The impact of chronic kidney disease on cognitive function.

PURPOSE OF REVIEW: The risk of cognitive impairment is higher in people with CKD than in the general population. The complex relationship between CKD and cognitive dysfunction has not been extensively characterized. Here, we review epidemiological associations, specific patterns of CKD-related cognitive impairment, the underlying mechanisms, and recently published data on relevant biomarkers. RECENT FINDINGS: Despite some discrepancies, recent published studies have confirmed that CKD is associated with cognitive function (e.g. incident cognitive events). Although patients with CKD often exhibit impairments in executive functions and attention, it is noteworthy that other cognitive functions (e.g. memory) can be preserved. The key mechanisms described recently include vascular damage, genetic factors, the accumulation of uremic toxins, disruption of the blood-brain barrier, glymphatic system dysfunction, and changes in the gut-brain axis. Kidney function is increasingly seen as a game changer in the interpretation of biomarkers of cognitive impairment and, especially, hallmarks of Alzheimer disease. SUMMARY: The data reviewed here highlight the need for interdisciplinary collaboration between nephrologists and neurologists in the care of patients with CKD at risk of cognitive impairment. In order to further improving diagnosis and therapy, future research must elucidate the mechanisms underlying the CKD-cognitive impairment association and confirm the value of biomarkers.

Drugs with a negative impact on cognitive functions (part 3): antibacterial agents in patients with chronic kidney disease.

The relationship between chronic kidney disease (CKD) and cognitive function has received increased attention in recent years. Antibacterial agents (ABs) represent a critical component of therapy regimens in patients with CKD due to increased susceptibility to infections. Following our reviewing work on the neurocognitive impact of long-term medications in patients with CKD, we propose to focus on AB-induced direct and indirect consequences on cognitive function. Patients with CKD are predisposed to adverse drug reactions (ADRs) due to altered drug pharmacokinetics, glomerular filtration decline, and the potential disruption of the blood-brain barrier. ABs have been identified as a major cause of ADRs in vulnerable patient populations. This review examines the direct neurotoxic effects of AB classes (e.g. beta-lactams, fluoroquinolones, aminoglycosides, and metronidazole) on the central nervous system (CNS) in patients with CKD. We will mainly focus on the acute effects on the CNS associated with AB since they are the most extensively studied effects in CKD patients. Moreover, the review describes the modulation of the gut microbiota by ABs, potentially influencing CNS symptoms. The intricate brain-gut-kidney axis emerges as a pivotal focus, revealing the interplay between microbiota alterations induced by ABs and CNS manifestations in patients with CKD. The prevalence of antibiotic-associated encephalopathy in patients with CKD undergoing intravenous AB therapy supports the use of therapeutic drug monitoring for ABs to reduce the number and seriousness of ADRs in this patient population. In conclusion, elucidating AB-induced cognitive effects in patients with CKD demands a comprehensive understanding and tailored therapeutic strategies that account for altered pharmacokinetics and the brain-gut-kidney axis.

Urea Level and Depression in Patients with Chronic Kidney Disease.

Depression is common in patients with chronic kidney disease (CKD). Experimental studies suggest the role of urea toxicity in depression. We assessed both the incidence of antidepressant prescriptions and depressive symptoms (measured by CESD (Center for Epidemiologic Depression) scale) in 2505 patients with CKD (Stage 3-4) followed up over 5 years in the Chronic Kidney Disease Renal Epidemiology and Information Network (CKD-REIN) cohort. We used a joint model to assess the association between the serum urea level and incident antidepressant prescriptions, and mixed models for the association between the baseline serum urea level and CESD score over the 5-year follow-up. Among the 2505 patients, 2331 were not taking antidepressants at baseline. Of the latter, 87 started taking one during a median follow-up of 4.6 years. After adjustment for confounding factors, the hazard ratio for incident antidepressant prescription associated with the serum urea level (1.28 [95%CI, 0.94,1.73] per 5 mmol/L increment) was not significant. After adjustment, the serum urea level was associated with the mean change in the CESD score (ß = 0.26, [95%CI, 0.11,0.41] per 5 mmol/L increment). Depressive symptoms burden was associated with serum urea level unlike depression events. Further studies are needed to draw firm conclusions and better understand the mechanisms of depression in CKD.

