Description of the condition
Hepatorenal syndrome is kidney failure developing in patients with advanced cirrhosis or fulminant hepatic impairment as a consequence of severe renal vasoconstriction (Kjaergard 2003; Guevara 2011; Wadei 2012). Haemodynamic changes present early in patients with liver disease. Besides renal vasoconstriction, circulatory failure resulting in cardiac dysfunction has recently been recognised as playing an important role in the hepatorenal syndrome. This condition is characterised by cirrhosis with ascites; serum creatinine more than 133 mmol/L (1.5 mg/dL); no decrease of serum creatinine to a level of less than or equal to 133 mmol/L after at least two days from diuretic withdrawal and volume expansion with albumin; absence of shock; no current or recent treatment with nephrotoxic drugs; and absence of kidney disease (proteinuria more than 500 mg/day, microhaematuria, and/or abnormal renal ultrasonography) (Arroyo 2008).
There are two types of hepatorenal syndromes. Both type 1 and type 2 hepatorenal syndromes present with intrarenal vasoconstriction due to the haemodynamic alterations caused by severe liver failure and portal hypertension. Type 1 hepatorenal syndrome is a rapidly progressive renal failure, occurring in days, frequently associated with failure in other organs (mainly heart, brain, or liver). By contrast, type 2 hepatorenal syndrome is a steady and moderate renal failure where the main clinical problem is refractory ascites (Guevara 2011). The annual incidence of hepatorenal syndrome in patients with cirrhosis and ascites is estimated to be 8% (Arroyo 2008). Renal histology shows no lesions that explain the impairment in the renal function. It occurs in the setting of a severe circulatory dysfunction with arterial hypotension and intense stimulation of hormone secretion (renin-angiotensin, sympathetic nervous system, and antidiuretic hormone) (Arroyo 2008). There are two key features in the pathogenesis of hepatorenal syndrome; the first mechanism is the intense dilatation or the arteries in the splanchnic territory, resulting in the pooling of blood in this area, and the second is the reduction of blood ejected by the heart, caused by an alteration in its muscle fibres due to cirrhosis (Hasper 2011). A false diagnosis of hepatorenal syndrome is common. One has to meticulously exclude other disorders that can cause renal failure in cirrhosis to reach the correct diagnosis.
Untreated, median survival is two weeks for patients with type 1 hepatorenal syndrome and four to six months in patients with type 2 hepatorenal syndrome (Gines 2003). Therapeutic efforts are designed to increase renal perfusion and mean arterial blood pressure, and include vasopressors as terlipressin and albumin (Davenport 2012; Gluud 2012). Because of its overall poor prognosis, hepatorenal syndrome is better prevented than treated. Preventive strategies include the administration of albumin following large-volume paracentesis (more or equal to 5 L of ascites) and pentoxifylline in patients with alcoholic hepatitis (Whitfield 2009; Wadei 2012). Other therapeutic options include midodrine, norepinephrine, liver transplant, and transjugular intrahepatic portosystemic shunts.
Description of the intervention
Liver transplantation is the treatment of choice for any patient with advanced cirrhosis, including those with type 1 and type 2 hepatorenal syndrome. The ideal goals of treatment for hepatorenal syndrome are to prolong survival until a liver donor becomes available, and to optimise conditions for successful liver transplantation with vasoconstrictors and occasionally transjugular intrahepatic portosystemic shunts (Arroyo 2008; Wadei 2012).
Conventional management of hepatorenal syndrome patients
Type 1 hepatorenal syndrome patients need to be managed in an intensive care unit because these patients have multiorgan failure and deteriorate rapidly. Type 2 hepatorenal syndrome patients usually can be treated in a non-intensive care setting or as an outpatient. Management goal is to maintain intravascular volume with exogenous albumin. Synthetic plasma expanders are not recommended.
