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.

Barriers and Unmet Educational Needs Regarding Implementation of Medication Adherence Management Across Europe: Insights from COST Action ENABLE.

BACKGROUND: Medication adherence is essential for the achievement of therapeutic goals. Yet, the World Health Organization estimates that 50% of patients are nonadherent to medication and this has been associated with 125 billion euros and 200,000 deaths in Europe annually. OBJECTIVE: This study aimed to unravel barriers and unmet training needs regarding medication adherence management across Europe. DESIGN: A cross-sectional study was conducted through an online survey. The final survey contained 19 close-ended questions. PARTICIPANTS: The survey content was informed by 140 global medication adherence experts from clinical, academic, governmental, and patient associations. The final survey targeted healthcare professionals (HCPs) across 39 European countries. MAIN MEASURES: Our measures were barriers and unmet training needs for the management of medication adherence across Europe. KEY RESULTS: In total, 2875 HCPs (pharmacists, 40%; physicians, 37%; nurses, 17%) from 37 countries participated. The largest barriers to adequate medication adherence management were lack of patient awareness (66%), lack of HCP time (44%), lack of electronic solutions (e.g., access to integrated databases and uniformity of data available) (42%), and lack of collaboration and communication between HCPs (41%). Almost all HCPs pointed out the need for educational training on medication adherence management. CONCLUSIONS: These findings highlight the importance of addressing medication adherence barriers at different levels, from patient awareness to health system technology and to fostering collaboration between HCPs. To optimize patient and economic outcomes from prescribed medication, prerequisites include adequate HCP training as well as further development of digital solutions and shared health data infrastructures across Europe.

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.

Albuminuria as a risk factor for mild cognitive impairment and dementia-what is the evidence?

Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria's effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria's link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease.

Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care.

Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease.

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10-30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD.

Profiling of cardiac ß-adrenoceptor subtypes in the cardiac left ventricle of rats with metabolic syndrome: Comparison with streptozotocin-induced diabetic rats.

Little is known about metabolic syndrome (MetS)-associated cardiomyopathy, especially in relation to the role and contribution of beta-adrenoceptor (ß-AR) subtypes. Therefore, we examined the roles of ß-AR subtypes in the cardiac function of rats with MetS (MetS group) and compared it with that of rats with streptozotocin (STZ)-induced diabetes (STZ group). Compared with the normal control rats, the protein levels of cardiac ß1- and ß2-AR in the MetS group were significantly decreased and with no changes in their mRNA levels, whereas the protein levels of ß3-AR were similar to those of the controls. However, as shown previously, the protein levels of cardiac ß1- and ß2-AR in the STZ group were decreased, whereas the ß3-AR levels were significantly increased by comparison with the controls. Additionally, the mRNA levels of ß2- and ß3-AR were increased, but ß1-AR mRNA was decreased in the STZ group. Furthermore, left ventricular developed pressure responses to ß3-AR agonist BRL37344 were increased in the STZ group but not in the MetS group, whereas for both groups, the responses to noradrenaline were not different from those of the controls. However, the response to stimulation with high concentrations of fenoterol was depressed in the MetS group, compared with the controls, but not in the STZ group. Consequently, our data suggest that the contribution of the ß-AR system to cardiac dysfunction in the rats with MetS is not the same as that in the STZ group, although they have similar cardiac dysfunction with similar ultrastructural changes to the myocardium.

Cognitive decline related to chronic kidney disease as an exclusion factor from kidney transplantation: results from an international survey.

Background and hypothesis: There seems to be a lack of consensus on the necessity and the modality of psychological and specifically cognitive assessment of candidates for kidney transplantation. Both points are often delegated to individual hospitals/centres, whereas international guidelines are inconsistent. We think it is essential to investigate professionals' opinions to advance towards a consistent clinical practice. Methods: This paper presents the results of an international survey among clinical professionals, mainly nephrologists from the CONNECT (Cognitive decline in Nephro-Neurology: European Cooperative Target) network and beyond (i.e. from personal contacts of CONNECT members). The survey investigated their opinions about the question of whether cognitive decline in patients with chronic kidney disease may affect their eligibility for kidney transplantation. Results: Our results show that most clinicians working with patients affected by chronic kidney disease think that cognitive decline may challenge their eligibility for transplantation despite data that suggest that, in some patients, cognitive problems improve after kidney transplantation. Conclusion: We conclude that three needs emerge as particularly pressing: defining agreed-on standards for a multifaceted and multifactorial assessment (i.e. including both clinical/medical and psychosocial factors) of candidates with chronic kidney disease to kidney transplantation; further investigating empirically the causal connection between chronic kidney disease and cognition; and further investigating empirically the possible partial reversibility of cognitive decline after kidney transplantation.