Exclusive oral antibiotic treatment for hospitalized community-acquired pneumonia: a post-hoc analysis of a randomized clinical trial.

OBJECTIVES: In this study, we aimed to assess the efficacy of different ways of administration and types of beta-lactams for hospitalized community-acquired pneumonia (CAP). METHODS: In this post-hoc analysis of randomized controlled trials (RCT) on patients hospitalized for CAP (pneumonia short treatment trial) comparing 3-day vs. 8-day durations of beta-lactams, which concluded to non-inferiority, we included patients who received either amoxicillin-clavulanate (AMC) or third-generation cephalosporin (3GC) regimens, and exclusively either intravenous or oral treatment for the first 3 days (followed by either 5 days of oral placebo or AMC according to randomization). The choice of route and molecule was left to the physician in charge. The main outcome was a failure at 15 days after the first antibiotic intake, defined as temperature >37.9°C, and/or absence of resolution/improvement of respiratory symptoms, and/or additional antibiotic treatment for any cause. The primary outcome according to the route of administration was evaluated through logistic regression. Inverse probability treatment weighting with a propensity score model was used to adjust for non-randomization of treatment routes and potential confounders. The difference in failure rates was also evaluated among several sub-populations (AMC vs. 3GC treatments, intravenous vs. oral AMC, patients with multi-lobar infection, patients aged ≥65 years old, and patients with CURB65 scores of 3-4). RESULTS: We included 200 patients from the original trial, with 93/200 (46.5%) patients only treated with intravenous treatment and 107/200 (53.5%) patients only treated with oral therapy. The failure rate at Day 15 was not significantly different among patients treated with initial intravenous vs. oral treatment [25/93 (26.9%) vs. 28/107 (26.2%), adjusted odds ratios (aOR) 0.973 (95% CI 0.519-1.823), p 0.932)]. Failure rates at Day 15 were not significantly different among the subgroup populations. DISCUSSION: Among hospitalized patients with CAP, there was no significant difference in efficacy between initial intravenous and exclusive oral treatment. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT01963442.

Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD), and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives, and society. However, the underlying pathomechanisms are poorly understood, and current therapies mostly aim at supporting patients in their daily lives. This illustrates the urgent need to elucidate the pathogenesis and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modeling of cognitive disorders in CKD. We discuss the use of mice, rats, and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving the therapy of people with CKD and MCI.

Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review.

Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.

[Neurocognitive disorders in chronic kidney disease]. / Les troubles neurocognitifs dans la maladie rénale chronique.

Neurocognitive disorders (NCD) are common in patients with chronic kidney disease (CKD). It is essential to identify and characterize these disorders at an early stage, so as to be able to offer appropriate treatment. In a chronic disease such as CKD, the patient's involvement in decision-making is a major challenge, given the prospects for suppletive treatment: hemodialysis, peritoneal dialysis, kidney transplantation or non-dialytic drug therapy. Many factors are associated with the development and progression of NCD in patients with CKD, and a variety of conditions can influence the outcome of cognitive assessment in these patients.

Do Proton Pump Inhibitors Reduce Upper Gastrointestinal Bleeding in Older Patients with Atrial Fibrillation Treated with Oral Anticoagulants? A Nationwide Cohort Study in France.

