Hepatorenal Syndrome

Hepatorenal syndrome is a life-threatening condition where the kidneys suddenly fail in people with severe liver disease. Despite normal kidney structure, the organs stop working because narrowed blood vessels prevent adequate blood flow, creating a medical emergency that requires immediate attention.

Table of contents

• What is hepatorenal syndrome?
• Causes and risk factors
• Who is most affected?
• Symptoms and warning signs
• Types of hepatorenal syndrome
• How is it diagnosed?
• Treatment options
• Outlook and prognosis
• Prevention

What is hepatorenal syndrome?

Hepatorenal syndrome is a serious medical condition that affects both the liver and the kidneys. It occurs when people with advanced liver disease develop kidney failure, even though their kidneys themselves have no structural damage^[1]. The condition represents a functional kidney failure, meaning the kidneys stop working properly not because they are diseased, but because of changes happening elsewhere in the body^[2].

In hepatorenal syndrome, severe liver disease causes blood vessels in the kidneys to narrow or constrict. When this happens, the kidneys cannot receive enough blood to function properly, and they begin to shut down^[2]. This is why kidneys from people with hepatorenal syndrome can be successfully transplanted into other patients and work normally—the kidneys themselves are healthy^[1].

The condition was first observed in the late 1800s when doctors noticed the connection between liver disease and kidney failure. Research in the mid-1900s confirmed that this kidney failure was functional in nature, as patients showed normal kidney tissue when examined and did not have protein in their urine^[1].

• Liver
• Kidneys
• Portal vein
• Blood vessels

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Causes and risk factors

The underlying cause of hepatorenal syndrome is advanced liver disease, which triggers a complex chain of events in the body. Cirrhosis (severe scarring of the liver) and portal hypertension (high blood pressure in the vein that runs through the liver) set off a process that leads to the production and release of substances that widen blood vessels throughout the body^[1].

In developing countries, viral hepatitis is the most common cause of liver failure that leads to hepatorenal syndrome. Most often, this is Hepatitis B or, less commonly, Hepatitis C. In developed countries, the most common causes are medications (especially acetaminophen), chronic alcohol use, drugs that affect liver enzymes, and non-alcoholic steatohepatitis (NASH)—a condition where fat builds up in the liver and causes inflammation^[1].

Less common causes include other viruses such as CMV, HHV6, and Parvovirus B19. Blood vessel problems like blockages in the liver or portal vein, as well as metabolic conditions such as nonalcoholic fatty liver disease, can also lead to liver failure and subsequently to hepatorenal syndrome^[1].

Several specific conditions increase the risk of developing hepatorenal syndrome once someone already has liver disease. These include bleeding in the digestive system, overusing diuretics (medications that help the body get rid of excess fluid), and spontaneous bacterial peritonitis (SBP)—a serious infection of fluid in the abdomen^[2]. In fact, about one-third of patients who develop spontaneous bacterial peritonitis will go on to develop hepatorenal syndrome^[1].

Who is most affected?

Hepatorenal syndrome typically affects people who have had chronic, progressive liver disease for some time and are approaching liver failure. It can also occur with sudden, severe liver failure from an acute cause^[2].

Among patients with decompensated liver disease (advanced liver disease where the liver can no longer perform its essential functions), approximately 4% develop hepatorenal syndrome^[1]. Studies suggest that up to 40% of people with end-stage liver disease will eventually develop this condition^[2]. Most of these patients have portal hypertension resulting from alcoholic hepatitis, cirrhosis, or cancers that have spread to the liver^[1].

The risk increases over time. For patients with decompensated liver disease, the chance of developing hepatorenal syndrome is 18% at one year and rises to 39% at five years^[1]. The highest-risk patients are those with low sodium levels in their blood and high levels of a hormone called renin^[1].

Hepatorenal syndrome affects people of all ages and sexes, though it is more common in people in the second half of their lives. Up to 10% of people hospitalized with chronic or acute liver failure will develop it^[2].

