doi:10.1111/j.1440-1746.2010.06583.

REVIEW

Terlipressin in hepatorenal syndrome: Evidence for present indications

_6583 109..114

Harshal Rajekar* and Yogesh Chawla

*Department of General Surgery, and Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh-160012, India

Key words hepatorenal syndrome, renal failure in cirrhosis, Terlipressin. Correspondence Dr. Y Chawla, Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarrh-160012, India. Email: ykchawla@gmail.com Conict of interest No conict of interest to disclose.

Abstract
Hepatorenal syndrome (HRS) is the most frequent life threatening complication of advanced liver failure and cirrhosis. HRS results from a functional renal dysfunction due to circulatory disturbances in patients with advanced liver disease and portal hypertension. Reduction in the effective circulating blood volume and hence hypoperfusion of the kidney is the basic underlying common pathogenetic mechanism for the development of hepatorenal syndrome. The prognosis for HRS remains very poor with types 1 and 2both having an expected survival time of 2 weeks and 6 months, respectively. Although the available data are derived from studies including a limited number of patients mainly affected by type 1 HRS, vasoconstrictor drugs, in particular the vasopressin analog Terlipressin, seem to be the most effective approach for the management of HRS. Associated with albumin infusion, these drugs have been shown to lead to reduced mortality and improved renal function in HRS. Terlipressin administration signicantly increases mean arterial pressure and systemic vascular resistance; while the heart rate, cardiac output, HVPG and portal venous blood ow decrease signicantly. This decrease correlates well with the decrease in plasma renin activity. Thus the vasoconstrictor effect of Terlipressin reverses the basic pathology of HRS by reducing the plasma renin activity. The improvement in hemodynamics with Terlipressin is associated with an increase in glomerular ltration rate and deactivation of the vasoconstrictor and sodium-conserving hormones with reduced activity of the RAAS resulting in increased natriuresis. Terlipressin thus reverses HRS and is useful in bridging the patient to liver transplantation and may hence indirectly improve survival. Patients with HRS who show an improvement in renal function with Terlipressin and albumin seem to have an excellent posttransplantation outcome similar to that of patients without HRS. Thus, the use of Terlipressin has been shown to be safe, with minimal side effects that usually disappear after dose reduction, and results in an improved outcome in patients with HRS.

Hepatorenal Syndrome (HRS) was rst recognized in cirrhosis by Hecker and Sherlock in 1956.1 All nine of their patients died, with postmortem examination of the kidneys showing normal histology. They proposed that HRS is caused by a reduction in renal perfusion secondary to systemic arterial vasodilation. HRS is now increasingly being recognized as a form of renal dysfunction in the setting of liver failure. It is the most frequent fatal complication of cirrhosis with nearly 50% of patients dying within 2 weeks of this diagnosis.2 Development of ascites in patients with MELD scores of 10 is associated with an 8% and 11% risk of HRS at 1 and 5 years, respectively.3 At a MELD score of 18 or more nearly 40% of patients are expected to develop HRS within a year.4 HRS has also been seen in 30% of patients with severe acute alcoholic hepatitis and in 55% in fulminant liver failure.5,6 HRS responds relatively poorly to treatment and the outcome is poor in the absence of liver transplantation, though

recent advances in medical management including treatment with vasoconstrictors have resulted in an improved prognosis.

Denition of HRS
HRS is characterized by severe renal arterial vasoconstriction, which develops in decompensated cirrhosis or acute liver failure (ALF) with no other underlying pathology responsible for the worsening of renal function. The denition, developed in 1996, has been recently updated to include albumin as a volume expander. The major diagnostic criteria for hepatorenal syndrome include:79 1 Chronic or acute liver disease with advanced hepatic failure and portal hypertension. 2 Serum creatinine > 1.5 mg/dL, reecting decreased glomerular ltration rate.
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3 Absence of shock, bacterial infection, and current or recent treatment with nephrotoxic drugs; absence of gastrointestinal or renal uid losses. 4 No sustained improvement in renal function (decrease in serum creatinine to <1.5 mg/dL) after diuretic withdrawal and plasma volume expansion with intravenous albumin (1 g/kg body weight up to a maximum of 100 g).9,10 5 Proteinuria < 500 mg/dL and no evidence of parenchymal renal disease by urinalysis, or of obstructive uropathy by ultrasonography. Minor diagnostic criteria for hepatorenal syndrome: i. ii. iii. iv. v. Urine volume < 500 mL/24 h Urine sodium < 10 mEq/L Urine osmolality greater than plasma osmolality Urine red blood cells < 50 per high power eld Serum sodium < 130 mEq/L

