What is hepatorenal syndrome and its pathophysiology?

From the Guidelines

Hepatorenal syndrome (HRS) is a life-threatening condition characterized by rapid kidney failure in patients with advanced liver disease, particularly cirrhosis with ascites, and its pathophysiology involves splanchnic arterial vasodilation, renal vasoconstriction, and systemic inflammation, as recently highlighted in the 2024 guidelines on the use of vasoactive drugs and intravenous albumin in cirrhosis 1. The pathophysiology of HRS is complex and multifactorial, involving:

• Splanchnic arterial vasodilation caused by portal hypertension, which triggers a cascade of compensatory mechanisms, including the activation of the renin-angiotensin-aldosterone system, sympathetic nervous system, and antidiuretic hormone release 1
• Renal vasoconstriction, which reduces renal blood flow and glomerular filtration rate, ultimately leading to kidney failure 1
• Systemic inflammation, which plays a crucial role in the development of HRS, particularly in patients with cirrhosis and ascites 1
• Cardiac dysfunction, including cirrhotic cardiomyopathy, which further compromises cardiac output and worsens renal perfusion 1 The classification of HRS has been revised, with HRS-1 now referred to as HRS-acute kidney injury (HRS-AKI), characterized by a rapid reduction in renal function, and HRS-2 referred to as HRS-non-AKI (HRS-NAKI), representing renal dysfunction that does not progress rapidly 1. Management of HRS focuses on vasoconstrictor therapy, typically terlipressin or norepinephrine, combined with albumin, while liver transplantation remains the definitive treatment for eligible patients 1. Key factors that may impair the response to vasoconstrictors include:
• Baseline value of serum creatinine
• Degree of inflammation
• Degree of cholestasis It is essential to note that the treatment of HRS should be individualized, and the use of vasoconstrictors, particularly terlipressin, in association with albumin, has been proposed in the treatment of type 2 HRS, although the impact on outcomes is still controversial 1.

From the Research

Definition of Hepatorenal Syndrome

• Hepatorenal syndrome (HRS) is a form of kidney dysfunction that characteristically occurs in liver cirrhosis, characterized by a marked impairment of kidney function in response to circulatory and hemodynamic alterations that occur in advanced stages of liver cirrhosis, aggravated by systemic inflammation and bacterial translocation 2.
• HRS is a unique type of kidney failure that occurs in advanced cirrhosis, characterized by functional impairment of the kidneys due to vasoconstriction of the renal arteries in the setting of preserved tubular function and absence of significant histologic abnormalities 3.

Pathophysiology of Hepatorenal Syndrome

• The pathophysiology of HRS involves increased splanchnic blood flow, activation of several vasoconstriction factors, severe vasoconstriction of the renal arteries, nitric oxide dysfunction, and systemic inflammation 4.
• HRS is characterized by severe impairment of kidney function due to circulatory dysfunction, marked splanchnic vasodilation, leading to reduction of effective arterial blood volume and glomerular filtration rate 5.
• The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years, and the mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal syndrome need to be clarified 6.

Types of Hepatorenal Syndrome

• There are two forms of HRS: the acute form, referred to as acute kidney injury (HRS-AKI), and the chronic form, referred to as chronic kidney disease 2.
• HRS-AKI is one of the most severe forms of AKI in patients with cirrhosis and it consists of an abrupt impairment of kidney function, frequently triggered by an infection, appearing in the setting of advanced decompensated cirrhosis 2.
• Type 1 HRS is characterized by an acute progressive decrease in kidney function and very short survival without treatment, whereas type 2 features stable less severe kidney failure and longer survival compared with type 1 3.

Diagnosis and Treatment of Hepatorenal Syndrome

• Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis 4.
• The optimal treatment of HRS is liver transplantation (LT), and while awaiting LT, treatment options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by intravenous albumin infusion 4.
• Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option, and several controlled studies proved that terlipressin is effective at reversing hepatorenal syndrome and may improve short-term survival 6.