BACKGROUND: Proton pump inhibitors (PPIs) are largely used in older adults and data are needed in off-label indications, such as the prevention of upper gastrointestinal bleeding (UGIB) in patients receiving oral anticoagulants (OACs). This study aimed to assess whether PPIs reduce the risk of UGIB in patients initiating oral anticoagulation. METHODS: We conducted a longitudinal study based on the French national health database. The study population included 109,693 patients aged 75-110 years with a diagnosis of atrial fibrillation who initiated OACs [vitamin K antagonist (VKA) or direct OAC (DOAC)] between 2012 and 2016. We used multivariable Cox models weighted by inverse of probability of treatment to estimate the adjusted hazard ratio (aHR) of UGIB between PPI users and nonusers over a 6- and 12-month follow-up. RESULTS: PPI users represented 23% of the study population (28% among VKA initiators and 17% among DOAC initiators). The mean age (83 ± 5.3 years) and proportion of women (near 60%) were similar between groups. The risk of UGIB in the first 6 months after initiation of OAC decreased by 20% in PPI users compared with PPI nonusers [aHR6 months = 0.80, 95% confidence interval (CI) 0.65-0.98], but was not significantly modified when the follow-up was extended to 12 months (aHR12 months = 0.90, 95% CI 0.76-1.07), with a stronger effect among patients treated with vitamin K antagonists (aHR6 months = 0.73, 95% CI 0.58-0.93; aHR12 months = 0.81, 95% CI 0.67-0.99). CONCLUSIONS: This study suggests that PPIs were associated with reduced risk of gastrointestinal bleeding after initiation of oral anticoagulation in older patients with atrial fibrillation, particularly within 6 months after initiation of an antivitamin K antagonist.

Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients.

There is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood-brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects.

A New Approach for Cognitive Impairment Pattern in Chronic Kidney Disease.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) is associated with an elevated risk of neurocognitive disorders (NCDs). It remains unclear whether CKD-related NCDs have specific cognitive pattern or are earlier-onset phenotypes of the main NCDs (vascular NCDs and Alzheimer's disease). METHODS: We used the Mini Mental State Examination score (MMSE) to assess cognitive pattern in 3003 CKD patients (stage 3 to 4) followed up over 5 years in the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort. After normalizing MMSE scores to a 0-to-100 scale, the associations between the baseline estimated glomerular filtration rate (eGFR, using the CKD-EPI-creatinine formula) and changes in each MMSE domain score were assessed in linear mixed models. RESULTS: Patients (age: 67±13 years old; males: 65%, mean eGFR: 33±12 ml/min/1.73 m²) had a good baseline cognitive functions: the mean MMSE score was 26.9/30 ±2.9. After adjustment for age, sex, educational level, depression (past or present), cardiovascular risk factors, cerebrovascular disease, a lower baseline eGFR (per 10 ml/min/1.73 m²) was associated with a 0.53-point decrement (p<0.001; 95%CI [-0.98,-0.08]) for orientation, a 1.04-point decrement (p=0.03; 95%CI [-1.96,-0.13]) for attention and calculation, a 0.78-point decrement (p=0.003; 95%CI [-1.30,-0.27]) for language, and a 0.94-point decrement (p=0.02; 95%CI [-1.75,-0.13]) for praxis. Baseline eGFR was not, however, associated with significant changes over time in MMSE domain scores. CONCLUSION: A lower eGFR in CKD patients was associated with early impairments in certain cognitive domains: praxis, language and attention domains before an obvious cognitive decline. Early detection of NCD in CKD patients must be perform before clinically cognitive decline using preferably tests assessing executive, attentional functions and language than memory test. This could lead to a better management of cognitive impairment and their consequences on CKD management.

Importance of cytochrome 3A4 and 2D6-mediated drug-drug interactions in oxycodone consumption among older adults hospitalized for hip fracture: a cross-sectional study.

Hip fracture is a common injury and represents a major health problem with an increasing incidence. In older adults, opioids such as oxycodone are often preferred to other analgesics such as tramadol because of a lower risk of delirium. Different parameters, such as inhibition of cytochrome P450 (CYP450) 2D6 and/or 3A4, can potentially lead to pharmacokinetic variations of oxycodone representing a risk of adverse drugs effects or lack of drug response. There is a risk of drug-drug interactions involving CYP450 in older adults due to the high prevalence of polypharmacy. This study sought to identify patient characteristics that influence oxycodone administration. A single-center observational study included 355 patients with a hip fracture hospitalized in a geriatric postoperative unit. Composite endpoint based on form, duration, and timing to intake separated patients into three groups: "no oxycodone", "low oxycodone ", and "high oxycodone ". CYP450 interactions were studied based on a composite variable defining the most involved CYP450 pathways between CYP2D6 and CYP3A4. CYP450 interactions with CYP2D6 pathway involved were associated with the risk of "high oxycodone" [odds ratio adjusted on age and the type of hip fracture (OR*) 4.52, 95% confidence interval (CI) 1.39-16.83, p = 0.02)], as well as serum albumin levels (OR* 1.09, 95% CI 1.02-1.17, p = 0.01). Cognitive impairment was negatively associated with the risk of "high oxycodone" (OR* 0.38, 95% CI 0.18-0.77, p = 0.02). This study showed an association between CYP2D6 interactions and higher oxycodone consumption indirectly reflecting the existence of uncontrolled postoperative pain.

