Pharmacological management of hepatorenal syndrome: Lessons from non-responders

Abstract

Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: Relationship of serum creatinine to hemodynamicsJournal of HepatologyVol. 55Issue 2PreviewAdministration of terlipressin plus albumin is effective in reversing type 1 HRS as compared to albumin alone. However, only about 1/3 of patients respond to treatment, therefore, predictors of response and survival would help identify the patients most likely to benefit from treatment. Full-Text PDF Treatment of hepatorenal syndrome (HRS) with terlipressin and albumin has become a major breakthrough in the field of cirrhosis [[1]Ginès P. Schrier R.W. Renal failure in cirrhosis.New Engl J Med. 2009; 361: 1279-1290Crossref PubMed Scopus (609) Google Scholar]. The introduction of terlipressin as the first effective drug for type-1 HRS represents an advance of comparable importance to those such as spironolactone for the management of ascites, propranolol for prevention of variceal bleeding, or norfloxacin for the prevention of spontaneous bacterial peritonitis [2Kerr D.N. Read A.E. Haslam Rm, Sherlock S. The use of steroidal spironolactone in the treatment of ascites.The Lancet. 1958; 2: 1084-1087Abstract PubMed Scopus (6) Google Scholar, 3Lebrec D. Nouel O. Bernuau J. Bouygues M. Rueff B. Benhamou J.P. Propranolol in prevention of recurrent gastrointestinal bleeding in cirrhotic patients.The Lancet. 1981; 1: 920-921Abstract PubMed Scopus (63) Google Scholar, 4Ginès P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (518) Google Scholar].Over the last decade, since the studies on terlipressin for type-1 HRS became first available, we have learnt that terlipressin in association with albumin is effective in reversing type-1 HRS, defined as a reduction of serum creatinine from pretreatment values to final values below 1.5 mg/dl (133 μmol/L), in nearly half of the patients and that recurrence of HRS after the treatment withdrawal is uncommon [1Ginès P. Schrier R.W. Renal failure in cirrhosis.New Engl J Med. 2009; 361: 1279-1290Crossref PubMed Scopus (609) Google Scholar, 5Gluud L.L. Christensen K. Christensen E. Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.Hepatology. 2010; 51: 576-584Crossref PubMed Scopus (233) Google Scholar, 6European Association for the Study of the Liver, Ginès P, Angeli P, Lenz K, Møller S, Moore K, Moreau R, et al. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397–417.Google Scholar]. We have also learnt that reversal of type-1 HRS, due to terlipressin and albumin is associated with improved prognosis, yet this has been proven only in meta-analyses and not in most of the individual randomized studies, because of the limited number of patients included [7Martín-Llahí M. Pépin M.N. Guevara M. Díaz F. Torre A. Monescillo A. et al.Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.Gastroenterology. 2008; 134: 1352-1359Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 8Sanyal A.J. Boyer T. Garcia-Tsao G. Regenstein F. Rossaro L. Appenrodt B. et al.A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar]. Finally, the treatment with terlipressin and albumin for patients developing type-1 HRS while awaiting liver transplantation is an attractive approach to improve the outcome after transplantation and may reduce the requirements of renal replacement therapy and the need for combined liver–kidney transplantation [9Restuccia T. Ortega R. Guevara M. Ginès P. Alessandria C. Ozdogan O. et al.Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study.J Hepatol. 2004; 40: 140-146Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 10Gonwa T.A. Davis C. Evaluation and management of pretransplant renal insufficiency and criteria for simultaneous liver–kidney transplantation.Liver Transpl. 2009; 15: S25-S31Crossref PubMed Scopus (77) Google Scholar]. The main problems of terlipressin are its relatively high cost, particularly for some areas of the world (yet its cost has decreased dramatically in some countries because of the recent introduction of generic terlipressin), and a significant frequency of side effects, mainly ischemic complications, due to its powerful vasoconstrictor action on several vascular beds, such as the splanchnic circulation, skin and muscle, and heart. Nevertheless, side effects can be minimized by starting therapy with low doses and maintaining a strict clinical surveillance of patients throughout the treatment.The study by Boyer et al. [[11]Boyer T.D. Sanyal A. Garcia-Tsao G. Beli A. Carl D. Bexon A.S. et al.Predictors of Response to terlipressin and albumin in hepatorenal syndrome type-1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar] published in the current issue of the Journal of Hepatology represents a significant contribution to the improvement of our knowledge on the management of type-1 HRS. The study is a report of a post hoc analysis of 112 patients with type-1 HRS included in a randomized, double-blind comparison of terlipressin and albumin vs. placebo [[8]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 terlipressin for type 1 hepatorenal syndrome.