pre-existing renal disease do not meet the traditional diagnostic criteria for HRS and are not included in therapeutic clinical trials.79 It is unclear whether a chronically reduced baseline GFR, from chronic intrinsic renal disease, predisposes cirrhotic patients to develop HRS. In selected cases renal biopsy may be necessary for diagnosis and for selection of patients for combined liverkidney transplant.

Type 4 hepatorenal syndrome: acute liver failure

Patients with ALF develop HRS, although the frequency varies depending on the ALF etiology.10 Both organ failures can usually be reversed by urgent liver transplantation. The pathophysiology of HRS in ALF is believed to be similar to that postulated for HRS occurring in cirrhosis, but this contention remains speculative in the absence of pathophysiologic studies.

The minor criteria are supportive but not required for the diagnosis. Five major criteria must all be present for the diagnosis of HRS..8,9,11 Though usually oliguric, non-oliguric HRS (urine volumes > 500 mL/d) and HRS with urinary sodium excretion greater than 10 mEq/L can occur.1214

Pathophysiology
Type 1 hepatorenal syndrome
Studies over the last decade have helped in better understanding the pathophysiology of HRS.8,1820 Both chronic liver disease and ALF cause portal hypertension, which leads to arterial vasodilatation and pooling of blood in the splanchnic bed, with a decrease in systemic vascular resistance. Hyperdynamic circulation and activation of the renin-angiotensin system ensues to maintain arterial blood pressure. Circulatory disturbances progressively worsen till systemic hemodynamic stability depends on vasoconstriction of the extra-splanchnic vascular beds (e.g. renal, brain, muscle, skin, etc.). As liver failure worsens, prolonged activation of the reninangiotensin-aldosterone system leads to renal vasoconstriction, resulting in decreased renal perfusion, decreased GFR and rising serum creatinine levels. Intra-renal vasoactive mediators, such as prostaglandins, kallikrein, adenosine, leukotrienes, F2-isoprostanes, and endothelin, may play an important role in this severe and sustained renal vasoconstriction.2124 Cardiac and adrenal dysfunction may contribute to circulatory disturbances in type 1 HRS.8,25 Unlike compensated cirrhotics without renal failure, the cardiac output is normal or even subnormal in patients with HRS.19,20

Clinical presentation and classication

Patients with liver failure can develop two distinct clinical forms of HRS, designated as type 1 and type 2, based on the time course and precipitating factors. An additional type 3 and type 4 have also been described but not adequately studied.

Type 1 hepatorenal syndrome

The serum creatinine level doubles to greater than 2.5 mg/dL within 2 weeks in type 1 HRS The key features are the rapid progression and high mortality, with a median survival of only 1 to 2 weeks.3,8 It may be precipitated by bacterial infection like spontaneous bacterial peritonitis, variceal hemorrhage, major surgery, acute alcoholic hepatitis, or acute hepatic injury superimposed on cirrhosis. The acute hepatic decompensation can occur from acute viral hepatitis; drug-induced liver injury (acetaminophen; idiopathic drug-induced hepatitis); or hepatic ischemia.

Type 2 hepatorenal syndrome

In type 2 HRS, renal failure as evidenced by a rising serum creatinine develops over several weeks or months with a reciprocal gradual reduction in glomerular ltration rate (GFR) in the absence of a precipitating factor. The median survival of type 2 HRS is about 6 months, which is signicantly longer than for type 1 HRS.15 Many patients with type 2 HRS eventually progress to type 1 HRS because of a precipitating factor or without an obvious precipitating factor other than worsening liver failure. The mechanisms of this progression are not clear.

Type 2 hepatorenal syndrome

Similar hemodynamic and humoral abnormalities described for type 1 HRS are also seen in type 2 HRS, but are present to a lesser extent. Gradually deteriorating liver function results in progressive circulatory dysfunction, which progressively leads to reduction in renal perfusion and GFR.