Symptoms and warning signs

People with hepatorenal syndrome often experience vague symptoms that make them feel generally unwell. These can include a bad taste in the mouth, fatigue, nausea, and stomach pain^[2]. As the condition progresses, they produce less urine than normal as they become oliguric (producing very little urine)^[1].

Because hepatorenal syndrome occurs in people with advanced liver disease, patients also show symptoms of liver failure. These include confusion, disorientation, or drowsiness (called hepatic encephalopathy—a condition where toxins that the diseased liver cannot filter out begin affecting the brain). Other liver-related symptoms include easy bruising and bleeding, itchy skin, and jaundice (yellowing of the skin and the whites of the eyes)^[2].

Additional signs include light-colored stools and dark-colored urine, as well as a swollen abdomen. The swelling can result from ascites (fluid buildup in the belly), an enlarged liver, or an enlarged spleen^[2].

Physical examination may reveal orthostatic hypotension (a drop in blood pressure when standing up suddenly), swelling in the limbs, changes in mental state, muscle spasms or jerks, decreased urine production, and unexplained weight gain^[6].

Types of hepatorenal syndrome

Hepatorenal syndrome has traditionally been divided into two types with different characteristics and outlooks. More recently, experts have updated the classification system to align with modern definitions of kidney injury^[3].

Type 1 hepatorenal syndrome (now called HRS-AKI, where AKI stands for acute kidney injury) develops rapidly, often within two weeks or less. Patients experience a sudden, severe decline in kidney function with creatinine levels (a waste product that kidneys normally filter) rising above 2.5 mg/dL. This type can be triggered by bacterial infections, bleeding in the digestive system, removal of large amounts of abdominal fluid without giving albumin (a protein solution), or excessive response to diuretics, alcohol, or drugs^[3]. It leads rapidly to worsening of both kidney and liver function, along with confusion and mental changes. The average survival time without treatment is just two to four weeks^[4].

HRS-AKI is now classified in stages. Stage 1 means creatinine has increased by at least 0.3 mg/dL or 1.5 to 2 times from the starting level. Stage 2 indicates a doubling to tripling of creatinine, while Stage 3 represents at least a tripling of creatinine or levels reaching 4.0 mg/dL or higher^[3].

Type 2 hepatorenal syndrome (now called HRS-NAKI, for non-acute kidney injury) typically develops spontaneously and progresses more slowly. The primary clinical feature is refractory ascites—fluid in the abdomen that does not respond to treatment. This type involves a gradual, progressive worsening of kidney function^[3].

How is it diagnosed?

Diagnosing hepatorenal syndrome involves first confirming that a patient has both liver disease and kidney failure, then ruling out other possible causes of the kidney problems^[2]. There are no specific tests that directly identify hepatorenal syndrome, so doctors diagnose it by excluding other causes of acute kidney injury in patients with cirrhosis^[1].

Healthcare providers order a variety of blood tests, urine tests, and imaging studies to check both liver function and kidney function. Blood tests may show increased levels of BUN (blood urea nitrogen) and serum creatinine, which are waste products that build up when kidneys fail. Tests also check for low blood sodium levels and very low urine sodium concentration^[6].

Urine tests typically show increased urine specific gravity. Liver function tests reveal problems such as increased prothrombin time (blood takes longer to clot), low serum albumin (a protein made by the liver), and sometimes increased ammonia levels^[6].

Imaging studies may include abdominal ultrasound to examine the liver and check for fluid buildup. Doctors also look for signs of hepatic encephalopathy, which may be confirmed with an EEG (a test that measures electrical activity in the brain)^[6].

The physical examination shows signs of chronic liver failure. Importantly, the kidneys themselves appear normal on examination—this is a key feature of hepatorenal syndrome^[1].

Treatment options

The only definitive cure for hepatorenal syndrome is a liver transplant^[2]. When patients receive a new, healthy liver, their kidney function typically improves or returns to normal because the kidneys themselves were not damaged^[1].

However, because of long waiting lists at transplant centers, most patients need treatment while waiting for a transplant. These “bridge” treatments aim to support kidney function and keep patients stable until a liver becomes available^[8].

