Significance Statement: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment observed in patients with CKD. Some uremic toxins, such as indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR). The authors found that cognitive impairment in three models of CKD in rats is correlated with serum levels of indoxyl sulfate as well as blood-brain barrier disruption as detected by SPECT/CT imaging. Using AhR^−/− knockout mice, the authors described for the first time that indoxyl sulfate–induced activation of AhR is responsible for blood-brain barrier disruption. These findings demonstrate that blood-brain barrier disruption seems to be an important mechanism involved in cognitive impairment in the context of CKD and that AhR may be a promising therapeutic target to prevent cognitive impairment in 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.

Chronic kidney disease (CKD) is associated with an increased risk of cognitive impairment. This cognitive impairment is associated with an increased permeability of blood-brain barrier (BBB) in rodents with CKD, linked to activation of aryl hydrocarbon receptor (AhR) by indoxyl sulphate (IS). The objective of the BREIN study was to confirm the increased BBB permeability in humans with CKD. The BREIN comparative study (NCT04328415) prospectively included patients with end-stage kidney disease (ESKD) and controls healthy volunteers matched in age, sex, and level of education to a patient. In all participants, BBB permeability was quantified by brain ^99mTc-DTPA SPECT/CT as a percentage of injected activity (% IA). A battery of neurocognitive tests was performed, and serum uremic toxins accumulation and AhR activation were assessed. Fifteen patients with ESKD and 14 healthy volunteers were analyzed. Patients with ESKD had higher BBB permeability compared to controls: 0.29 ± 0.07 versus 0.14 ± 0.06 %IA, P = 0.002. Patients with ESKD displayed lower Montreal Cognitive Assessment test (MoCA) score: 22.0 ± 5.0 versus 27.3 ± 2.8, P = 0.008; impaired short-term memory (doors test): 12.5 ± 3.4 versus 16.5 ± 3.4, P = 0.005; higher Beck depression score 8.1 ± 9.1 versus 2.7 ± 3.4, P = 0.046; and slightly more daily cognitive complaints: 42.5 ± 29.3 versus 29.8 ± 14.0 P = 0.060. Patients with ESKD displayed higher IS levels (86.1 ± 48.4 vs. 3.2 ± 1.7 μmol/l, P = 0.001) and AhR activating potential (37.7 ± 17.8% vs. 24.7 ± 10.4%, P = 0.027). BBB permeability was inversely correlated with MoCA score (r = −0.60, 95% confidence interval [−0.772 to −0.339], P = 0.001) in the overall population. Patients with ESKD display an increased BBB permeability compared to matched healthy volunteers. Association with uremic toxins and cognitive impairment needs to be assessed in larger cohorts of patients.

Patients with chronic kidney disease (CKD) have an increased risk of both ischaemic and haemorrhagic stroke compared with the general population. Both acute and chronic kidney impairment are independently associated with poor outcome after the onset of a stroke, after adjustment for confounders. End-stage kidney disease (ESKD) is associated with a 7- and 9-fold increased incidence of both ischaemic and haemorrhagic strokes, respectively, poorer neurological outcome and a 3-fold higher mortality. Acute kidney injury (AKI) occurs in 12% of patients with stroke and is associated with a 4-fold increased mortality and unfavourable functional outcome. CKD patients seem to have less access to revascularisation techniques like thrombolysis and thrombectomy despite their poorer prognosis. Even if CKD patients could benefit from these specific treatments in acute ischaemic stroke, their prognosis remains poor. After thrombolysis, CKD is associated with a 40% increased risk of intracerebral haemorrhage (ICH), a 20% increase in mortality and poorer functional neurological outcomes. After thrombectomy, CKD is not associated with ICH but is still associated with increased mortality, and AKI with unfavourable outcome and mortality. The beneficial impact of gliflozins on the prevention of stroke is still uncertain. Non-traditional risk factors of stroke, like uraemic toxins, can lead to chronic cerebrovascular disease predisposing to stroke in CKD, notably through an increase in the blood–brain barrier permeability and impaired coagulation and thrombosis mechanisms. Preclinical and clinical studies are needed to specifically assess the impact of these non-traditional risk factors on stroke incidence and outcomes, aiming to optimize and identify potential therapeutic targets.