Management of Hepatorenal syndrome Type 3 hepatorenal syndrome: coexistent kidney disease and hepatorenal syndrome
A recent study found that 85% of end-stage cirrhotics had preexisting intrinsic renal disease on renal biopsy.16,17 Patients with
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The ideal treatment of HRS should aim to improve renal function or reverse HRS, prolong survival and increase the likelihood of receiving a liver transplant in appropriate candidates with acceptable adverse effects.

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Type 1 HRS should be diagnosed early, with aggressive treatment of the precipitating event, and management of any complications. Therapy includes supportive with maintenance of euvolemia, adequate hydration, discontinuation of diuretics and other nephrotoxic medications including NSAIDS and aminoglycosides, and withholding any vasodilators. Sepsis should be identied and treated, and likewise gastrointestinal bleeding should be managed appropriately. Many studies conducted during the last decade have suggested that vasopressor therapy plus volume expansion with intravenous albumin improves the prognosis of HRS. Though these results may be subject to sampling bias because of inconsistent study inclusion criteria26,27 prudent use of this combined therapy seems justied in type 1 HRS. In some reports, responders to vasoconstrictor plus albumin therapy had improved survival, and a signicant proportion of patients were successfully bridged to liver transplantation.2832 The vasoconstrictors that have been used in HRS include omnipressin and vasopressin which have reported a moderate success but have been reported to be associated with an unacceptable rate of ischemic adverse effects. Norepinephrine may be an effective alternative to vasopressin analogs for the management of HRS. However more data is needed before it can be recommended. The effects of noradrenaline on splanchnic vasculature and portal pressure are unclear as yet. The drug mostly used in treatment of HRS is Terlipressin. Terlipressin is a prohormone of lysine-VP (three glycyl residues and lysine-VP). Following intravenous administration, the glycyl residues are cleaved from the prohormone by endothelial peptidases allowing prolonged release of lysine-VP.33,34 This mechanism prolongs the half-life of Terlipressin, enabling administration in divided doses without the need for an infusion as with vasopressin, and minimizes systemic toxicity. Terlipressin is not yet approved by the Food and Drug Administration (FDA) in the USA for use in HRS, though it is commonly used in Europe and Asia. Terlipressin administration after 30 min has been shown to signicantly increase mean arterial pressure and systemic vascular resistance while the heart rate, cardiac output, HVPG portal venous blood ow decreases signicantly. The hepatic and renal arterial resistance indices decrease and correlate well with a decrease in plasma renin activity. This effect is seen both in patients with and without ascites.35 Studies have shown a fall in EF and CO by -16% and -17%, respectively, while myocardial perfusion and stroke volume remains unaltered with Terlipressin.36 Terlipressin has afnity for both V1 and V2 receptors. Terlipressin selectively causes splanchnic and extra-renal vasoconstriction by stimulation of V1 receptors,37 which are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region38 and thereby reduces the splanchnic blood ow and portal pressure. Reduction in portal pressure results in reduction of NO levels and improvement in the hyperdynamic circulation.33,39 This improves the effective circulatory volume and renal perfusion pressure.39,40 V2 receptor stimulation by Terlipressin mediates water transport in the renal collecting ducts by increasing the number of aquaporin-2 water channels in the apical plasma membrane.41 Krag et al. were able to show that Terlipressin reduces free water clearance by way of their afnity to V2 receptors.36 This antidiuretic effect of Terlipressin may be clinically signicant in the context of HRS. Terlipressin thus counteracts the

