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.

Pain was reported by 60–90% of patients with depression, and chronic pain states are often linked to depression. Animal models of pain/depression are generally lacking for the identification of centrally active drugs. In the present study, pain sensitivity was assessed in a mouse model of anxiety/depression on the basis of chronic corticosterone (CORT) administration through the drinking water (CORT model). We measured thermal hyperalgesia as shown by a decrease in the latency to hind paw licking in the hot plate test and cold allodynia reflected by a decrease in the time spent on the plate set at 20°C in the thermal preference plate test. Subsequently, we determined the effect of chronic administration of the selective serotonin reuptake inhibitor fluoxetine (an antidepressant known to reverse anxiety/depressive-like state in CORT-treated mice) on pain relief. Fluoxetine administration reduced both heat hyperalgesia and cold allodynia, thus unveiling a putative link between mood and nociception in the CORT model. This hypothesis is consistent with previous clinical studies reporting the analgesic efficacy of fluoxetine in depressed patients suffering from pain disorders. Together, these results suggest that the CORT model, with pain/anxiety/depressive-like state, is a good candidate for translational research.

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR^−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR^−/− males. AhR^−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR^−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

Background: Patient-led education contributes to the implementation of practical experience of working with patients in health care professional curricula. There are few descriptions of patients’ involvement in pharmacists’ training and most often, the patients have been used as passive props to facilitate training. More recently, greater emphasis has been given to a more active form of patient involvement but the application in the curriculum of pharmacy has not been conceptualized. Thus, the aim of our study was to implement a workshop involving patients as partners in undergraduate pharmacy educational programme, and to evaluate its impact of on students’ perspectives. Method: On a prospective observational study basis, the impact was assessed in terms of relevance, learning outcomes and achievement transfer using the Kirkpatrick training assessment method. In addition, we evaluated social representations of the students before and after the workshop. Results: Ninety-four students attended the sessions. All participants were satisfied and emphasized the relevance of the involvement of patients. Postworkshop scores were significantly improved in both competencies to be acquired. At the end of the workshop, students reported two to three actions to implement in order to meet patients’ expectations, illustrating an intent to transfer learning outcomes in professional context. Interestingly, about patients’ expectations on pharmacist’s role, students’ social representations had evolved significantly after the session. Conclusion: These results highlight the positive impact of the innovative workshops and the additive value of patients’ involvement in the pharmacy undergraduate programme.