Methodological challenges and biases in the field of cognitive function among patients with chronic kidney disease.

Chronic kidney disease (CKD) affects approximately 850 million people globally and is associated with an increased risk of cognitive impairment. The prevalence of cognitive impairment among CKD patients ranges from 30 to 60%, and the link between CKD and cognitive impairment is partially understood. Methodological challenges and biases in studying cognitive function in CKD patients need to be addressed to improve diagnosis, treatment, and management of cognitive impairment in this population. Here, we review the methodological challenges and study design issues, including observational studies' limitations, internal validity, and different types of bias that can impact the validity of research findings. Understanding the unique challenges and biases associated with studying cognitive function in CKD patients can help to identify potential sources of error and improve the quality of future research, leading to more accurate diagnoses and better treatment plans for CKD patients.

Plasma lipidomic analysis to investigate putative biomarkers of P-glycoprotein activity in healthy volunteers.

P-glycoprotein (P-gp) is an efflux transporter involved in the bioavailability of many drugs currently on the market. P-gp is responsible for several drug-drug interactions encountered in clinical practice leading to iatrogenic hospital admissions, especially in polypharmacy situations. ABCB1 genotyping only reflects an indirect estimate of P-gp activity. Therefore, it would be useful to identify endogenous biomarkers to determine the P-gp phenotype to predict in vivo activity prior to the initiation of treatment and to assess the effects of drugs on P-gp activity. The objective of this study was to assess changes in plasma lipidome composition among healthy volunteers selected on the basis of their ABCB1 genotype and who received clarithromycin, a known inhibitor of P-gp. Untargeted lipidomic analysis based on liquid chromatography-tandem mass spectrometry was performed before and after clarithromycin administration. Our results revealed changes in plasma levels of some ceramides (Cers) {Cer(d18:1/22:0), Cer(d18:1/22:1), and Cer(d18:1/20:0) by ~38% (p < 0.0001), 13% (p < 0.0001), and 13% (p < 0.0001), respectively} and phosphatidylcholines (PCs) {PC(17:0/14:1), PC(16:0/18:3), and PC(14:0/18:3) by ~24% (p < 0.001), 10% (p < 0.001), and 23.6% (p < 0.001)} associated with both ABCB1 genotype and clarithromycin intake. Through the examination of plasma lipids, our results highlight the relevance of untargeted lipidomics for studying in vivo P-gp activity and, more generally, to safely phenotyping transporters.

Cognitive disorders in patients with chronic kidney disease: Approaches to prevention and treatment.

BACKGROUND: Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition. METHODS: Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives. RESULTS: A particular attention on kidney function assessment is suggested during work-up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce. CONCLUSIONS: There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD.

Real-life impact of respiratory panel PCR assay on antibiotic prescription in geriatric acute care in the pre-COVID-19 era.

OBJECTIVES: In this era of bacterial resistance, avoiding inappropriate use of antibiotic treatments is of major importance. Respiratory tract infections are frequent among older patients, and differentiating viral from bacterial infections is a challenge. The aim of our study was to evaluate the impact of recently available respiratory PCR testing on antimicrobial prescription in geriatric acute care. METHODS: We performed a retrospective study, including all hospitalized geriatric patients who had had multiplex respiratory PCR testing prescribed from 1st October 2018 to 30th September 2019. The PCR test comprised a respiratory viral panel (RVP) and a respiratory bacterial panel (RBP). PCR testing could be prescribed at any time during hospitalization by geriatricians. Our primary endpoint was antibiotic prescription after viral multiplex PCR testing results. RESULTS: All in all, 193 patients were included, 88 (45.6%) of whom had positive RVP, while none had positive RBP. Patients with positive RVP had significantly fewer antibiotic prescriptions following test results than patients with negative RVP (odds ratio (OR) 0.41, 95% confidence interval (CI) 0.22-0.77; p = 0.004). Among positive-RVP patients, factors associated with antibiotic continuation were presence of radiological infiltrate (OR 12.02, 95%CI 3.07-30.29), and detected Respiratory Syncytial Virus (OR 7.54, 95%CI 1.74-32.65). That said, discontinuation of antibiotic treatment seems safe. CONCLUSION: In this population, the impact of viral detection by respiratory multiplex PCR on antibiotic therapy was low. It could be optimized by means of clearly formulated local guidelines, qualified staff and specific training by infectious disease specialists. Cost-effectiveness studies are necessary.