systemic vasodilatation and hence increases blood pressure and thereby improves renal perfusion and renal function. Krag et al. showed that the improved hemodynamics with Terlipressin is associated with an increase in GFR and deactivation of the vasoconstrictor and sodium-conserving hormones (i.e. norepinephrine and renin) with reduced activity of the RAAS resulting in increased natriuresis.36 The natriuretic effect of Terlipressin is enhanced by decreased sympathetic activity (decreased plasma norepinephrine), decreased renin secretion, and increased atrial natriuretic peptide (ANP) secretion. High activity in the sympathetic nervous system decreases RBF by renal arterial vasoconstriction through alpha-1-adrenergic receptors, and increases sodium reabsorption and renin secretion by effects on the juxtaglomerular cells.42,43 This seems to be reversed by Terlipressin. The mechanism of release of ANP from the heart is mainly facilitated by an increase in the effective circulating volume and atrial lling pressures. It has also been shown that ANP secretion increases in response to vasopressin analogs and pressor agents,44 which might be unrelated to the circulatory effects of these agents. In a recent meta-analysis, Sagi et al. inferred that therapy with Terlipressin and albumin improves the renal function in patients with cirrhosis and HRS type 1.45 The improvement seen with Terlipressin therapy was sustained in most of the patients for the duration of follow-up (90 to 180 days). There was a trend towards improvement in overall and transplant-free survival in the Terlipressin group. Another recent meta-analysis has shown that vasoconstrictive drugs alone decreased mortality to 58% without albumin versus 74% with albumin but this has been fraught with inter-trial heterogeneity. The effect on mortality was seen at 15 days (RR 0.60) but not at 30 days, 90 days or 180 days Subgroup analysis showed that Terlipressin plus albumin decreased mortality compared to albumin alone (RR 0.81). Moreover survival benet was seen in only type 1 HRS but not type 2 HRS.46 Sagi et al.45 reported a pooled percentage of HRS reversal as 46% and recurrence in 8% reversal and 55% recurrence compared with 52% reported previously by Fabrizi et al.47 This probably reects the longer duration of therapy and a longer follow-up in the studies by Sagi et al. Terlipressin therapy appeared safe and well tolerated with only a few serious adverse events. Two previous meta-analyses have also reported improved efcacy of Terlipressin in the treatment of HRS.47,48 Cochrane meta-analysis in 2005 which included a small number of patients also suggested a survival advantage in HRS with Terlipressin. A randomized, prospective, placebo-controlled clinical trial by Sanyal et al. used Terlipressin at doses of 1 mg intravenously every 6 h until the serum creatinine level decreased to less than 1.5 mg/dL on two measurements 48 h apart, or for up to 14 days49,50 If after 3 days the serum creatinine did not decline by at least 30% from baseline, the dose of Terlipressin was increased to 2 mg every 6 h. In this clinical trial, Terlipressin was signicantly more effective than placebo in reversing type 1 HRS with a similar safety prole.49,50 A later report from the same group demonstrated that earlier therapy with Terlipressin increases the probability of HRS reversal, whereas patients with a baseline serum creatinine greater than 5.6 mg/dL had no reversal of HRS in this study. The minimum duration for successful therapy was 3 to 5 days.28,50 Prolongation of treatment beyond 7 days up to 20 days has been shown to increase the response rates with Terlipressin and albumin.
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A recent study from Mexico showed an improvement in urinary Na excretion and normalization of serum Na in patients given Terlipressin and albumin. Response was seen in 61% of patients. In responders the survival was 112.8 days in contrast to 11 days in non-responders.51 In most of the studies Terlipressin has been used as a bolus but a study has suggested continuous infusion as an alternative to IV bolus administration. In 32 consecutive patients with HRS continuous IV Terlipressin with a starting dose 3 mg/day and albumin 2030 g/day when given for 11 2 days reversed HRS in 42% with cardiovascular adverse events in 9% only. This response was as good as daily bolus dose but had lower severe complications.52 Survival in HRS has been attributed to different predictive factors as suggested by different studies. Colle et al. have found that three factors predicted survival, namely: (i) Terlipressin at least 3 mg/ day; (ii) absence of HRS precipitating factors; and (iii) improved renal function during Terlipressin therapy.53 Moreau et al. found a decrease in survival predicted by a decrease in creatinine < 20% and a CTP score of 11 or more on day 054 Sanyal et al. attributed alcoholic hepatitis, MELD, CTP score and creatinine at baseline.50 Nazar et al. identied that the probability of survival at 3 months after developing HRS was signicantly greater in patients who responded to Terlipressin compared with non-responders (44% and 14%, respectively; median survival, 70 days and 7 days, respectively; P < 0.001).55 