ReviewAdvances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome☆
Introduction
Hepatorenal syndrome (HRS) is a frequent complication in patients with advanced cirrhosis and ascites. It is characterized by an intense renal vasoconstriction, which leads to very low renal perfusion and glomerular filtration rate (GRF). The renal ability to excrete sodium and free water is also severely reduced [1], [2]. Renal histology shows no significant lesions sufficient to justify the impairment in renal function. HRS is the extreme expression of the circulatory dysfunction of cirrhosis. Patients present arterial hypotension and intense stimulation of the renin–angiotensin system, sympathetic nervous system and antidiuretic hormone. Circulatory dysfunction in cirrhosis has been classically considered to be the consequence of an arterial vasodilation in the splanchnic circulation (peripheral arterial vasodilation hypothesis). However, recent data indicate that a reduction in cardiac output also plays a significant role. Non-azotemic cirrhotic patients with ascites, and increased activity of both the renin–angiotensin and sympathetic nervous systems as well as intense sodium retention are specially predisposed to develop HRS [3]. The syndrome may develop spontaneously during the natural course of the disease or be precipitated by factors that induce renal hypoperfusion such as bacterial infections. The annual incidence of HRS in patients with cirrhosis and ascites has been estimated as 8% [3]. Due to the functional nature of renal failure, there is no specific diagnostic marker for HRS [2], [4], [5]. Thus, diagnosis relies on the exclusion of other causes of renal insufficiency [6]. HRS is the complication of cirrhosis associated with the worst prognosis and, for many years, it has been considered as a terminal event of the disease. However, effective treatments of HRS which improve survival have recently been introduced, and a significant number of patients may now benefit from liver transplantation.
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Diagnosis
The first step in the diagnosis of HRS is the demonstration of a reduced GFR, and this is not easy in advanced cirrhosis. The muscle mass, and therefore, the release of creatinine, is considerably reduced in these patients and they may present normal serum creatinine concentration in the setting of a very low GFR (Fig. 1). Similarly, urea is synthesized by the liver and may be reduced as a consequence of hepatic insufficiency. Therefore, false negative diagnosis of HRS is relatively common [7],
Clinical types of HRS
There are two types of HRS [10]. Type-1 HRS is characterized by a severe and rapidly progressive renal failure, which has been defined as doubling of serum creatinine reaching a level greater than 2.5 mg/dl in less than 2 weeks. Although type-1 HRS may arise spontaneously it frequently occurs in close relationship with a precipitating factor, such as severe bacterial infection, mainly SBP, gastrointestinal hemorrhage, major surgical procedure or acute hepatitis superimposed to cirrhosis. The
Splanchnic arterial vasodilation
The development of portal hypertension in cirrhosis is associated to arterial vasodilation in the splanchnic circulation due to the local release of nitric oxide and other vasodilatory substances [23], [24], [25], [26]. Early in the course of the disease, the decrease in systemic vascular resistance is compensated by the development of a hyperdynamic circulation (increased heart rate and cardiac output) [27], [28], [29]. However, as the disease progresses and arterial vasodilation increases,
Pathogenesis of type-1 and type-2 HRS
Clinical data suggest that type-1 and type-2 HRS are different syndromes and not different expressions of a common underlying disorder. Renal failure in type-1 HRS is severe and progressive whereas in type-2 it is moderate and steady. As expected, circulatory function is also stable in type-2 HRS whereas a rapidly progressive impairment in circulatory function occurs in type-1 HRS. Type-1 HRS is frequently associated to a precipitant event, mainly SBP. In contrast, type-2 HRS develops
Liver transplantation
Liver transplantation is the treatment of choice of HRS [64], [65], [66], [67]. Immediately after transplantation a further impairment in GFR may be observed and many patients require hemodialysis (35% of patients with HRS as compared with 5% of patients without HRS) [64]. Because cyclosporine or tacrolimus may contribute to this impairment in renal function, it has been suggested to delay the administration of these drugs until a recovery of renal function is noted, usually 48–72 h after
Available treatments for type-2 HRS
In patients with type-2 HRS the main clinical problem is refractory ascites. Therefore, treatment of type-2 HRS should consider not only survival but also the control of ascites.
Prevention of HRS
Three randomized controlled studies in large series of patients have shown that HRS can be prevented in specific clinical settings. In the first study [59], the administration of albumin (1.5 g/kg IV at infection diagnosis and 1 g/kg IV 48 h later ) to patients with cirrhosis and spontaneous bacterial peritonitis markedly reduced the incidence of circulatory dysfunction and type-1 HRS (10% incidence of type-1 HRS in patients receiving albumin vs. 33% in the control group). Hospital mortality rate
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This study was supported in part by grants from Instituto de Salud Carlos III (C03/2) and CIBER of Enfermedades Hepáticas y Digestivas (CIBERehd). Dr. Carlos Terra was supported by a fellowship grant from Coordenação de Aperfeiçoamento de Pessoal de Nı´vel Superior (CAPES).