Intravenous terlipressin and albumin infusion constitute the treatment of choice for hepatorenal syndrome patients in Europe (Appendix 1). Whether the evidence is strong enough to support the use of terlipressin for clinical practice could be debated due to the results of a trial sequential analysis performed in a Cochrane systematic review (Gluud 2012). Alessandria 2002 concluded that terlipressin might be useful when selecting cirrhotic patients with renal failure as candidates for a transjugular intrahepatic portosystemic shunt or liver transplantation. Other vasoconstrictors used in hepatorenal syndrome are octreotide with midodrine (Appendix 1). A study that analysed the efficacy of midodrine concluded that patients treated with octreotide, midodrine, and albumin presented improvement in kidney function and greater likelihood for liver transplantation compared with the no treatment group (Skagen 2009). Another vasoconstrictor used for hepatorenal syndrome patients is intravenous norepinephrine in combination with albumin and furosemide with good results in renal function and mortality (Duvoux 2002). However, despite their broad use, a meta-analysis from 2010 has shown no differences between several vasoconstrictors and patient survival (Gluud 2010).
Transjugular intrahepatic portosystemic shunts
Transjugular intrahepatic portosystemic shunts is a portal decompression method that involves inserting intrahepatic prosthesis between portal and hepatic veins through transjugular approach. The main adverse effects comprise encephalopathy and complications related to the procedure (bleeding, vascular perforation). Studies have reported improvement for type 1 and 2 hepatorenal syndrome patients (Salerno 2007; Rössle 2010; Wadei 2012).
How the intervention might work
A transjugular intrahepatic portosystemic shunt decreases portal pressure and favours the return of blood volume from the splanchnic territory to systemic circulation, decreasing the amount of blood in the splanchnic vascular bed, thus suppressing the activity of renin-angiotensin aldosterone system and sympathetic nervous system. This reduces the vasoconstrictor effect these systems have on the renal circulation. The effect of transjugular intrahepatic portosystemic shunts improving urinary sodium excretion and renal function in cirrhotic patients with refractory ascites is well documented (Wong 1995; Jalan 1996; Gerbes 1998). Other benefits, such as improvement in renal perfusion, reduced portal pressure, and plasma norepinephrine levels, have been demonstrated (Stadlbauer 2008).
Efficacy of transjugular intrahepatic portosystemic shunts in hepatorenal syndrome
Studies evaluating the effect of a transjugular intrahepatic portosystemic shunt in type 1 hepatorenal syndrome and preserved liver function have shown marked reduction of portal pressure gradient and improvement of renal function 30 days after the transjugular intrahepatic portosystemic shunt compared to conventional therapy (Guevara 1998). Other studies have demonstrated similar benefits, and, following the transjugular intrahepatic portosystemic shunt, 3, 6, 12, and 18 months survival was higher with the transjugular intrahepatic portosystemic shunt compared to conventional therapy (Brensing 2000). An important observation from these two studies is the slow and delayed recovery of renal function following the transjugular intrahepatic portosystemic shunt (within two to four weeks), unlike vasoconstrictor therapy, in which responders have faster recovery of renal function (one to two weeks). The results of these studies suggest that transjugular intrahepatic portosystemic shunts improve renal function in patients with type 1 hepatorenal syndrome and in the majority of non-transplantable cirrhotics with hepatorenal syndrome. Adverse events reported with a transjugular intrahepatic portosystemic shunt insertion in patients with type 2 hepatorenal syndrome include fever and vomiting (Testino 2003). Hepatic encephalopathy is the main complication and the one that, if present prior to transjugular intrahepatic portosystemic shunt insertion, will worsen after the intervention. Another study evaluated combined therapy with vasoconstrictors and transjugular intrahepatic portosystemic shunts in type 1 hepatorenal syndrome and demonstrated that patients with transjugular intrahepatic portosystemic shunts improved renal function and sodium excretion in 12 months (Wong 2004). These results suggest that transjugular intrahepatic portosystemic shunts are not necessarily an alternative for patients not candidates to vasoconstrictors, but that these patients often benefit from the intervention.
Why it is important to do this review
Most studies have been conducted to evaluate the efficacy and safety of vasopressors and albumin for the management of hepatorenal syndrome. However, information regarding the beneficial and harmful effects of transjugular intrahepatic portosystemic shunts is inconclusive. The purpose of this review is, therefore, to evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunts for patients with hepatorenal syndrome to reduce morbidity and mortality.