They also identied that serum bilirubin levels and an early increase in arterial pressure predict response to treatment with Terlipressin and albumin in type 1 HRS. This observation is consistent with previous studies showing that response to treatment is associated with an improvement of circulatory function that is markedly impaired in patients with HRS.28,49,53,54,5658 Terlipressin has been shown to improve even patients with renal failure who do not t into the criteria of HRS. In patients with renal failure in cirrhosis who had a renal response with an improvement in creatinine concentration at 4 days, 69% survived for 6 weeks after the start of Terlipressin therapy, compared with 46%.59 The treatment duration of Terlipressin therapy is uncertain at present. Retrospective analysis of the pivotal Terlipressin trial in HRS has shown that a response is usually seen during the rst 2 days of therapy and in all responders by day 4. If there is no response by day 4, treatment may be discontinued.60 Albumin has been shown to markedly improve the benecal effects of Terlipressin.57 In the study by Triantos et al. albumin was started before Terlipressin therapy, which when stopped had similar outcomes compared with those in whom it was continued.59 Available literature shows that not all patients with HRS respond to Terlipressin therapy. The lack of benet for HRS in some patients may be related to severity of liver failure (higher the MELD lower the response) or due to a decrease in CO seen with vasoconstrictors.61 Reasons for the lack of improvement of systemic hemodynamics in some patients treated with Terlipressin are unknown but may include increased levels of vasodilator cytokines, increased bacterial products or latent infections, and presence of concomitant adrenal insufciency. These possible causes deserve investigation in order to improve the efcacy of treatment. Patients who revert back to HRS after initial improvement with Terlipressin and albumin may be given therapy for as long as 62 days to 8 months while awaiting orthotopic liver transplantation (OLT), with no major side effects in spite of switching to octreotide and midodrine.62
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The treatment protocol of Terlipressin for hepatorenal syndrome includes an initial dose: 1 mg intravenous bolus every 4 h. At day 3 if baseline serum creatinine is not reduced by > 25%, increase Terlipressin dose up to 2 mg every 4 h. IV albumin is given as needed to maintain central venous pressure of 1015 cm. H2O treatment is advocated until reversal of HRS or a maximum of 2 weeks. Therapy can be repeated if HRS recurs. Diuretics are not used during vasoconstrictor plus albumin therapy in most of the protocols, but others have used furosemide in combination with albumin to keep central venous pressure within desirable range.13 If patients develop uid overload during treatment with Terlipressin, treatment with furosemide is benecial in reducing circulatory overload. Type 2 HRS is more commonly seen in clinical practice than type 1 HRS and liver transplantation can potentially permanently reverse HRS and other complications of chronic liver failure. In four small pilot studies of therapy with Terlipressin and albumin53,58,63 and one prospective controlled trial of therapy with noradrenaline plus albumin,28 the combined reversal rate of type 2 HRS was about 80% which, however, frequently recurred after discontinuation of therapy. Further studies are thus required to evaluate the efcacy of Terlipressin with or without albumin for type 2 HRS. Currently, intravenous vasoconstrictor therapy can be cautiously considered in selected patients with type 2 HRS. A liver transplant is substantially more benecial if HRS is reversed by vasoconstrictor and albumin therapy before transplantation.29 Beta receptor antagonism in a patient with HRS may be undesirable because of the effects on hemodynamics through a reduction in cardiac output, but may be desirable because of the antirenin effect of these agents. Propranolol may also have a benecial effect on the circulatory hemodynamics by reduction of portal pressure. Duhamel and colleagues64 suspected that propranolol therapy may have precipitated HRS in 3 of 12 analyzed patients. Responders to beta receptor antagonists had a lower risk of developing HRS in one study.29 Most experts believed that beta receptor antagonists should be discontinued during HRS, but there is no evidence to support this. Other treatment modalities that have been tried in HRS include (a) midodrine and octreotide: An oral alpha-adrenergic agonist (midodrine) in combination with octreotide has been shown to improve type 1 HRS with results comparable with those reported for Terlipressin.12,65 Midodrine is a direct vasoconstrictor, whereas octreotide inhibits endogenous vasodilators. (b) Transjugular intrahepatic portosystemic shunt (TIPS) is a theoretically attractive therapy because it dramatically lowers both the portal pressure and the pooling of blood in the splanchnic vascular bed a key pathogenetic factor in HRS. However, many patients with type 1 HRS would not meet the usual criteria for TIPS insertion (i.e. serum bilirubin < 5 mg/dL, INR < 2, and Childs-Pugh score < 12).

