Researchers from the University of Bristol have led an international team of scientists in gaining a new understanding of the mechanisms behind haemolytic uraemic syndrome (HUS), the leading cause of renal failure in children.
The research, published in Med, could open the door to potential treatment for children who may otherwise face a lifetime of dialysis and a high mortality risk.
HUS is characterised by the triad of microangiopathic anaemia, nonimmune thrombocytopaenia, and acute kidney injury. The most common cause is Shiga toxin-producing Escherichia coli infection (STEC-HUS), which is associated with severe sequelae including end-stage renal disease (ESRD) or associated mortality in up to 5% of cases. Most (90%) STEC-HUS cases occur in children, though it can also affect adults, leading to ESRD or death in up to 12% of patients.
Most Cases Acquired From Ingestion of Infected Meat or Soil
The researchers noted that in 90% of HUS cases in children, STEC is acquired from enteric ingestion of infected meat or soil, often resulting in haemorrhagic gastroenteritis, which allows the toxin to enter the circulation. There are currently no specific therapies for STEC-HUS.
HUS is one of the thrombotic microangiopathies whose central pathology involves endothelial cell injury, leading to platelet activation and neutrophil recruitment, and culminating in thrombus formation, inflammation, and end-organ damage. However, the team said, it remained unclear exactly why the glomerular microvasculature was so susceptible to injury from systemic shiga toxin (formerly known as verotoxin).
The researchers therefore set out to use laboratory models to identify the mechanism underpinning the disease pathway. They first engineered transgenic mice to express the Shiga toxin receptor exclusively in renal podocytes, which they hypothesised might be an important target receptor in STEC-HUS. They then challenged the mice with systemic Shiga toxin.
Complement Activation Preceded HUS Development
They found vascular endothelial growth factor A was reduced in the targeted podocytes, and this led to loss of glomerular endothelial cell glycocalyx, with a consequent reduction in the cells' inhibitory complement factor H binding, and local activation of the complement pathway. The mice then developed STEC-HUS.
The team then examined human cells from a series of kidney biopsies taken from a variety of patients with proven STEC-HUS. They found that terminal complement activation was present in the glomeruli of all patients, but not in cells from control subjects.
They then tested treating the cells with the complement inhibitor eculizumab. Some case reports had suggested that the drug might have potential benefit in HUS, but results had been inconclusive. However, according to the researchers, all studies had been in patients with established disease.
Their experiments showed in both mouse models and human kidney cells that using eculizumab to inhibit the complement pathway successfully prevented Shiga toxin-driven HUS. "This implies that early complement inhibition has therapeutic potential in this devastating disease," they said.
Potential for Therapeutic Intervention Early in the Disease Process
The researchers stressed that complement inhibition in their model was initiated early and before challenge with Shiga toxin, which would not be possible clinically. However, the results suggested that the early identification of STEC-HUS disease—for example through increased clinical awareness and/or the identification of early biomarkers—could allow prompt intervention with complement inhibitors early in the disease process, before loss of kidney function.
Richard Coward, professor of renal medicine at the University of Bristol and a lead author on the study said, "As a children's kidney doctor, one of the most difficult and devastating diseases we treat is STEC-HUS, which causes kidney failure and death in some children." The team's discovery that renal podocytes are key target cells for Shiga toxin suggests that the disease "can be treated if the complement pathway is blocked in the blood early in the disease," he said.
Dr Aisling McMahon, executive director of research and policy at Kidney Research UK, which partly funded the research, said, "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."
The team now plan further research to assess how quickly eculizumab needs to be given, and to carry out early trials in children with STEC-HUS.
In a comment to Medscape News UK, Fiona Loud, policy director at Kidney Care UK, said, "It is encouraging to see breakthroughs like this, which will ultimately give hope to many families across the UK."
She explained that about 1000 children in the UK were undergoing treatment for kidney failure, often via peritoneal dialysis, "a relentless and demanding treatment which usually takes many hours every day or night." She added, "We look forward to seeing how research can take this discovery further in the future."