Terlipressin in hepatorenal syndrome: Evidence for present indications

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 2-both 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 significantly increases mean arterial pressure and systemic vascular resistance; while the heart rate, cardiac output, HVPG and portal venous blood flow decrease significantly. 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 filtration 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. Key words Conflict of interestNo conflict of interest to disclose.Hepatorenal Syndrome (HRS) was first 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 Յ10 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 a...

The Effects of Terlipressin on Regional Hemodynamics and Kidney Function in Experimental Hyperdynamic Sepsis

“…Because of its longer half-life [11], [12], [14], TP has been given as a bolus injection (typically 1 mg) every 4–6 hours [14]. Although in patients with septic shock bolus injection of TP restores MAP, with improvement in CCr and UO [4], [9], [10], [15], it has a number of potential deleterious effects [6], [16], such as decreased oxygen delivery, and, in some cases, myocardial, splanchnic and digital ischemia [12], [17].…”

“…TP has proved efficacious in the treatment of the hepatorenal syndrome [9], another condition characterized by marked systemic vasodilatation and renal vasoconstriction (a state similar to sepsis). Given such biological properties and efficacy in the hepatorenal syndrome, intermittent intravenous boluses of TP have been used to restore blood pressure in septic shock patients [4], [10].…”

Renal dysfunction in patients with cirrhosis: Where do we stand?

“…The protocol has been proposed to be administered until there are signs of improvement, but not more than two weeks. The decrease of sCr <1.5 mg/ dL (133 μmol/L) or the decrease of sCr > 50% but ≥ 1.5 mg/dL (133 μmol/L), the decrease of bilirubin < 10mg/ dL and the elevation of MAP ≥ 5 mmHg at day 3 of treatment are the predictors of response [87,92,93] . If patient respond, some centers continue therapy with midodrine (an oral α1-adrenergic agonist with vasoconstrictive properties) indefinitely to keep higher MAP and to compensate refractory ascites [94] .…”

“…The combination of them leads to renal function normalization in 34%-65% of cases [81,82] , expends the number of patients undergoing LT [83] , additionally improving their outcome [84] and it increases short -term survival by 34%-43% [82,85,86] ; while it is hypothesized that ameliorates also tubular damage [5] . They have been applied in a special protocol which has shown efficacy in 59% of cases [87] and its discontinuation has been followed by HRS recurrence in 15%-22% [82,85,86,[88][89][90][91] . The protocol has been proposed to be administered until there are signs of improvement, but not more than two weeks.…”

A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design

“…This brings the definition of HRS reversal more in line with the standard accepted in the medical community. 38,39 Another important change to the REVERSE trial, as compared with Study OT-0401, is the method of using an SCr rate-of-rise nomogram in the inclusion criteria. In Study OT-0401, patients had to have an SCr value of $2.5 mg/dL and a doubling of SCr within 2 weeks.…”