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar], and was aimed at assessing predictive factors of response to therapy and correlating changes in systemic hemodynamics with changes in renal function. The results have important clinical and pathophysiological implications. From a clinical standpoint, this study demonstrates that serum creatinine concentration before the treatment was the only independent predictive factor in reversal of type-1 HRS by terlipressin and albumin, patients with lower serum creatinine levels being those with the highest likelihood of response to therapy. Reversal of HRS was very unusual in patients with pretreatment serum creatinine levels above 5 mg/dl. Serum creatinine was also found to be an important predictive factor of response to therapy of type-1 HRS in previous studies including a lower number of patients [[7]Martín-Llahí M. Pépin M.N. Guevara M. Díaz F. Torre A. Monescillo A. et al.Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.Gastroenterology. 2008; 134: 1352-1359Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar]. These findings deliver an important clinical concept that is, early treatment of type-1 HRS with terlipressin and albumin enhances the chances of response. Translated into clinical practice, this means that the diagnosis of type-1 HRS should be performed within a short time frame, ideally 24–48 h, following the currently accepted guidelines [[12]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis. A consensus workshop of the international ascites club.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar], and the treatment with terlipressin and albumin should be started as soon as the diagnosis is made. From a pathophysiological perspective, the study by Boyer et al. [[11]Boyer T.D. Sanyal A. Garcia-Tsao G. Beli A. Carl D. Bexon A.S. et al.Predictors of Response to terlipressin and albumin in hepatorenal syndrome type-1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar] shows that patients who responded to terlipressin had an increase in arterial pressure which was followed by an improvement in renal function, whereas in non-responders to terlirpressin, arterial pressure did not change, and renal function did not improve or continue to decline. These findings are in keeping with those from previous studies including a lower number of patients [13Nazar A. Pereira G.H. Guevara M. Martín-Llahi M. Pepin M.N. Marinelli M. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type-1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (168) Google Scholar, 14Colle I. Durand F. Pessione F. Rassiat E. Bernuau J. Barrière E. Clinical course, predictive factors, and prognosis in patients with cirrhosis and type-1 hepatorenal syndrome treated with terlipressin: a retrospective analysis.J Gastroenterol Hepatol. 2002; 17: 882-888Crossref PubMed Scopus (135) Google Scholar]. Interestingly, a recent investigation showed that patients in whom mean arterial pressure increased by more than 5 mm Hg at day 3 of the treatment had a greater probability of response than those in whom arterial pressure increased less than 5 mm Hg (73% vs. 36%, respectively) [[13]Nazar A. Pereira G.H. Guevara M. Martín-Llahi M. Pepin M.N. Marinelli M. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type-1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (168) Google Scholar]. Unfortunately, in the study by Boyer et al. [[11]Boyer T.D. Sanyal A. Garcia-Tsao G. Beli A. Carl D. Bexon A.S. et al.Predictors of Response to terlipressin and albumin in hepatorenal syndrome type-1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar] the activity of vasoconstrictor systems, particularly the renin-angiotensin-aldosterone system and the sympathetic nervous system, which are important players in the maintenance of circulatory function in cirrhosis, was not assessed. Previous studies have shown that response to terlipressin and albumin is associated not only with an increase in arterial pressure but also with marked suppression of the activity of the renin-angiotensin system and sympathetic nervous system [[13]Nazar A. Pereira G.H. Guevara M. Martín-Llahi M. Pepin M.N. Marinelli M. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type-1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (168) Google Scholar]. This suppression of the activity of the vasoconstrictor systems has also been demonstrated in patients with type-1 HRS showing response to other vasoconstrictor drugs, such as ornipressin, midodrine, and norepinephrine [15Guevara M. Ginès P. Fernández-Esparrach G. Sort P. Salmeron J.M. Jimenez W. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.Hepatology. 1998; 27: 35-41Crossref PubMed Scopus (307) Google Scholar, 16Angeli P. Volpin R. Gerunda G. Craighero R. Roner P. Merenda R. Reversal of type-1 hepatorenal syndrome with the administration of midodrine and octreotide.Hepatology. 1999; 29: 1690-1697Crossref PubMed Scopus (461) Google Scholar, 17Duvoux C. Zanditenas D. Hézode C. Chauvet A. Monin J.L.. Roudot-Thoraval F. Effects of noradrenaline and albumin in patients with type-1 hepatorenal syndrome: a pilot study.Hepatology. 2002; 36: 374-380Crossref PubMed Scopus (309) Google Scholar]. Conversely, no such suppression occurs in patients who do not respond to vasoconstrictors. Taken together, these data unequivocally demonstrate that the severe renal dysfunction that occurs in type-1 HRS is due to a marked impairment of circulatory function and that pharmacological improvement of the circulatory function is able to reverse renal failure. The reason(s) why pharmacological treatment is hardly effective in patients with very advanced type-1 HRS (i.e. serum creatinine greater than 5 mg/dl) is not known at present and deserves investigation. Possibilities, among others, include an insufficient vasoactive effect of vasoconstrictor drugs, association of HRS with other causes of renal failure, and progression of type-1 HRS from functional renal failure to ischemic kidney damage.Despite the recent advances in the management of HRS, a number of important challenges remain ahead. First, the number of patients not responding to pharmacological therapy (patients in whom serum creatinine either does not decrease during the treatment or decreases but not to a level below 1.5 mg/dl) is still high [[5]Gluud L.L. Christensen K. Christensen E. Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.Hepatology. 2010; 51: 576-584Crossref PubMed Scopus (233) Google Scholar]. New approaches should be investigated to increase the percentage of responders. In this regard, it will be interesting to evaluate the efficacy of terlipressin given by continuous infusion instead of i.v. bolus, as currently used in all published studies. Studies in experimental animals and patients with septic shock suggest that the beneficial hemodynamic effects of terlipressin are enhanced when used as continuous infusion compared to intermittent administration [18Lange M. Morelli A. Ertmer C. et al.Continous versus bolus infusion of terlipressin in ovine endotoxemia.Shock. 2007; 28: 623-629Crossref PubMed Scopus (17) Google Scholar, 19Morelli A. Ertmer C. Lange M. Westphal M. Continuous terlipressin infusion in patients with septic shock: less may be best, and the earlier the better?.Intensive Care Med. 2007; 33: 1669-1670Crossref PubMed Scopus (31) Google Scholar]. A preliminary report of a randomized study suggests that this might be the case also in type-1 HRS, but definite results are needed [[20]Angeli P. Fasolato S. Cavallin M. Maresio G. Callegaro A. Sticca A. 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 trial.Hepatology. 2008; 48: 378AGoogle Scholar]. Second, the combination of pharmacological therapy with non-pharmacological therapies should be investigated, particularly in severe cases that have a low probability of response to pharmacological therapy alone. In this regard, a recent study showed that the combination of terlipressin and albumin and an extracorporeal liver support system using fractionated plasma separation and adsorption may improve survival in patients with type-1 HRS [[21]Rifai K. Kribben A. Gerken G. Haag S. Herget-Rosenthal S. Treichel U. Extracoporeal liver support by fractionated plasma separation, adsorption (PROMETHEUS) in patients with acute on chronic liver failure (Helios Study): a prospective randomized Controlled multicenter study.J Hepatol. 2010; 52: S3Abstract Full Text PDF PubMed Google Scholar]. However, since this observation was made with a subanalysis of a larger study, specific studies assessing this strategy in a specific population of patients with type-1 HRS should be performed. Third, the efficacy of pharmacological treatment of type-1 HRS associated with infections is not known since studies reported so far have excluded patients with active infections. Specific studies should be performed in this patient population. Finally, most of the information on the efficacy of pharmacological treatment of HRS refers to patients with type-1 HRS and little information exists on the efficacy and safety of the treatment in type-2 HRS. Investigations should be performed to assess not only the efficacy of pharmacological treatment on renal function in these patients but also in the long-term outcomes, particularly the occurrence of type-1 HRS and survival.Financial supportSome of the studies reported in this manuscript have been supported by grants from the Fondo de Investigación