Existing drug may prevent a leading cause of kidney failure in children
New results from researchers at the University of Bristol, published today in Med have demonstrated how infection with a toxin-producing bacteria can lead to a condition called haemolytic uraemic syndrome (HUS), a leading cause of kidney failure in children. The results suggest that early treatment with the drug eculizumab might prevent life-threatening kidney damage and death in some children.
What is HUS?
HUS is a rare but serious condition that affects the blood and blood vessels. It causes the tiny filtration units in the kidneys to become blocked by small blood clots, which can lead to kidney failure. HUS can affect people of any age, but it is a leading cause of kidney failure in children.
In most cases, HUS is caused by infection with a particular strain of E coli bacteria, found in contaminated food (particularly poorly cooked beef burgers) or soil, which makes a toxin called Shiga toxin. During infection, the Shiga toxin can enter the bloodstream and damage the blood vessels, but until now it has been unclear how and why it targets the kidney filters.
HUS is a serious illness and sadly about 5% of children who develop the condition will die. Patients are given supportive treatment to manage the symptoms, but there is currently no medication to directly treat HUS.
Understanding how Shiga toxin targets the kidneys
With funding from Kidney Research UK and the Medical Research Council, the Bristol team led by Professor Richard Coward, have discovered how Shiga toxin infection has such a devastating effect on the kidneys.
Using several laboratory-based models, the team were able to show that Shiga toxin directly interacts with a molecule on the surface of cells called podocytes (a critical part of the kidney’s filtration unit). This leads to activation of part of the immune system called the ‘complement pathway’ (which protects us from bacteria and viruses but can be harmful if not properly controlled) causing blood clots to form in the tiny blood vessels of the kidney’s filters.
Blocking the complement pathway to stop HUS
The team then showed that by blocking a part of the complement pathway early on they were able to prevent the development of HUS after Shiga toxin exposure in laboratory-based models. First author Dr Emily Bowen says ‘’for the first time we have been able to generate a model of Shiga toxin HUS that replicates human disease. Future work using this model will facilitate greater insight into the window of opportunity available for treatment with complement inhibitors’’.
Blocking the complement system with a drug called eculizumab has already proved effective in treating atypical haemolytic uraemic syndrome (aHUS), a very similar disease that usually arises due to genetic faults affecting the complement system.
In a recent clinical trial in France, researchers tested whether eculizumab could be used to treat children with Shiga toxin-driven HUS. They showed that the drug was safe to use in these patients, but they did not see an immediate improvement in kidney health. However, in this trial the researchers were only able to test the drug on children with established HUS; these new results from the Bristol team suggest that, if administered earlier, eculizumab could prevent Shiga toxin-driven HUS.
What could this mean for patients?
These exciting results suggest that if doctors could identify HUS cases early, eculizumab could be effective in preventing a leading cause of kidney failure in children. Increased awareness of the condition, research into potential early markers of disease and improved diagnosis of Shiga toxin-producing E coli infection could help doctors to intervene before infection causes kidney damage.
“This research has not only shown exactly how Shiga toxin is able to target the kidney and cause such devastating damage but has also discovered a way in which HUS could be stopped in its tracks using a drug that is already in clinical use. This is another great example of the importance of research in identifying new treatment options for patients, and we look forward to the next steps in this project”. Dr Aisling McMahon, executive director of research and policy at Kidney Research UK
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