- Email: [email protected]
Pharmacological treatment of hepatorenal syndrome: A note of optimism
Letters to the Editor / Journal of Hepatology 47 (2007) 726–731
Prothrombintime (sec)
250
729
important and needs further verification in a large number of patients.
200
patient deceased patient deceased
150
patient transplanted
Reference
patient listed and spontaneously recovered
[1] Escudie L, Francoz C, Vinel JP, Moucari R, Cournot M, Paradis V, et al. Amanita phalloides poisoning: reassessment of prognostic factors and indication for emergency liver transplantation. J Hepatol 2007;47:466–473.
100 50
two patients recovered
0 0
6
12
18
24
30
36
Hours of follow up
Fig. 1. The pattern of Prothrombin time every 6 h during follow up.
All patients had the worst prognostic factor: onset of diarrhea and nausea in less than 8 h following mushroom ingestion, and the proportion of those who died or were transplanted was 50%. The most important difference between the two groups of patients was the pattern of prothrombin time elevation during the first hours of follow-up. We believe that this clinical observation is
Melanie Deutsch John Koskinas Dimitris Kountouras Athanasios J. Archimandritis Hippocration General Hospital, Academic Department of Internal Medicine, Athens, Greece E-mail address: [email protected] (M. Deutsch)
doi:10.1016/j.jhep.2007.08.003
Pharmacological treatment of hepatorenal syndrome: A note of optimism To the Editor: Until recently, hepatorenal syndrome (HRS), a severe complication of advanced liver failure, has been orphan of an effective therapy. Since intrarenal vasoconstriction was the recognized hallmark of patients with HRS [1], any previous attempts of therapy were addressed to vasodilate the kidney vascular bed with low-dose dopamine [2] or other vasodilator drugs such as Captopril [3]. All these attempts failed, however, due to the lack of a selective renal effect, and liver transplantation was the unique effective rescue, although it could be performed in a very few cases. The turning point in the treatment of HRS occurred 20 years ago when the hypothesis of peripheral arterial vasodilation [4] highlighted the importance of vasodilation in extra-renal vascular beds (particularly the splanchnic bed) as a cause of a chain of events leading to marked activation of the vasoconstrictor systems, ascites, and, finally, a irreversible decline of the renal function (Fig. 1). This concept opened the way to two new therapeutic approaches: the first is transjugular intrahepatic portosystemic shunt (TIPS) which corrects portal hypertension and redirects to the heart a part of the blood sluggish in the splanchnic bed [5]; the second is the administration of vasocostrictors which reduce the splanchnic inflow and increase peripheral resistances [6]. Both these treat-
ments are aimed at correcting the effective hypovolemia, de-activate baroreceptors and improve renal blood perfusion. Whereas safe TIPS insertion requires a strict patient selection and less than 50% of patients are suitable for this procedure, the use of vasoconstrictors has few contraindications and then they are considered the firstchoice treatment for any patient with HRS [7]. To date, the most widely used vasoconstrictor is terlipressin, an analogue of vasopressin with lower side effects. The preliminary results of two ongoing randomized controlled trials show that terlipressin + albumin is superior to albumin alone in resolving renal failure but without a significant advantage for short-term survival [8,9]. Drawbacks of terlipressin are its cost and its unavailability on the American market. Therefore, other compounds have been investigated such as midodrine and norepinephrine. However, we are still lacking controlled trials confirming the effectiveness and safety of these two compounds in HRS. Alessandria et al. [10], for the first time, compared the efficacy of norepinephrine and that of terlipressin in a cohort of cirrhotic patients with either HRS type-1 or HRS type-2. Although this is a pilot study with a small sample size and weak statistical power, it provides us with several important clues. The study suggests that the two
730
Letters to the Editor / Journal of Hepatology 47 (2007) 726–731
Portal hypertension
Splanchnic vasodilation + insufficient cardiac output
Effective Hypovolemia
TIPS
cytokines
Bacterial infections
Vasoconstrictors + albumin
Bleeding
RAA, ADH, SNS activation
Intrarenal vasoconstriction
NSAIDs or aminoglycosides Hepatorenal syndrome
Fig. 1. According to the updated peripheral vasodilation hypothesis [7], portal hypertension does start a chain of events which cause intrarenal vasoconstriction and renal failure. Bacterial infection, variceal bleeding and nephrotoxic drugs are three potential triggers of renal failure by enhancing some specific mechanisms reported in this algorithm. TIPS and vasoconstrictors + albumin can block this algorithm at different levels. Continuous red arrows indicate the progression of the algorithm. Dotted red arrows indicate the trigger effect of precipitating factors. Dotted blue arrows indicate where treatments affect the algorithm. Light blue arrow indicates how the activation of vasoconstrictor systems tries to block the pathogenetic cascade.
