Chronic kidney disease (CKD) is associated with cognitive impairment. CKD is associated with increased permeability of the blood-brain barrier (BBB), resulting in increased cognitive impairment in animals and in humans. The aim of this study is to describe the inflammatory profile in blood and cerebro-spinal fluid (CSF) during a CKD model induced by adenine rich diet (ARD) in rats, in relation to BBB permeability and to explore the cognitive and mood impairment phenotypes. ARD rats displayed a 5-fold increase in BBB permeability, quantified with brain 99 mTc-DTPA SPECT/CT isotopic imaging, without alteration of brain perfusion. CKD is associated with increased PDGFRß levels in CSF (445 ± 85.6 vs. 303 ± 104.9 pg/mL, p = 0.03), suggesting pericyte dysfunction, but not with CSF levels of inflammatory cytokines, despite increased systemic inflammation. Neurobehavioural evaluation highlighted that ARD rats had impairment of short-term spatial memory, social memory and depressive features but not anxiety. In conclusion, CKD induces systemic inflammation and BBB permeability associated with pericyte dysfunction and alteration of memory and depressive features in rats. BBB disruption seems to be a crucial mechanism involved in cognitive and mood impairment during CKD.

BACKGROUND:Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells.METHODS:To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR-/- knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of 99mTc-DTPA, an imaging marker of blood-brain barrier permeability.RESULTS:In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between 99mTc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR-/- knockout mice were protected against indoxyl sulfate-induced blood-brain barrier disruption and cognitive impairment.CONCLUSIONS:AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.