Study uncovers how hepatitis E can lead to kidney damage
Findings may help patients get treatment before kidney failure occurs
Researchers have identified a possible mechanism by which infection with the hepatitis E virus (HEV), a known cause of liver inflammation, can lead to kidney disease.
By examining kidney tissue from a deceased person chronically infected with HEV, scientists discovered that a viral protein released from infected liver cells into the blood is recognized by the body’s immune system. This drives the formation of antibody-protein complexes that make their way to the kidneys and cause damage.
“Our findings potentially explain several still incompletely understood observations on hepatitis E-associated [kidney] disease, and establish a molecular link between HEV infection and kidney dysfunction,” researchers wrote.
Raising awareness of hepatitis E
“We hope that our discovery will help to raise awareness of hepatitis E, including here in Switzerland,” Achim Weber, MD, the study’s senior author and a professor at the University of Zurich and the University Hospital Zurich, in Switzerland, said in a university news story.
The study, “HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status,” was published in Nature Communications.
Hepatitis E, like other forms of hepatitis, is characterized by inflammation of the liver. It is one of the most common causes of acute hepatitis, where liver inflammation lasts less than six months, and is “a major global health problem,” Weber said.
Caused by infection with HEV, which is most commonly spread through exposure to contaminated drinking water or food, hepatitis E is often misconstrued as a disease that largely affects resource-limited countries with poor access to clean drinking water.
As such, it has been underdiagnosed in areas such as Europe and North America for many years, according to the authors.
“When I was a medical student, we were taught that hepatitis E only affects people in Asia, Africa and Central America,” Weber said.
For most people, hepatitis E infections are acute, leading to no signs or mild symptoms that clear up on their own, so it can be easy to overlook how important it is to diagnose.
Hepatitis E infections can lead to more serious liver damage
However, the infection can lead to more serious liver damage, particularly in vulnerable populations including those who are immunocompromised, malnourished, or pregnant, or have other liver conditions.
Interestingly, HEV infections have been reported to affect organs beyond the liver, including the brain and kidneys. To date, there’s been a lack of research into how this arises.
“We’ve known this for a long time, but no one understood exactly why,” Weber said.
The scientists’ recent discoveries about how HEV leads to kidney damage were made when Weber and colleagues were performing an autopsy on a man who had undergone a kidney transplant 11 years before and who was subsequently found to have chronic hepatitis E.
In addition to irreversible liver damage, the patient had glomerulonephritis, a disease where glomeruli, the waste-filtering units of the kidneys, become damaged. Left unaddressed, glomerulonephritis can lead to kidney failure.
Looking back at previous biopsies from the patient, the researchers identified a progressive course of kidney damage and worsening kidney function that corresponded with increased levels of a noninfectious form of a HEV protein called ORF2 in the kidneys.
There was no sign that the hepatitis E virus was actively replicating in the kidneys, although it was doing so in the liver.
ORF2 protein implicated in immune response to patient’s HEV infection
That prompted the scientists to look more closely at how a chronic HEV infection in the liver might ultimately lead to kidney damage. They found that in this patient, glomerulonephritis seemed to be related to the buildup of immune complexes against HEV’s ORF2 protein that build up in glomeruli.
When the immune system is defending itself against a potentially harmful invader, it will generate antibodies against it. These antibodies bind to the target protein to form what’s known as an immune complex.
The scientists then examined kidney tissue from three people who had died from liver failure in the context of acute hepatitis E. They again found evidence of ORF2-containing immune complexes in glomeruli, although to a lesser extent than what was observed in the patient with the chronic infection. Moreover, these complexes were associated with signs of early glomerulonephritis.
Given that all analyzed patients had a compromised immune system, the findings “establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated [glomerulonephritis] in the immunocompromised state,” the researchers wrote.
Ultimately, the researchers believe that during an HEV infection, liver cells release high amounts of a noninfectious form of the ORF2 protein into the bloodstream. Although not actively infectious, the protein is still recognized by the immune system as foreign, promoting the production of antibodies against it.
The immune complexes that subsequently form eventually make their way to the kidneys, and if they accumulate too quickly, glomeruli aren’t able process and remove them properly, causing inflammatory damage that drives glomerulonephritis.
Through the course of their experiments, the scientists also established ways to measure ORF2 in kidney biopsies, which they hope will help to determine whether glomerulonephritis is related to a HEV infection in affected patients, enabling treatment to be started before kidney failure occurs.
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