compounds have comparable efficacy in improving renal function while the cost of therapy is markedly lower with norepinephrine. Surprisingly, norepinephrine did not cause any severe side effect. In particular the authors did not observe the most dreaded cardiac or vascular side effects these compounds can cause. This favorable result might be explained by the fact that patients with advanced cirrhosis can have an altered beta-adrenoreceptor signal transduction with a reduced risk of arrhythmias [11]. Efficacy of norepinephrine is encouraging but it has been obtained in a group largely composed of patients with HRS type-2, the less severe type of HRS. Moreover, the great number of patients who could receive a very early liver transplantation made it impossible to estimate if norepinephrine treatment can really prolong survival. Indeed, seven of the 10 patients who received norepinephrine were transplanted within the first month, a time span lower than the average survival of historical patients with HRS type-2. Therefore, we need to re-evaluate the survival and the chance of transplantation in a greater group of patients with HRS type-1. Interestingly, 14 of the 36 patients taken into consideration for the trial were excluded because they were responsive to a blood volume expansion obtained with albumin infusion. This confirms, if still necessary, how critical the diagnosis of HRS is and how important it is to exclude that a sufficient expansion of the blood volume corrects renal failure. For this purpose albumin is now recommended instead of saline solution [7]. Moreover, the study by Alessandria et al. [10] shows a great
variability in the doses of albumin needed to obtain a central venous pressure (CVP) between 10 and 15 cm H2O. This finding undermines the indication to give albumin at predefined doses not only in the therapy of HRS, but also in other critical conditions such as the prevention of HRS in patients with spontaneous bacterial peritonitis [12] or the prevention of paracentesis-induced circulatory dysfunction [13]. The use of doses of albumin individually titrated could also explain the high rate of success obtained both with norepinephrine and terlipressin by the authors [10]. Lastly, the study did not identify any predictive factor of treatment success and confirmed that in many patients renal failure recurs after withdrawal of pharmacological therapy. This corroborates the policy to try the pharmacological therapy in any cirrhotic patient with HRS independently of the degree of renal and hepatic dysfunctions, to adjust albumin infusion by the CVP values, and to closely control renal function after stopping treatment because retreatment is highly effective in case of recurrence. In conclusion, although the interpretation of the results of this trial deserves confirmation due to the limited number of patients and the inclusion of both type-1 and type-2 HRS, it gives us some important new information: norepinephrine is a safe drug in most patients with advanced cirrhosis, albumin is essential for both diagnosing and treating HRS, the doses of albumin needed are rather different from patient to patient and measurement of CVP can be useful to reach a sufficient dose of albumin, the diagnosis of HRS deserves particular attention to satisfy all the related criteria.
References [1] Epstein M, Berk DP, Hollemberg NK, Adams DF, Chalmers T, Abrams HL, et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 1970;49:175–185. [2] Wilson JR. Dopamine in the hepatorenal syndrome. JAMA 1977;238:2719–2720. [3] Daskalopoulos G, Pinzani M, Murray N, Hirschberg R, Zipser RD. Effects of captopril on renal function in patients with cirrhosis and ascites. J Hepatol 1987;4:330–336. [4] Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of sodium and water retention in cirrhosis. Hepatology 1988;8:1151–1157. [5] Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, et al. Long-term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotic with hepatorenal syndrome: a phase II study. Gut 2000;47:288–295. [6] Moreau R, Durand, Poynard T, Duhamel C, Cervoni JP, Ichai P, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002;122:923–930. [7] Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318. [8] Sanyal A, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Teuber P, et al. A prospective randomized double-blind,
Letters to the Editor / Journal of Hepatology 47 (2007) 726–731
[9]
[10]
[11]
[12]
placebo-controlled trial of terlipressin for typ 1 hepatorenal syndrome (HRS). Hepatology 2006;44:694A. Martin-Llahi M, Pepin MN, Guevara M, Torre A, Monescillo A, Soriano G, et al. Randomized comparative study of terlipressin and albumin vs albumin alone in patients with cirrhosis and hepatorenal syndrome. J Hepatol 2007;46:S36. Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Torrani Cerenzia M, Martini S, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblended, pilot study. J Hepatol 2007;47:499–505. Ma Z, Miyamoto A, Lee SS. Role of altered beta-adrenoceptor signal transduction in the pathogenesis of cirrhotic cardiomyopathy in rats. Gastroenterology 1996;110:1191–1198. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-delArbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;5:403–409.
731
[13] Gines A, Fernandez-Esparrach G, Monescillo A, Vila C, Domenech E, Abecasis R, et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 1996;111:1002–1010.
Francesco Salerno Massimo Cazzaniga Giulia Gobbo Medicina Interna, Policlinico IRCCS San Donato, Universita` di Milano, Via Morandi, 30, 20097 San Donato Milanese, Italy E-mail address: [email protected] (F. Salerno) doi:10.1016/j.jhep.2007.08.004
Prothrombintime (sec)
250
729
important and needs further verification in a large number of patients.
