Blood-Brain Barrier Evaluation In Nephrology (BREIN)

Overview

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.