End Stage Renal Disease and Cognitive Impairment Clinical Trial
Official title:
Evaluation of the Blood-brain Barrier Disruption During Chronic Kidney Disease by 99mTc-DTPA Cerebral Scintigraphy (BREIN)
Patients with Chronic Kidney Disease (CKD) have impaired psycho-cognitive functions in
parallel with deteriorating kidney function. The pathophysiology of cognitive impairment in
CKD is poorly understood and there is currently no therapy to limit cognitive decline. As
kidney function deteriorates, uremic toxins accumulate in the patient's body. Their cerebral
toxicity, whether direct or indirect through cerebral endothelial dysfunction, is a
hypothesis that may explain the cognitive abnormalities, as well as the increased severity of
strokes in patients with CKD. Among uremic toxins, indoxyl sulfate (IS) is an indolic toxin
that is poorly purified by dialysis and whose high levels have already been shown to be
associated with an increased cardiovascular risk in patients with CKD. Our hypothesis is that
the psycho-cognitive disorders observed in patients with CKD are linked to cerebral
endothelial dysfunction associated with high levels of IS.
In two models of CKD in rats, found impaired cognitive performance and increased blood-brain
barrier (BBB) permeability, as assessed by brain scintigraphy with 99mTc-DTPA, compared to
healthy control rats. Impaired cognitive performance was correlated with BBB permeability and
circulating IS levels. Rats receiving an IS-enriched diet had higher BBB permeability and
more impaired cognitive performance than MRC rats without an IS-enriched diet, suggesting a
central role of IS.
The 99mTc-DTPA brain scintigraphy has already been used in clinical research to assess the
BBB disruption after stroke, outside the context of CKD, and the tracer is available in human
nuclear medicine.
Our hypothesis is that patients with CKD would have increased permeability of the BBB
compared to healthy age- and sex-matched controls, and that this permeability would correlate
with circulating levels of IS as in our preclinical animal models.
The main objective of this project is to evaluate the permeability of the BBB by brain
scintigraphy with 99mTc-DTPA in patients with end-stage CKD and compare it to healthy age-
and sex-matched controls.
A 18-month inclusion period will allow us to recruit 15 patients with end-stage CKD and 15
healthy volunteers matched in age and gender, as an important number of patients with
end-stage CKD are followed in our department. If we confirm the results obtained in animal
models, we will be able to propose the analysis of BBB disruption in isotope imaging as a
criterion for evaluating therapeutic approaches modulating the toxicity of indolic uremic
toxins in order to limit cognitive decline.
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