Conclusion
Terlipressin reverses HRS and is useful in bridging the patient to liver transplantation and may hence indirectly improve survival. Patients with HRS treated with Terlipressin prior to transplantation

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may have a survival advantage. However, in an organ allocation system based on the MELD score, improvement in creatinine levels will result in a reduction in the MELD score and reduce the chances of getting an organ at the earliest. How this eventually affects the patient survival and chances of getting transplanted remains to be seen. The observation by Restuccia et al. that patients with HRS who show an improvement in renal function with Terlipressin and albumin have an excellent posttransplantation outcome similar to that of patients without HRS29 suggest that Terlipressin plus albumin is an effective therapeutic option for patients with HRS awaiting liver transplantation.

References
1 Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal liver failure. Lancet. 1956; 271: 11215. 2 Nguyen GC, Sergev DL, Thuluvath PJ. Nationwide increase in hospitalizations and hepatitis among inpatients with cirrhosis and sequelae of portal hypertension. Clin. Gastroenterol. Hepatol. 2007; 5: 10929. 3 Planas R, Montoliu S, Balleste B et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin. Gastroenterol. Hepatol. 2006; 4: 138594. 4 Fernandez J, Navasa M, Planas R et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007; 133: 81824. 5 Moore K. Renal failure in acute liver failure. Eur. J. Gastroenterol. Hepatol. 1999; 11: 96775. 6 Verma S, Ajudia K, Mendler M et al. Prevalence of septic events, type 1 hepatorenal syndrome, and mortality in severe alcoholic hepatitis and utility of discriminant function and MELD score in predicting these adverse events. Dig. Dis. Sci. 2006; 51: 163743. 7 Arroyo V, Gines P, Gerbes A et al. Denition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology. 1996; 23: 16476. 8 Arroyo V, Terra C, Gines P. Advances in the pathogenesis and treatment of type 1 and type-2 hepatorenal syndrome. J. Hepatol. 2007; 46: 93546. 9 Salerno F, Gerbes A, Gines P et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007; 56: 13108. 10 Salerno F, Cazzaniga M, Gobbo G. Pharmacological treatment of hepatorenal syndrome: a note of optimism. J. Hepatol. 2007; 47: 72931. 11 Runyon B. AASLD Practice Guideline: management of adult patients with refractory ascites. Hepatology. 2004; 39: 84156. 12 Wong F, Pantea L, Sniderman K et al. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2004; 40: 5564. 13 Duvoux C, Zanditenas D, Hezode C et al. Effects of noradrenaline and albumin in patients with type 1 hepatorenal syndrome: a pilot study. Hepatology. 2002; 36: 37480. 14 Dudley F, Kanel G, Wood L et al. Hepatorenal syndrome without avid sodium retention. Hepatology. 1986; 6: 24851. 15 Alessandria C, Ozdogan O, Guevara M et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005; 41: 12829. 16 McGuire B, Julian B, Bynon S et al. Brief communication: glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation. Ann. Intern. Med. 2006; 144: 73541. 17 McGuire B, Julian B, Novak J et al. High prevalence of glomerulonephritis in patients with end-stage HCV-induced cirrhosis. Hepatology. 2007; 46: 474A.