200
patient deceased patient deceased
150
patient transplanted
Reference
patient listed and spontaneously recovered
[1] Escudie L, Francoz C, Vinel JP, Moucari R, Cournot M, Paradis V, et al. Amanita phalloides poisoning: reassessment of prognostic factors and indication for emergency liver transplantation. J Hepatol 2007;47:466–473.
100 50
two patients recovered
0 0
6
12
18
24
30
36
Hours of follow up
Fig. 1. The pattern of Prothrombin time every 6 h during follow up.
All patients had the worst prognostic factor: onset of diarrhea and nausea in less than 8 h following mushroom ingestion, and the proportion of those who died or were transplanted was 50%. The most important difference between the two groups of patients was the pattern of prothrombin time elevation during the first hours of follow-up. We believe that this clinical observation is
Melanie Deutsch John Koskinas Dimitris Kountouras Athanasios J. Archimandritis Hippocration General Hospital, Academic Department of Internal Medicine, Athens, Greece E-mail address: [email protected] (M. Deutsch)
doi:10.1016/j.jhep.2007.08.003
Pharmacological treatment of hepatorenal syndrome: A note of optimism To the Editor: Until recently, hepatorenal syndrome (HRS), a severe complication of advanced liver failure, has been orphan of an effective therapy. Since intrarenal vasoconstriction was the recognized hallmark of patients with HRS [1], any previous attempts of therapy were addressed to vasodilate the kidney vascular bed with low-dose dopamine [2] or other vasodilator drugs such as Captopril [3]. All these attempts failed, however, due to the lack of a selective renal effect, and liver transplantation was the unique effective rescue, although it could be performed in a very few cases. The turning point in the treatment of HRS occurred 20 years ago when the hypothesis of peripheral arterial vasodilation [4] highlighted the importance of vasodilation in extra-renal vascular beds (particularly the splanchnic bed) as a cause of a chain of events leading to marked activation of the vasoconstrictor systems, ascites, and, finally, a irreversible decline of the renal function (Fig. 1). This concept opened the way to two new therapeutic approaches: the first is transjugular intrahepatic portosystemic shunt (TIPS) which corrects portal hypertension and redirects to the heart a part of the blood sluggish in the splanchnic bed [5]; the second is the administration of vasocostrictors which reduce the splanchnic inflow and increase peripheral resistances [6]. Both these treat-
ments are aimed at correcting the effective hypovolemia, de-activate baroreceptors and improve renal blood perfusion. Whereas safe TIPS insertion requires a strict patient selection and less than 50% of patients are suitable for this procedure, the use of vasoconstrictors has few contraindications and then they are considered the firstchoice treatment for any patient with HRS [7]. To date, the most widely used vasoconstrictor is terlipressin, an analogue of vasopressin with lower side effects. The preliminary results of two ongoing randomized controlled trials show that terlipressin + albumin is superior to albumin alone in resolving renal failure but without a significant advantage for short-term survival [8,9]. Drawbacks of terlipressin are its cost and its unavailability on the American market. Therefore, other compounds have been investigated such as midodrine and norepinephrine. However, we are still lacking controlled trials confirming the effectiveness and safety of these two compounds in HRS. Alessandria et al. [10], for the first time, compared the efficacy of norepinephrine and that of terlipressin in a cohort of cirrhotic patients with either HRS type-1 or HRS type-2. Although this is a pilot study with a small sample size and weak statistical power, it provides us with several important clues. The study suggests that the two
730
Letters to the Editor / Journal of Hepatology 47 (2007) 726–731
Portal hypertension
Splanchnic vasodilation + insufficient cardiac output
Effective Hypovolemia
TIPS
cytokines
Bacterial infections
Vasoconstrictors + albumin
Bleeding
RAA, ADH, SNS activation
Intrarenal vasoconstriction
NSAIDs or aminoglycosides Hepatorenal syndrome
Fig. 1. According to the updated peripheral vasodilation hypothesis [7], portal hypertension does start a chain of events which cause intrarenal vasoconstriction and renal failure. Bacterial infection, variceal bleeding and nephrotoxic drugs are three potential triggers of renal failure by enhancing some specific mechanisms reported in this algorithm. TIPS and vasoconstrictors + albumin can block this algorithm at different levels. Continuous red arrows indicate the progression of the algorithm. Dotted red arrows indicate the trigger effect of precipitating factors. Dotted blue arrows indicate where treatments affect the algorithm. Light blue arrow indicates how the activation of vasoconstrictor systems tries to block the pathogenetic cascade.