The main medical treatment combines medications that narrow blood vessels with albumin infusions. The most effective approach uses a medication called terlipressin together with albumin^[8]. Other medication combinations include octreotide plus midodrine with albumin, or norepinephrine, which studies suggest may be as beneficial as terlipressin^[9].

Additional supportive treatments include intravenous fluids to treat imbalances in body salts (electrolytes) and support blood flow to the kidneys, stopping certain medications like diuretics that may be making things worse, and antibiotics to treat any related infections^[2].

For patients with large amounts of fluid buildup in the abdomen, doctors may perform paracentesis—a procedure to drain the fluid. This must be done carefully, with albumin given to prevent further problems^[2].

Some patients may need dialysis or renal replacement therapy in the form of continuous veno-venous hemofiltration to help filter waste products from the blood when kidneys cannot do so^[8].

Another treatment option is a procedure called transjugular intrahepatic portosystemic shunt (TIPS). This involves placing a shunt (a kind of tube) inside the liver to redirect blood flow and reduce portal hypertension. TIPS can be considered for patients who do not respond to medical treatment^[8]. Studies show it results in decreased levels of hormones like aldosterone, renin, and noradrenaline within four to six months, corresponding to a reduction in portal hypertension^[14].

For patients who are not candidates for liver transplantation, treatment is mainly palliative, aimed at relieving symptoms and providing comfort^[9].

Outlook and prognosis

The prognosis for hepatorenal syndrome is poor without treatment. It is one of the most severe complications of cirrhosis because of its very poor outlook^[8]. The condition progresses rapidly, typically over a matter of weeks to months^[2].

For Type 1 hepatorenal syndrome (HRS-AKI), the condition is particularly aggressive, with average survival of only two to four weeks without intervention. The three-month mortality rate is approximately 90%^[4]. Death usually occurs due to complications such as secondary infections or severe bleeding^[6].

Type 2 hepatorenal syndrome (HRS-NAKI) progresses more slowly, giving patients somewhat more time, though the condition is still ultimately fatal without treatment^[3].

Possible complications include bleeding, damage to and failure of multiple organ systems, end-stage kidney disease requiring permanent dialysis, fluid overload leading to congestive heart failure or pulmonary edema (fluid in the lungs), coma from liver failure, and life-threatening infections^[6].

The outlook improves significantly with liver transplantation. Studies show that patients successfully treated for hepatorenal syndrome before receiving a liver transplant have outcomes and survival rates after transplant that are similar to those of patients who underwent transplantation without having had hepatorenal syndrome^[9].

With prompt diagnosis and appropriate bridge treatment while waiting for transplant, some patients can survive long enough to receive a new liver and recover kidney function^[2].

Prevention

The main goal in caring for patients with cirrhosis is to prevent hepatorenal syndrome before it develops^[8]. This involves several important strategies.

Maintaining liver health is the foundation of prevention. People can protect their liver by avoiding excessive alcohol consumption. For those at risk of viral hepatitis, getting vaccinated against Hepatitis B and avoiding behaviors that could lead to Hepatitis C infection are crucial steps^[1].

For people already diagnosed with cirrhosis or at risk for it, regular monitoring of liver function is essential. Healthcare providers should carefully manage patients with liver disease to prevent complications that can trigger hepatorenal syndrome^[1].

Specific preventive measures for patients with advanced liver disease include treating infections promptly, especially spontaneous bacterial peritonitis. When antibiotics are given for this infection and albumin is administered along with them, the risk of developing hepatorenal syndrome decreases^[9].

Careful management of fluid removal is also important. When doctors need to remove large amounts of fluid from the abdomen (more than 5 liters), they should give albumin to help prevent hepatorenal syndrome^[9].

Patients with liver disease should avoid nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and other medications that can harm the kidneys. Diuretics should be used cautiously and withdrawn if kidney function begins to decline^[9].

For patients at high risk—particularly those with low sodium levels in their blood and high renin activity—even more vigilant monitoring and preventive care are necessary^[1].