18 Wadei HM, Mai ML, Ashan N et al. Hepatorenal syndrome: pathophysiology and management. Clin. J. Am. Soc. Nephrol. 2006; 1: 106679. 19 Ruiz-del-Arbol L, Monescillo A, Arocena C et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005; 42: 43947. 20 Ruiz-del-Arbol W, Urman J, Fernandez J et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology. 2003; 38: 12108. 21 Schroeder E, Eich R, Smulyan H et al. Plasma renin in hepatic cirrhosis: relation to functional renal failure. Am. J. Med. 1970; 49: 18691. 22 Arroyo V, Planas R, Gaya J et al. Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin-E2 in cirrhosis: relationship to functional renal failure, and sodium and water excretion. Eur. J. Clin. Invest. 1983; 13: 2718. 23 Rimola A, Gines P, Arroyo V et al. Urinary excretion of 6-keto prostaglandin F1-alpha, thromboxane B-2 and prostaglandin E2 in cirrhosis with ascites: relationship to functional renal failure (hepatorenal syndrome). J. Hepatol. 1986; 3: 1117. 24 Llach J, Gines P, Arroyo V et al. Effect of dipyridamole on kidney function in cirrhosis. Hepatology. 1993; 17: 5964. 25 Lenz K. Hepatorenal syndrome: is it central hypovolemia, a cardiac disease, or part of gradually developing multiorgan dysfunction? Hepatology. 2005; 42: 2635. 26 Gluud L, Kjaer M, Christensen E et al. Terlipressin for hepatorenal syndrome. Cochrane Database Syst. Rev. 2006; 4: CD005162. 27 Tandon P, Bain VG, Tsuyuki RT et al. Systematic review: renal and other clinically relevant outcomes in hepatorenal syndrome trials. Aliment. Pharmacol. Ther. 2007; 25: 101728. 28 Alessandria C, Ottobrelli A, Debernardi-Venon W et al. Noradrenaline vs Terlipressin in patients with hepatorenal syndrome: a prospective randomized unblinded pilot study. J. Hepatol. 2007; 47: 499505. 29 Restuccia T, Ortega R, Guevara M et al. Effects of treatment of hepatorenal syndrome before transplantation on post transplantation outcome: a case-control study. J. Hepatol. 2004; 40: 1406. 30 Martin-Llahi M, Pepin M, Guevara M et al. Randomized comparative study of Terlipressin and albumin vs albumin alone in patients with cirrhosis and hepatorenal syndrome. J. Hepatol. 2007; 46: S36. 31 Sharma P, Kumar A, Sharma B et al. Noradrenaline versus Terlipressin in the treatment of type 1 hepatorenal syndrome: a randomized controlled trial. Hepatology. 2006; 44: 449A. 32 Sanyal A, Boyer T, Garcia-Tsao G et al. A prospective randomized double blind placebo-controlled trial of Terlipressin for type 1 hepatorenal syndrome. Hepatology. 2006; 44: 694A. 33 Moller S, Hansen EF, Becker U et al. Central and systemic hemodynamic effects of Terlipressin in portal hypertensive patients. Liver. 2000; 20: 519. 34 Cort JH, Albrecht I, Novakova J et al. Regional and systemic hemodynamic effect of some vasopressins: structural features of the hormone which prolongs activity. Eur. J. Clin. Invest. 1975; 5: 16575. 35 Narahara Y, Kanazawa H, Taki Y et al. Effects of Terlipressin on systemic, hepatic and renal hemodynamics in patients with cirrhosis. J. Gastroenterol. Hepatol. 2009; 24: 17917. 36 Krag A, Bendtsen F, Mortensen C et al. Effects of a single Terlipressin administration on cardiac function and perfusion in cirrhosis. Eur. J. Gastroenterol. Hepatol. 2010; 22: 108592. 37 Krag A, Moller S, Henriksen JH et al. Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome. Hepatology. 2007; 46: 186371.