compounds have comparable efficacy in improving renal function while the cost of therapy is markedly lower with norepinephrine. Surprisingly, norepinephrine did not cause any severe side effect. In particular the authors did not observe the most dreaded cardiac or vascular side effects these compounds can cause. This favorable result might be explained by the fact that patients with advanced cirrhosis can have an altered beta-adrenoreceptor signal transduction with a reduced risk of arrhythmias [11]. Efficacy of norepinephrine is encouraging but it has been obtained in a group largely composed of patients with HRS type-2, the less severe type of HRS. Moreover, the great number of patients who could receive a very early liver transplantation made it impossible to estimate if norepinephrine treatment can really prolong survival. Indeed, seven of the 10 patients who received norepinephrine were transplanted within the first month, a time span lower than the average survival of historical patients with HRS type-2. Therefore, we need to re-evaluate the survival and the chance of transplantation in a greater group of patients with HRS type-1. Interestingly, 14 of the 36 patients taken into consideration for the trial were excluded because they were responsive to a blood volume expansion obtained with albumin infusion. This confirms, if still necessary, how critical the diagnosis of HRS is and how important it is to exclude that a sufficient expansion of the blood volume corrects renal failure. For this purpose albumin is now recommended instead of saline solution [7]. Moreover, the study by Alessandria et al. [10] shows a great
variability in the doses of albumin needed to obtain a central venous pressure (CVP) between 10 and 15 cm H2O. This finding undermines the indication to give albumin at predefined doses not only in the therapy of HRS, but also in other critical conditions such as the prevention of HRS in patients with spontaneous bacterial peritonitis [12] or the prevention of paracentesis-induced circulatory dysfunction [13]. The use of doses of albumin individually titrated could also explain the high rate of success obtained both with norepinephrine and terlipressin by the authors [10]. Lastly, the study did not identify any predictive factor of treatment success and confirmed that in many patients renal failure recurs after withdrawal of pharmacological therapy. This corroborates the policy to try the pharmacological therapy in any cirrhotic patient with HRS independently of the degree of renal and hepatic dysfunctions, to adjust albumin infusion by the CVP values, and to closely control renal function after stopping treatment because retreatment is highly effective in case of recurrence. In conclusion, although the interpretation of the results of this trial deserves confirmation due to the limited number of patients and the inclusion of both type-1 and type-2 HRS, it gives us some important new information: norepinephrine is a safe drug in most patients with advanced cirrhosis, albumin is essential for both diagnosing and treating HRS, the doses of albumin needed are rather different from patient to patient and measurement of CVP can be useful to reach a sufficient dose of albumin, the diagnosis of HRS deserves particular attention to satisfy all the related criteria.
References [1] Epstein M, Berk DP, Hollemberg NK, Adams DF, Chalmers T, Abrams HL, et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 1970;49:175–185. [2] Wilson JR. Dopamine in the hepatorenal syndrome. JAMA 1977;238:2719–2720. [3] Daskalopoulos G, Pinzani M, Murray N, Hirschberg R, Zipser RD. Effects of captopril on renal function in patients with cirrhosis and ascites. J Hepatol 1987;4:330–336. [4] Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of sodium and water retention in cirrhosis. Hepatology 1988;8:1151–1157. [5] Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, et al. Long-term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotic with hepatorenal syndrome: a phase II study. Gut 2000;47:288–295. [6] Moreau R, Durand, Poynard T, Duhamel C, Cervoni JP, Ichai P, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002;122:923–930. [7] Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318. [8] Sanyal A, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Teuber P, et al. A prospective randomized double-blind,
Letters to the Editor / Journal of Hepatology 47 (2007) 726–731
[9]
[10]
[11]
[12]
placebo-controlled trial of terlipressin for typ 1 hepatorenal syndrome (HRS). Hepatology 2006;44:694A. Martin-Llahi M, Pepin MN, Guevara M, Torre A, Monescillo A, Soriano G, et al. Randomized comparative study of terlipressin and albumin vs albumin alone in patients with cirrhosis and hepatorenal syndrome. J Hepatol 2007;46:S36. Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Torrani Cerenzia M, Martini S, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblended, pilot study. J Hepatol 2007;47:499–505. Ma Z, Miyamoto A, Lee SS. Role of altered beta-adrenoceptor signal transduction in the pathogenesis of cirrhotic cardiomyopathy in rats. Gastroenterology 1996;110:1191–1198. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-delArbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;5:403–409.
731
[13] Gines A, Fernandez-Esparrach G, Monescillo A, Vila C, Domenech E, Abecasis R, et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 1996;111:1002–1010.
Francesco Salerno Massimo Cazzaniga Giulia Gobbo Medicina Interna, Policlinico IRCCS San Donato, Universita` di Milano, Via Morandi, 30, 20097 San Donato Milanese, Italy E-mail address: [email protected] (F. Salerno) doi:10.1016/j.jhep.2007.08.004