Sanitaria (FIS PI080126 and EC/90077), Spain. CIBEREHD is funded by the Instituto de Salud Carlos III.Conflict of interestThe author declared a relationship with Orphan Therapeutics. Treatment of hepatorenal syndrome (HRS) with terlipressin and albumin has become a major breakthrough in the field of cirrhosis [[1]Ginès P. Schrier R.W. Renal failure in cirrhosis.New Engl J Med. 2009; 361: 1279-1290Crossref PubMed Scopus (609) Google Scholar]. The introduction of terlipressin as the first effective drug for type-1 HRS represents an advance of comparable importance to those such as spironolactone for the management of ascites, propranolol for prevention of variceal bleeding, or norfloxacin for the prevention of spontaneous bacterial peritonitis [2Kerr D.N. Read A.E. Haslam Rm, Sherlock S. The use of steroidal spironolactone in the treatment of ascites.The Lancet. 1958; 2: 1084-1087Abstract PubMed Scopus (6) Google Scholar, 3Lebrec D. Nouel O. Bernuau J. Bouygues M. Rueff B. Benhamou J.P. Propranolol in prevention of recurrent gastrointestinal bleeding in cirrhotic patients.The Lancet. 1981; 1: 920-921Abstract PubMed Scopus (63) Google Scholar, 4Ginès P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (518) Google Scholar]. Over the last decade, since the studies on terlipressin for type-1 HRS became first available, we have learnt that terlipressin in association with albumin is effective in reversing type-1 HRS, defined as a reduction of serum creatinine from pretreatment values to final values below 1.5 mg/dl (133 μmol/L), in nearly half of the patients and that recurrence of HRS after the treatment withdrawal is uncommon [1Ginès P. Schrier R.W. Renal failure in cirrhosis.New Engl J Med. 2009; 361: 1279-1290Crossref PubMed Scopus (609) Google Scholar, 5Gluud L.L. Christensen K. Christensen E. Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.Hepatology. 2010; 51: 576-584Crossref PubMed Scopus (233) Google Scholar, 6European Association for the Study of the Liver, Ginès P, Angeli P, Lenz K, Møller S, Moore K, Moreau R, et al. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397–417.Google Scholar]. We have also learnt that reversal of type-1 HRS, due to terlipressin and albumin is associated with improved prognosis, yet this has been proven only in meta-analyses and not in most of the individual randomized studies, because of the limited number of patients included [7Martín-Llahí M. Pépin M.N. Guevara M. Díaz F. Torre A. Monescillo A. et al.Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.Gastroenterology. 2008; 134: 1352-1359Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 8Sanyal A.J. Boyer T. Garcia-Tsao G. Regenstein F. Rossaro L. Appenrodt B. et al.A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar]. Finally, the treatment with terlipressin and albumin for patients developing type-1 HRS while awaiting liver transplantation is an attractive approach to improve the outcome after transplantation and may reduce the requirements of renal replacement therapy and the need for combined liver–kidney transplantation [9Restuccia T. Ortega R. Guevara M. Ginès P. Alessandria C. Ozdogan O. et al.Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study.J Hepatol. 2004; 40: 140-146Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 10Gonwa T.A. Davis C. Evaluation and management of pretransplant renal insufficiency and criteria for simultaneous liver–kidney transplantation.Liver Transpl. 2009; 15: S25-S31Crossref PubMed Scopus (77) Google Scholar]. The main problems of terlipressin are its relatively high cost, particularly for some areas of the world (yet its cost has decreased dramatically in some countries because of the recent introduction of generic terlipressin), and a significant frequency of side effects, mainly ischemic complications, due to its powerful vasoconstrictor action on several vascular beds, such as the splanchnic circulation, skin and muscle, and heart. Nevertheless, side effects can be minimized by starting therapy with low doses and maintaining a strict clinical surveillance of patients throughout the treatment. The study by Boyer et al. [[11]Boyer T.D. Sanyal A. Garcia-Tsao G. Beli A. Carl D. Bexon A.S. et al.Predictors of Response to terlipressin and albumin in hepatorenal syndrome type-1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar] published in the current issue of the Journal of Hepatology represents a significant contribution to the improvement of our knowledge on the management of type-1 HRS. The study is a report of a post hoc analysis of 112 patients with type-1 HRS included in a randomized, double-blind comparison of terlipressin and albumin vs. placebo [[8]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 terlipressin for type 1 hepatorenal syndrome.