Overview of Hepatorenal Syndrome

Human organs don't execute their responsibilities in isolation. They communicate with each other. They depend on each other. Understanding an organ's function requires one to understand the role of the other organs as well. 

The human body is like a really complicated orchestra. If you were to just listen to individual musicians, you might not appreciate the symphony. Once we understand this important concept, it becomes easier to appreciate that problems with one organ's function could adversely affect another. 

Definition of Hepatorenal Syndrome (HRS)

As the term suggests, the word "hepato" pertains to the liver, while "renal" refers to the kidney. Hence, hepatorenal syndrome implies a condition where liver disease leads to kidney disease or in extreme cases, complete kidney failure. 

But, why do we need to know about hepatorenal syndrome? Liver disease is a fairly common entity (think hepatitis B or C). And in the universe of liver disease, hepatorenal syndrome is not an uncommon condition. In fact, according to one statistic, 40 percent of patients with cirrhosis (scarred, shrunken liver) and ascites (fluid accumulation in the stomach in advanced liver disease) will develop hepatorenal syndrome within five years.

Risk Factors

The initiating factor in hepatorenal syndrome is always some kind of liver disease. This could be everything ranging from hepatitis B or C, drugs, autoimmune disease, liver tumors, and cirrhosis. Hepatorenal syndrome can also result in fulminant liver failure. All of these conditions can induce kidney disease and kidney failure of varying levels of severity in the hepatorenal patient. 

However, there are some identified risk factors that significantly increase the chances of having kidney failure because of liver disease.

• Spontaneous bacterial peritonitis, an infection of the abdominal cavity
• Esophageal varices, which is bleeding into the gut common in cirrhosis 

Water pills (diuretics like furosemide or spironolactone) that are given to patients with cirrhosis and fluid overload do not precipitate hepatorenal syndrome (although they can hurt the kidneys in other ways).

Disease Progression

The mechanisms by which liver disease creates problems with kidney function are thought to be related to the "diversion" of blood supply away from the kidneys and into the rest of the abdominal cavity organs (the so-called "splanchnic circulation").

One main factor determining blood supply to any organ is the resistance encountered during its flow to the organ. Based on the laws of physics, the narrower a blood vessel, the higher the resistance in the blood flow.

As an example, imagine if you were trying to pump water through two different garden hoses using an equal amount of pressure (which in a human body is generated by the heart). If both the hoses had lumens which were the same size/caliber, one would expect equal amounts of water to flow through them. Now, what would happen if one of those hoses was significantly wider (larger caliber) than the other? Well, more water will preferentially flow through the wider hose due to less resistance that the water encounters there.

Similarly, in the case of hepatorenal syndrome, widening (dilatation) of certain blood vessels in the abdominal splanchnic circulation diverts blood away from the kidneys (whose blood vessels get constricted). Although this does not necessarily proceed in distinct linear steps, for the sake of understanding, here is how we could map this out:

1. Step 1- The initial trigger is portal hypertension, an increase in blood pressure in certain veins that drain blood from the stomach, spleen, pancreas, and intestines, which is common in advanced liver disease. This alters blood flow in abdominal organ circulation by dilating splanchnic blood vessels due to the chemical nitric oxide.
2. Step 2 - While the above blood vessels are dilating and have more blood flow, vessels in the kidneys that start to constrict reduce blood supply. The detailed mechanisms for this are beyond the scope of this article, but it is thought to be related to the activation of the so-called renin-angiotensin system. 

These blood flow alterations then culminate and produce a relatively rapid decline in the kidney function. 

Diagnosis

Hepatorenal syndrome diagnosis is not a straightforward blood test; instead, it's usually what physicians call a diagnosis of exclusion. The prerequisite for diagnosis would be that the physician will need to exclude that kidney failure is not a result of any other causes, including dehydration,  NSAID pain meds, hepatitis B or C, autoimmune disease, or obstruction. Once that condition has been met, physicians study the decline in kidney function by looking at certain clinical features and tests below:

• An elevated level of creatinine in the blood, associated with a reduction in the kidneys filtration rate (GFR)
• Drop in urine output
• A low level of sodium present in the urine
• Kidney ultrasound, which will not necessarily show anything, but could exclude other causes of kidney failure in a patient presumed to have hepatorenal syndrome
• Testing for blood or protein in the urine. Nonexistent/minimal levels will support the diagnosis of hepatorenal syndrome
• Response to therapy is also used as a retrospective "surrogate test" for diagnosis. In other words, if kidney function markedly improves after "hydration" that could involve intravenous fluids or a protein infusion of albumin, it is less likely to be hepatorenal syndrome. In fact, resistance to these conservative therapies will usually spark suspicion about hepatorenal syndrome being present

Even diagnosing kidney failure might not always be straightforward in the patient with advanced liver disease or cirrhosis. This is because the most common test that we depend on to assess kidney function, the serum creatinine level, might not elevate too much in cirrhosis patients in the first place. Therefore, just looking at a serum creatinine level could mislead the diagnostician since it will lead to underestimation of the severity of kidney failure. Therefore, other tests like 24-hour urine creatinine clearance might be necessary to support or refute the level of kidney failure.

Types

Once the diagnosis is confirmed using the above criteria, physicians will classify hepatorenal syndrome into Type-I or Type-II. The difference lies in the severity and the course of the illness. Type I is the more severe kind, associated with a rapid and profound decline in kidney function.  

Treatment

Now that we understand that hepatorenal syndrome is set off by liver disease (with portal hypertension being the agent provocateur), it's easy to appreciate why treating underlying liver disease is a top priority and the crux of treatment. Unfortunately, that is not always possible. In fact, there might be entities for which no treatment exists or, as in the case of fulminant liver failure, where treatment (other than liver transplantation) might not even work.

Finally, there is the factor of time. Especially in Type-I HRS. Hence, while the liver disease might be treatable, it may not be possible to wait for its treatment in a patient with rapidly failing kidneys. In that case, medications and dialysis become necessary. Here are a few choices that we have:

• In September 2022, the Food and Drug Administration (FDA) approved Terlivaz (terlipressin) to improve kidney function in adults with HRS with a rapid decline in kidney function. Terlivaz is the first FDA-approved drug for HRS. Other treatments include norepinephrine, a common medication used in the ICU to raise blood pressure in people with excessively low blood pressure from shock, and a "cocktail regimen" of the medications octreotide, midodrine, and albumin. 
• If these medications don't work, an interventional procedure called TIPS (transjugular intrahepatic portosystemic shunt) placement might be beneficial, although that comes with its own set of problems.
• Finally, if everything fails and the kidneys do not recover, dialysis might be necessary as a "bridge therapy" until the liver disease can be addressed definitively.

Typically, if medications described above do not work within two weeks, treatment might be considered futile and the risk of death goes up drastically.

Prevention

It depends. If the patient has a known liver disease with complications that are recognized precipitants (as described above in the section on high-risk patients) of hepatorenal syndrome, certain preventive therapies might work. For instance, patients with cirrhosis and fluid in the abdomen (called ascites), might benefit from an antibiotic called norfloxacin. Patients might benefit from intravenous repletion of albumin as well.