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38 Hirasawa A, Shibata K, Kotosai K, Tsujimoto G. Cloning, functional expression and tissue distribution of human cDNA for the vascular-type vasopressin receptor. Biochem. Biophys. Res. Commun. 1994; 203: 729. 39 Kiszka-Kanowitz M, Henriksen JH, Hansen EF et al. Effect of Terlipressin on blood volume distribution in patients with cirrhosis. Scand. J. Gastroenterol. 2004; 39: 48692. 40 Gadano A, Moreau R, Vachiery F et al. Natriuretic response to the combination of atrial natriuretic peptide and Terlipressin in patients with cirrhosis and refractory ascites. J. Hepatol. 1997; 26: 122934. 41 Fenton RA, Knepper MA. Mouse models and the urinary concentrating mechanism in the new millennium. Physiol. Rev. 2007; 87: 1083112. 42 Hackenthal E, Paul M, Ganten D et al. Morphology, physiology, and molecular biology of renin secretion. Physiol. Rev. 1990; 70: 1067116. 43 Bichet DG, Van Putten VJ, Schrier RW. Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis. N. Engl. J. Med. 1982; 307: 15527. 44 Manning PT, Schwartz D, Katsube NC et al. Vasopressin-stimulated release of atriopeptin: endocrine antagonists in uid homeostasis. Science. 1985; 229: 3957. 45 Sagi SV, Mittal S, Kasturi KS, Sood GK. Terlipressin therapy for reversal of type 1 hepatorenal syndrome: a meta-analysis of randomized controlled trials. J. Gastroenterol. Hepatol. 2010; 25: 8805. 46 Gluud LL, Christensen K, Christensen E et al. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010; 51: 57684. 47 Fabrizi F, Dixit V, Martin P. Meta-analysis: Terlipressin therapy for the hepatorenal syndrome. Aliment. Pharmacol. Ther. 2006; 24: 93544. 48 Gluud LL, Kjaer MS, Christensen E. Terlipressin for hepatorenal syndrome. Cochrane Database Syst. Rev. 2005; 4: CD005162. 49 Sanyal AJ, Boyer T, Garcia-Tsao G et al. A randomized, prospective, double-blind, placebo-controlled trial of Terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008; 134: 13608. 50 Sanyal A, Boyer T, Teuber P et al. Prognostic factors for hepatorenal syndrome (HRS) reversal in patients with type 1 HRS enrolled in a randomized double blind placebo controlled trial. Hepatology. 2007; 46: 564A. 51 Muoz LE, Alcal EG, Cordero P et al. Reversal of hepatorenal syndrome in cirrhotic patients with Terlipressin plus albumin. First experience in Mexico. Ann. Hepatol. 2009; 8: 20711.

52 Gerbes AL, Huber E, Glberg V. Terlipressin for hepatorenal syndrome: continuous infusion as an alternative to i.v. bolus administration. Gastroenterology. 2009; 137: 1179. 53 Colle I, Durand F, Pessione F et al. 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: 8828. 54 Moreau R, Durand F, Poynard T et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology. 2002; 122: 92330. 55 Nazar A, Pereira GH, Guevara M et al. Predictors of Response to Therapy with Terlipressin and Albumin in Patients with Cirrhosis and Type 1 Hepatorenal Syndrome. Hepatology. 2010; 51: 21926. 56 Uriz J, Gins P, Crdenas A et al. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. Hepatology. 2000; 33: 438. 57 Ortega R, Gins P, Uriz J et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology. 2002; 36: 9418. 58 Neri S, Pulvirenti D, Malaguarnera M et al. Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome. Dig. Dis. Sci. 2008; 53: 8305. 59 Triantos CK, Samonakis D, Thalheimer U et al. Terlipressin therapy for renal failure in cirrhosis. Eur. J. Gastroenterol. Hepatol. 2010; 22: 4816. 60 Keaveny A, Garcia-Tsao G, Bexon A et al. Early indicators of outcome in type 1 hepatorenal syndrome: focus on serum creatinine in the pivotal Terlipressin Trial. The American Transplant Congress May 30June 3, 2009, Boston, MA, USA. 61 Caraceni P, Santi L, Mirici F et al. Long-term treatment of hepatorenal syndrome as a bridge to liver transplantation. Dig. Liver. Dis. 2010; [Epub ahead of print]. 62 Gines A, Salmeron JM, Gines P et al. Oral misoprostol or intravenous prostaglandin E2 do not improve renal function in patients with cirrhosis and ascites with hyponatremia or renal failure. J. Hepatol. 1993; 17: 2206. 63 Alessandria C, Jenon W, Marzano A et al. Renal failure in cirrhotic patients: role of Terlipressin in clinical approach to hepatorenal syndrome type 2. Eur. J. Gastroenterol. Hepatol. 2002; 14: 13638. 64 Duhamel C, Mauillon J, Berkelmans A et al. Hepatorenal syndrome in cirrhotic patients: Terlipressine is a safe and efcient treatment; propranolol and digitalic treatments: precipitating and preventing factors? Am. J. Gastroenterol. 2000; 95: 29845. 65 Angeli P, Volpin R, Gerunda G et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology. 1999; 29: 16907.

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