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar], and was aimed at assessing predictive factors of response to therapy and correlating changes in systemic hemodynamics with changes in renal function. The results have important clinical and pathophysiological implications. From a clinical standpoint, this study demonstrates that serum creatinine concentration before the treatment was the only independent predictive factor in reversal of type-1 HRS by terlipressin and albumin, patients with lower serum creatinine levels being those with the highest likelihood of response to therapy. Reversal of HRS was very unusual in patients with pretreatment serum creatinine levels above 5 mg/dl. Serum creatinine was also found to be an important predictive factor of response to therapy of type-1 HRS in previous studies including a lower number of patients [[7]Martín-Llahí M. Pépin M.N. Guevara M. Díaz F. Torre A. Monescillo A. et al.Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.Gastroenterology. 2008; 134: 1352-1359Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar]. These findings deliver an important clinical concept that is, early treatment of type-1 HRS with terlipressin and albumin enhances the chances of response. Translated into clinical practice, this means that the diagnosis of type-1 HRS should be performed within a short time frame, ideally 24–48 h, following the currently accepted guidelines [[12]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis. A consensus workshop of the international ascites club.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar], and the treatment with terlipressin and albumin should be started as soon as the diagnosis is made. From a pathophysiological perspective, the study by Boyer et al. [[11]Boyer T.D. Sanyal A. Garcia-Tsao G. Beli A. Carl D. Bexon A.S. et al.Predictors of Response to terlipressin and albumin in hepatorenal syndrome type-1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar] shows that patients who responded to terlipressin had an increase in arterial pressure which was followed by an improvement in renal function, whereas in non-responders to terlirpressin, arterial pressure did not change, and renal function did not improve or continue to decline. These findings are in keeping with those from previous studies including a lower number of patients [13Nazar A. Pereira G.H. Guevara M. Martín-Llahi M. Pepin M.N. Marinelli M. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type-1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (168) Google Scholar, 14Colle I. Durand F. Pessione F. Rassiat E. Bernuau J. Barrière E. Clinical course, predictive factors, and prognosis in patients with cirrhosis and type-1 hepatorenal syndrome treated with terlipressin: a retrospective analysis.J Gastroenterol Hepatol. 2002; 17: 882-888Crossref PubMed Scopus (135) Google Scholar]. Interestingly, a recent investigation showed that patients in whom mean arterial pressure increased by more than 5 mm Hg at day 3 of the treatment had a greater probability of response than those in whom arterial pressure increased less than 5 mm Hg (73% vs. 36%, respectively) [[13]Nazar A. Pereira G.H. Guevara M. Martín-Llahi M. Pepin M.N. Marinelli M. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type-1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (168) Google Scholar]. Unfortunately, in the study by Boyer et al. [[11]Boyer T.D. Sanyal A. Garcia-Tsao G. Beli A. Carl D. Bexon A.S. et al.Predictors of Response to terlipressin and albumin in hepatorenal syndrome type-1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar] the activity of vasoconstrictor systems, particularly the renin-angiotensin-aldosterone system and the sympathetic nervous system, which are important players in the maintenance of circulatory function in cirrhosis, was not assessed. Previous studies have shown that response to terlipressin and albumin is associated not only with an increase in arterial pressure but also with marked suppression of the activity of the renin-angiotensin system and sympathetic nervous system [[13]Nazar A. Pereira G.H. Guevara M. Martín-Llahi M. Pepin M.N. Marinelli M. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type-1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (168) Google Scholar]. This suppression of the activity of the vasoconstrictor systems has also been demonstrated in patients with type-1 HRS showing response to other vasoconstrictor drugs, such as ornipressin, midodrine, and norepinephrine [15Guevara M. Ginès P. Fernández-Esparrach G. Sort P. Salmeron J.M. Jimenez W. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.Hepatology. 1998; 27: 35-41Crossref PubMed Scopus (307) Google Scholar, 16Angeli P. Volpin R. Gerunda G. Craighero R. Roner P. Merenda R. Reversal of type-1 hepatorenal syndrome with the administration of midodrine and octreotide.Hepatology. 