Hepatorenal Syndrome

There are two different types of hepatorenal syndrome based on the progression of kidney injury. The first is hepatorenal syndrome type 1, now known as HRS-AKI, which is characterized by an acute decline in kidney function. This form of HRS has a high mortality rate and is often triggered by precipitating factors such as bacterial infections (e.g., spontaneous bacterial peritonitis [SBP]), gastrointestinal bleeding, or large-volume paracentesis without albumin replacement. 

Individuals with liver disease who do not meet the criteria for acute kidney injury (AKI) but have a functional decline in kidney function are classified under the term HRS-NAKI (i.e., non-AKI), previously known as hepatorenal syndrome type 2.  

Hepatorenal syndrome is a type of functional kidney failure, meaning it's caused by decreased blood flow to the kidneys rather than damage to the kidneys themselves.   

In a healthy liver, nutrient-rich blood from the GI tract is sent to the liver through the portal vein before returning to the systemic circulation. With cirrhosis, scarring of the liver prevents blood from flowing through the portal vein, causing it to accumulate in the abdominal blood vessels, otherwise known as splanchnic circulation. 

As blood begins to pool in the splanchnic circulation, there is a compensatory vasodilation triggered by the release of substances like nitric oxide and prostaglandins. Splanchnic vasodilation helps to lower the pressure in the portal vein, but it also reduces the amount of blood circulating through the rest of the body, causing a drop in blood pressure. 

In response, the body activates a series of compensatory mechanisms to bring blood pressure back up and restore circulating blood volume. The result is a widespread vasoconstriction that raises systemic blood pressure at the expense of decreasing blood flow to non-vital organs, especially the kidneys. With reduced blood flow, the kidneys cannot filter as much blood, leading to a decline in kidney function. 

Hepatorenal syndrome presents as a decline in kidney function in individuals with advanced liver disease, particularly cirrhosis or acute liver failure, such as that caused by viral or alcoholic hepatitis. As the kidneys lose their ability to filter waste products and excess fluid from the blood, these can accumulate in the body, leading to electrolyte imbalances and signs of fluid overload, such as swelling of the lower legs, ascites (i.e., accumulation of fluid in the abdominal cavity), and shortness of breath.  

Fluid overload is often worsened by the fact that diuretics like furosemide or spironolactone are less effective as they rely on the kidney’s ability to excrete water and sodium. In advanced cases, ascites may become refractory, meaning it no longer improves after treatment with optimal doses of diuretics.  

Hepatorenal syndrome is diagnosed by identifying worsening kidney function in individuals with advanced liver disease when other causes of kidney injury have been ruled out. HRS-AKI is defined by an increase in serum creatinine of at least 0.3 mg/dL in 48 hours or an increase of 50% from baseline creatinine levels. For HRS-NAKI, diagnosis requires a subacute or chronic decline in kidney function in the absence of other causes of kidney disease. 

Because HRS is often difficult to differentiate from other causes of kidney failure, additional criteria must be met to confirm the diagnosis. First, no evidence of structural kidney damage can be demonstrated by urine analysis and renal ultrasound. Additionally, there should be no signs of shock or active treatment with nephrotoxic medications, like NSAIDs. Finally, there should be no improvement in kidney function after diuretic withdrawal or volume expansion with albumin. 

Treatment of hepatorenal syndrome begins by addressing any precipitating factors that may be worsening kidney function, including withdrawing diuretics and nephrotoxic medications (e.g., NSAIDs), as well as treating any existing infections.  

Next, a challenge of intravenous albumin is administered as the initial therapeutic measure. Albumin is a large plasma protein that cannot pass through the walls of blood vessels, so it generates an osmotic gradient that helps to draw fluid from the extracellular space into the bloodstream. Albumin is usually administered alongside terlipressin, a medication that causes preferential vasoconstriction of the splanchnic circulation, thereby improving blood flow to the kidneys. Alternatives include midodrine and octreotide, which are less effective but may be used if terlipressin is not available. 

Even though hepatorenal syndrome is considered a reversible condition, in practice kidney function is only restored in around 40 to 50% of cases. Because cirrhosis is usually irreversible, liver transplantation is the only definitive cure of HRS in most cases. In individuals with severe renal failure, dialysis may be used as a bridge to liver transplantation or as supportive treatment in those who are not eligible for a transplant.