the survival of patients with HRS treated with liver transplantation is approximately 60% at 3 years, a survival rate much higher than that expected by the natural course of the disease.
      There have been few studies on the prevention of HRS. The administration of albumin (1.5 g/kg at diagnosis and 1 g/kg at day 3) is effective in the prevention of HRS secondary to SBP and has been shown to improve survival [
      • Sort P.
      • Navasa M.
      • Arroyo V.
      • Aldeguer X.
      • Planas R.
      • Ruiz-del-Arbol L.
      • et al.
      Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
      ]. Short-term treatment (4-week) with pentoxyfylline (400 mg three times a day) was shown to prevent the development of HRS in patients with severe alcoholic hepatitis [
      • Akriviadis E.
      • Bortla R.
      • Briggs W.
      • Han S.
      • Reynolds T.
      • Shakil O.
      Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.
      ]. In a more recent study, long-term treatment with pentoxyfylline was associated with reduced frequency of some complications of cirrhosis, including renal failure, yet this was not the primary end-point of the study [
      • Lebrec D.
      • Thabut D.
      • Oberti F.
      • Perarnau J.M.
      • Condat B.
      • Barraud H.
      • et al.
      Pentoxifylline does not decrease short term mortality but does reduce complications in patients with advanced cirrhosis.
      ]. More studies are needed to assess the usefulness of pentoxyfylline in the prevention of HRS. Finally, long-term administration of norfloxacin to patients with advanced cirrhosis (severe liver failure with or without renal impairment or hyponatremia) (400 mg/day) reduced the incidence of HRS and improved survival compared with placebo [
      • Fernández J.
      • Navasa M.
      • Planas R.
      • Montoliu S.
      • Monfort D.
      • Soriano G.
      • et al.
      Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
      ]. The potential mechanism(s) by which pentoxyfylline and norfloxacin prevent HRS in cirrhosis is/are not well understood, but may be related, at least in part, to a reduction in cytokine levels that may have deleterious effects on renal function.

      Future therapeutic options

      Approximately 50–60% of patients with HRS do not respond to treatment with vasoconstrictors [
      • Nazar A.
      • Pereira G.H.
      • Guevara M.
      • Martín-Llahi M.
      • Pepin M.N.
      • Marinelli M.
      • et al.
      Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome.
      ]. Therefore, one of the main challenges for the future is to increase the number of patients with HRS responding to pharmacological therapy. The first step in improving the efficacy of pharmacological therapy is to understand the pathogenic reasons for the lack of response. In this regard, it would be important to perform studies in a large series of patients with the aim of identifying predictive factors of response. Possible approaches to improve the efficacy of vasoconstrictors include modifications in the method of administration of the drugs and the combination of vasoconstrictors with other therapies (Table 2). Preliminary results of an ongoing study suggest that terlipressin is more effective when given as continuous infusion than as iv bolus [
      • Angeli P.
      • Fasolato S.
      • Cavallin M.
      • Maresio G.
      • Callegaro A.
      • Sticca A.
      • et al.
      Terlipressin given as continuous intravenous infusion is the more suitable schedule for the treatment of type 1 hepatorenal syndrome (HRS) in patients with cirrhosis: results of a controlled clinical study.
      ]. This might be to a lesser effect related to the drug in impairing cardiac function in the former compared to the latter method of administration [
      • Morelli A.
      • Ertmer C.
      • Lange M.
      • Westphal M.
      Continuous terlipressin infusion in patients with septic shock: less may be best, and the earlier the better?.
      ]. A single study in a very small series of patients suggests that treatment with vasoconstrictors, followed by insertion of TIPS, is associated with a marked improvement of renal function and prolonged survival [
      • Wong F.
      • Pantea L.
      • Sniderman K.
      Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome.
      ]. This combined approach would require confirmation in a larger series of patients. An increased renal adenosine production has been suggested to play a role in the pathogenesis of HRS [
      • Llach J.
      • Ginès P.
      • Arroyo V.
      • Salmeron J.M.
      • Ginès A.
      • Jiménez W.
      Effect of dypiridamole on kidney function in cirrhosis.
      ]. On this ground, the potential benefit of antagonizing the effects of adenosine on renal function was investigated. Unfortunately, the administration of an antagonist of A1 adenosine receptors, increased natriuresis but did not improve glomerular filtration rate and no further studies have been published investigating the use of adenosine receptors since 1998 [
      • Stanley A.J.
      • Forrest E.H.
      • Dabos K.
      • Bouchier I.A.
      • Hayes P.C.
      Natriuretic effect of an adenosine-1 receptor antagonist in cirrhotic patients with ascites.
      ]. Considering the potential relationship between impairment of cardiac function and occurrence of HRS mentioned earlier in this article [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ], the possibility of treating HRS by improving cardiac function should be investigated. Finally, two recent studies suggest that the so called extracorporeal liver support systems (either albumin dialysis using the molecular adsorbent recirculating system -MARSR- and fractionated plasma separation and adsorption -PrometheusR-) may be effective in the management of HRS [
      • Rifai K.
      • Kribben A.
      • Gerken G.
      • Haag S.
      • Herget-Rosenthal S.
      • Treichel U.
      • et al.
      Extracorporeal liver support by fractionated plasma separation and adsorption (Prometheus®) in patients with acute-on-chronic liver failure (HELIOS Study): a prospective randomized controlled multicenter study.
      ,
      • Mitzner S.R.
      • Stange J.
      • Klammt S.
      • Risler T.
      • Erley C.M.
      • Bader B.D.
      • et al.
      Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial.
      ,
      • Mitzner S.R.
      • Klammt S.
      • Peszynski P.
      • Hickstein H.
      • Korten G.
      • Stange J.
      • et al.
      Improvement of multiple organ functions in hepatorenal syndrome during albumin dialysis with the molecular adsorbent recirculating system.
      ]. The beneficial effects of such a therapy may be related to the improvement in circulatory function related to the elimination of vasodilator substances [
      • Arroyo V.
      • Fernandez J.
      • Mas A.
      • Escorsell A.
      Molecular adsorbents recirculating system (MARS) and the failing liver: a negative editorial for a positive trial?.
      ,
      • Dethloff T.
      • Tofteng F.
      • Frederiksen H.J.
      • Hojskov M.
      • Hansen B.A.
      • Larsen F.S.
      Effect of Prometheus liver assist system on systemic hemodynamics in patients with cirrhosis: a randomized controlled study.
      ,
      • Donati G.
      • Piscaglia F.
      • Colì L.
      • Silvagni E.
      • Righini R.
      • Donati G.
      • et al.
      Acute systemic, splanchnic and renal haemodynamic changes induced by molecular adsorbent recirculating system (MARS) treatment in patients with end-stage cirrhosis.
      ]. Studies specifically designed to address the efficacy and safety of extracorporeal liver support systems in patients with HRS should be performed to answer definitively the question of the potential effectiveness of such therapies in HRS.

      Conflict of interests

      The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or confilct of interest with respect to this manuscript.

      Acknowledgements

      Some of the studies reported in this manuscript have been supported by grants from the Fondo de Investigación Sanitaria (FIS PI080126 and EC/90077 ), Spain. Elsa Solà was the recipient of a grant from the Hospital Clínic and Fundación Banco de Bilbao-Vizcaya-Argentaria (FBVVA). CIBEREHD is funded by the Instituto de Salud Carlos III.

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