1999; 29: 1690-1697Crossref PubMed Scopus (461) Google Scholar, 17Duvoux C. Zanditenas D. Hézode C. Chauvet A. Monin J.L.. Roudot-Thoraval F. Effects of noradrenaline and albumin in patients with type-1 hepatorenal syndrome: a pilot study.Hepatology. 2002; 36: 374-380Crossref PubMed Scopus (309) Google Scholar]. Conversely, no such suppression occurs in patients who do not respond to vasoconstrictors. Taken together, these data unequivocally demonstrate that the severe renal dysfunction that occurs in type-1 HRS is due to a marked impairment of circulatory function and that pharmacological improvement of the circulatory function is able to reverse renal failure. The reason(s) why pharmacological treatment is hardly effective in patients with very advanced type-1 HRS (i.e. serum creatinine greater than 5 mg/dl) is not known at present and deserves investigation. Possibilities, among others, include an insufficient vasoactive effect of vasoconstrictor drugs, association of HRS with other causes of renal failure, and progression of type-1 HRS from functional renal failure to ischemic kidney damage. Despite the recent advances in the management of HRS, a number of important challenges remain ahead. First, the number of patients not responding to pharmacological therapy (patients in whom serum creatinine either does not decrease during the treatment or decreases but not to a level below 1.5 mg/dl) is still high [[5]Gluud L.L. Christensen K. Christensen E. Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.Hepatology. 2010; 51: 576-584Crossref PubMed Scopus (233) Google Scholar]. New approaches should be investigated to increase the percentage of responders. In this regard, it will be interesting to evaluate the efficacy of terlipressin given by continuous infusion instead of i.v. bolus, as currently used in all published studies. Studies in experimental animals and patients with septic shock suggest that the beneficial hemodynamic effects of terlipressin are enhanced when used as continuous infusion compared to intermittent administration [18Lange M. Morelli A. Ertmer C. et al.Continous versus bolus infusion of terlipressin in ovine endotoxemia.Shock. 2007; 28: 623-629Crossref PubMed Scopus (17) Google Scholar, 19Morelli A. Ertmer C. Lange M. Westphal M. Continuous terlipressin infusion in patients with septic shock: less may be best, and the earlier the better?.Intensive Care Med. 2007; 33: 1669-1670Crossref PubMed Scopus (31) Google Scholar]. A preliminary report of a randomized study suggests that this might be the case also in type-1 HRS, but definite results are needed [[20]Angeli P. Fasolato S. Cavallin M. Maresio G. Callegaro A. Sticca A. 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 trial.Hepatology. 2008; 48: 378AGoogle Scholar]. Second, the combination of pharmacological therapy with non-pharmacological therapies should be investigated, particularly in severe cases that have a low probability of response to pharmacological therapy alone. In this regard, a recent study showed that the combination of terlipressin and albumin and an extracorporeal liver support system using fractionated plasma separation and adsorption may improve survival in patients with type-1 HRS [[21]Rifai K. Kribben A. Gerken G. Haag S. Herget-Rosenthal S. Treichel U. Extracoporeal liver support by fractionated plasma separation, adsorption (PROMETHEUS) in patients with acute on chronic liver failure (Helios Study): a prospective randomized Controlled multicenter study.J Hepatol. 2010; 52: S3Abstract Full Text PDF PubMed Google Scholar]. However, since this observation was made with a subanalysis of a larger study, specific studies assessing this strategy in a specific population of patients with type-1 HRS should be performed. Third, the efficacy of pharmacological treatment of type-1 HRS associated with infections is not known since studies reported so far have excluded patients with active infections. Specific studies should be performed in this patient population. Finally, most of the information on the efficacy of pharmacological treatment of HRS refers to patients with type-1 HRS and little information exists on the efficacy and safety of the treatment in type-2 HRS. Investigations should be performed to assess not only the efficacy of pharmacological treatment on renal function in these patients but also in the long-term outcomes, particularly the occurrence of type-1 HRS and survival. Financial supportSome of the studies reported in this manuscript have been supported by grants from the Fondo de Investigación Sanitaria (FIS PI080126 and EC/90077), Spain. CIBEREHD is funded by the Instituto de Salud Carlos III. 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. CIBEREHD is funded by the Instituto de Salud Carlos III. Conflict of interestThe author declared a relationship with Orphan Therapeutics. The author declared a relationship with Orphan Therapeutics.