Toxin in blood of kidney disease patients could contribute to stroke risk, study suggests

There are estimated to be 7.2 million people in the UK currently living with CKD, more than 10% of the entire population.

A team at Nottingham Trent University and Queen Mary University of London investigated the effect on the central nervous system of ‘p-cresol sulfate’, a molecule produced by the gut microbiome.

While this molecule is efficiently cleared by the kidneys in healthy people, it accumulates in the blood of patients with CKD.

Investigating the effect of p-cresol sulfate on human tissue and in mice – and replicating their results using blood samples from dialysis patients – the team found that the toxin triggers a process which activates two enzymes that damage the wall of brain blood vessels.

The researchers observed how this impairs the critically protective blood–brain barrier, which acts as a shield to prevent harmful substances and toxins in the body from reaching the brain.

Damage to the blood–brain barrier is known to contribute to the risk of stroke, which can be up to 30 times greater in CKD patients than in the general population.

As part of the study, however, the researchers also found that a class of ‘inhibitor’ type drugs – which can block chemical reactions in the body – showed promising results in being able to prevent this damage from occurring.

In further tests, the team found that a class of enzyme inhibitor drugs was able to block the damaging effects of blood from CKD patients on cells in vitro.

They now hope to move the work forward to clinical trial to test the effectiveness of the medication in patients with kidney disease.

As well as enhanced stroke risk, patients with CKD, including those not yet requiring dialysis, exhibit significant cognitive decline, a change that seems to be at least partly driven by damage to the brain’s blood vessels.

The gut–brain axis – the two-way communication network between the brain and gut – has been associated with numerous disorders, although the mechanisms driving these are often poorly understood.

“Impaired kidney function impacts virtually every organ system in the body, and the central nervous system is no exception.” said Professor Lesley Hoyles, a microbiome researcher in Nottingham Trent University’s School of Science and Technology.

She said: “The risk of stroke is significantly higher in CKD patients, particularly for those in the later stage of the disease. Our results clearly link this toxin with damage to the blood–brain barrier, which we believe correlates with this risk.

“It is also further evidence of the role of gut microbe-derived molecules in human disease.”

Dr Simon McArthur, from the Institute of Dentistry, Queen Mary University of London, said: “Our work has shown p-cresol sulfate to be a potential therapeutic target to address the neurological consequences of kidney disease.

“The class of inhibitor drug we found to prevent the effects of this metabolite on brain vasculature is currently approved for clinical use in cancer, so it is possible that using these, or re-purposing similar drugs, could be valuable in helping to reduce stroke risk in patients with CKD.”

The study, which also involved the University of East Anglia’s Norwich Medical School, is published in the journal Gut Microbes, and was funded by Alzheimer’s Research UK.