Prevalence of prediabetes and undiagnosed diabetes in a large urban middle-aged population: the CARVAR 92 cohort.

BACKGROUND: The aim of this study was to assess the prevalence of prediabetes and unknown diabetes and its long-term change in a large middle-aged urban population. METHODS: We conducted a screening campaign between 2007 and 2018 for cardiovascular risk factors in the western suburbs of Paris including subjects aged 40-70 (CARVAR 92). Among subjects who reported no previous diabetes, prediabetes and undiagnosed diabetes were defined as follows: fasting plasma glucose (FPG) ≥ 6.1 mmol/l (110 mg/dl) and < 7 mmol/l (126 mg/dl) for prediabetes according to WHO criteria (FPG between 5.6 and 6.9 mmol/l according to ADA criteria) and FPG ≥ 7.0 mmol/l for undiagnosed diabetes. RESULTS: Of the 32,721 subjects in the CARVAR 92 cohort, 32,675 were included in this analysis. The median age of the patients was 56 years [30, 94], 45.4% were male, 5.9% had known diabetes, 36.4% were overweight and 18.7% obese. Among patients without previously known diabetes (n = 30,759), 8.1% had prediabetes according to WHO criteria (27.2% according to ADA criteria) and 2.3% had diabetes. Subjects with prediabetes and unknown diabetes were more likely to be male, older, and overweight or obese than non-diabetic subjects. From 2007 to 2018, the prevalence of prediabetes, unknown diabetes, and known diabetes decreased, except for prediabetes which remained stable for people aged 55-64. CONCLUSION: The prevalence of prediabetes and unknown diabetes remains high but decreased during a 12-year period. About one-quarter of diabetes cases remain undiagnosed. Our results highlight that there is still a room for screening and cardiovascular prevention campaigns. TRIAL REGISTRATION: IRB00012437.

Cognitive performance is associated with glomerular filtration rate in patients with chronic kidney disease: results from the CKD-REIN cohort.

BACKGROUND: Chronic kidney disease (CKD) is associated with cognitive impairment in general population. We assessed the association between kidney and cognitive functions in patients with CKD and the influence of cardiovascular (CV) risk factors, and depression on this association. METHODS: The CKD-Renal Epidemiology and Information Network cohort included 3033 patients with CKD stages 3-4, followed for 5 years. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and estimated glomerular filtration rate (eGFR) with the CKD-Epidemiology Collaboration equation-creatinin formula. Evolution of the MMSE score over time and its association with baseline eGFR were investigated with linear mixed models. We assessed the risk of incident cognitive outcome (hospitalisation or death with relevant International Classification of Disease-10 codes), with a Cox proportional hazard model. RESULTS: The mean age was 66.8, the mean eGFR was 33 mL/min/1.73 m2 and 387 patients (13.0%) had an MMSE score below 24 at baseline. A 10 mL/min/1.73 m2 decrement of baseline eGFR was associated with a mean MMSE decrease of 0.12 (95% CI 0.04 to 0.19) after adjustment for demographic characteristics, depression, CV risk factors and disease; but baseline eGFR was not associated with MMSE temporal evolution. HR for cognitive outcome during follow-up (median 2.01 years) associated with a 10 mL/min/1.73 m2 decrement of baseline eGFR was 1.35 (1.07, 1.70) (p=0.01) after adjustment. CONCLUSIONS: In patients with CKD, lower eGFR was associated with worse cognitive performance and incident cognitive events, independently of demographics, CV risk factors and depression. TRIAL REGISTRATION NUMBER: NCT03381950.