When the liver is diseased, why can the kidneys also be affected?

The liver and kidneys have very different functions. However, when the liver is severely affected, the kidneys may also become compromised. This is particularly the case in decompensated cirrhosis, meaning that the liver disease has reached a stage at which complications develop. At this advanced stage of liver disease, the kidneys remain particularly vulnerable to functional impairment. This kidney injury is a serious complication that can sometimes develop rapidly and worsen the prognosis.

But one question remains difficult to explain: why do some patients develop kidney injury while others, despite having comparable liver disease, do not? A new international study, published in The Lancet Gastroenterology & Hepatology, provides an initial answer: our genetic make-up may play a role.

Searching for a difference in our DNA

To conduct this research, the scientists studied the genetic make-up of thousands of people with cirrhosis. The main study included 3,220 South American and European patients with decompensated cirrhosis. The researchers then validated their observations in 1,728 additional patients from several independent cohorts. They also compared their results with those of people with compensated cirrhosis and with those of more than 400,000 people from the general population without cirrhosis. The aim was to identify variations in DNA that might be associated with blood creatinine, a marker used to assess kidney function.

The researchers identified a common genetic variation located in a region of the genome containing the SUSD1 gene. This variation was associated with higher creatinine levels and a higher frequency of kidney failure in people with decompensated cirrhosis. In patients carrying two copies of the variant considered to be at risk, the risk of kidney failure was approximately 60% higher than in those carrying two copies of the other version of the variant.

This result does not mean that a gene “condemns” the kidneys

It is important to understand clearly that this common genetic variation does not mean that a patient will necessarily develop kidney injury. An individual’s susceptibility to kidney injury depends on many factors, such as the severity of the liver disease, any other medical conditions, infections and medications. Genetics is one factor among many.

Another important observation is that the association between this genetic variation and kidney function was not observed in patients with compensated cirrhosis or in the general population. This therefore suggests that the effect of this genetic variation manifests itself in the context of an already severely diseased liver

What happens between the liver and the kidney?

The study also provides a lead for understanding this phenomenon. The researchers studied cells present in different tissues in order to assess the pathophysiological mechanisms linking SUSD1 to impaired kidney function. In particular, they identified the potential contribution of immune-system cells known as plasmacytoid dendritic cells. In patients whose kidneys were affected, these cells were more numerous, and certain communication pathways involving type I interferons—molecules produced notably during immune responses—were more active in the liver and kidneys. These results suggest that an immune-system reaction may contribute to the link between liver failure and kidney injury.

However, precisely how this reaction is triggered and the exact role played by the SUSD1 gene remain to be understood. The researchers therefore describe this as a biological lead that still requires further study.

“Our aim is to better understand why the kidneys become particularly vulnerable in some patients with decompensated cirrhosis. This study highlights a genetic component and an immune pathway that deserve further investigation. At this stage, it mainly provides insight into the possible mechanisms of the disease; it does not yet make it possible to predict a patient’s course or select their treatment,” explains Professor Éric Trépo, hepatologist at H.U.B. and F.R.S.-FNRS Research Associate.

Why is this discovery important for patients?

Because it helps improve our understanding of the biological mechanisms that may contribute to kidney injury, a complication that can be particularly difficult to manage.

This study suggests that part of this difference could be linked to patients’ own biology, including their genetic make-up. In the long term, better identification of particularly vulnerable patients could make it possible to further tailor their monitoring and care. The longer-term aim would be to identify situations at risk earlier and, if new therapeutic targets are confirmed, to develop treatments that act more precisely on the mechanisms responsible for kidney injury.

A pathway towards more personalised medicine

However, we are still at the beginning of this journey. This discovery does not mean that a genetic test capable of predicting kidney injury will soon be offered to all patients with cirrhosis. The predictive value of this association and its clinical usefulness still need to be assessed in prospective studies. But these results open up a new avenue of research: gaining a better understanding of the individual susceptibility of the patients concerned.

For people living with decompensated cirrhosis, this research could therefore ultimately contribute to more personalised care, if its clinical usefulness is demonstrated. This is one of the current challenges in hepatology research: gradually moving from medicine that treats complications when they occur to medicine capable of better anticipating each patient’s individual course.

This research project is supported by the Erasme Fund.

Projects supported by the Erasmus Fund.

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