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.

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor.

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.

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.

Alteration in contractile responses in human detrusor smooth muscle from obstructed bladders with overactivity.

INTRODUCTION: In this study, we aimed to evaluate changes in contractile responses under in vitro conditions in detrusor overactivity (DO) in patients with bladder outflow obstruction (BOO). MATERIALS AND METHODS: Detrusor strips obtained during open prostatectomy procedure from 16 patients with BOO related to benign prostate hyperplasia were evaluated under in vitro conditions. Patients were assigned to two groups as patients with (DO) and without (no DO) DO. Four detrusor strips were prepared from each bladder in dimensions of 2 x 10 mm, and were suspended in organ bath. Responses to carbachol (10(-8) to 10(-3)M), electrical field stimulation (EFS) (0.5-32 Hz), single-dose adenosine 5'-triphosphate (ATP) (10(-3)M) and KCl (120 mM) were recorded to evaluate the contractile responses. EFS responses were repeated in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 10 muM) and L-NAME + indomethacin. All responses were expressed as mg tension developed per mg of bladder tissue. Data obtained were compared using independent t test and one-way ANOVA test. Values of p < 0.05 were accepted as statistically significant. RESULTS: Of the 16 patients on whom open prostatectomy was performed because of BOO, 8 of the patients were determined as no DO and 8 as DO. There were no differences between groups regarding age and residual urine. We found statistically significant differences between groups regarding dimensions of prostate, maximum bladder capacity and maximum bladder pressure. In the comparison of cumulative dose of carbachol, it was seen that responses were higher in the DO group, but the differences were not statistically significant. In EFS application, contractile responses were found to increase significantly in the DO group. No changes were observed between groups for ATP and KCl. EFS responses were found to be significantly higher in presence of L-NAME + indomethacin in the no DO group; however, no difference was seen in the DO group. CONCLUSIONS: Detrusor contractile responses to EFS increased in patients with BOO in presence of overactivity. These changes in contractile responses are observed possibly as a result of deterioration in neuromodulation, rather than as a result of changes in purinergic or cholinergic receptor sensation or level. We suggest that a noncholinergic-nonpurinergic mechanism can have some effect on these changes.

The effect of diabetes mellitus on α1-adrenergic receptor subtypes in the bladder of rats.

OBJECTIVE: To detect the possible alterations on density or sensitivity of α1-adrenergic subtypes in diabetic bladder by reverse transcriptase-polymerase chain reaction technology and in vitro studies. METHODS: Experimental diabetes was induced by administration of streptozotocin with a single injection through the tail vein. Rats were divided into control and diabetic groups. Contractile responses of bladder strips from each group were obtained for postassium chloride, adenosine triphosphate, and electrical field stimulation (0.5-32 Hz) in organ bath. Electrical field stimulation responses of strips were evaluated in the presence of PPADS (nonselective P2 antagonist), atropine (cholinergic antagonist), 5 MU (α-1a-adrenergic antagonist), BMY-7378 (α-1d-adrenergic antagonist), and finally CED (α-1b-adrenergic antagonist). mRNA expression of α1-adrenergic subtypes was determined for each group. RESULTS: The difference between contractile responses related to electrical field stimulation with incubation with PPADS, atropine, 5 MU, BMY-7378, and CED, respectively, was not significant in the control and diabetic groups (P > .05). The electrical field stimulation responses of strips at 0.5-2 Hz without incubation were significantly different between the control and diabetic groups (P < .05). The contractile responses of strips with PPADS + atropine + 5 MU and BMY-7378 incubations in the diabetic group were significantly lower than in the control group in all doses (P < .05), The mRNA expression of α-1a-adrenergic in the diabetic group was significantly lower than in the control group (P < .05). No change was found in the expression of mRNA of α-1b-adrenergic. CONCLUSION: These results support the probability of changes in presynaptic and autonomic receptor sensitivity. We believe that α-1a-adrenergic and α-1d-adrenergic subtypes should be kept in mind in the treatment of diabetic cystopathy.

Effect of urothelium on bladder contractility in diabetic rats.

AIM: It is known that physiopathological changes in diabetes affect the function of the bladder. In this study, we aimed to demonstrate the possible effects of diabetes on the urothelium during this physiopathological process. METHODS: Diabetes was induced in rats by tail vein injection of 35 mg/kg streptozotocin. Eight weeks later, intact and denuded bladder strips were prepared from these rats. Electrical field stimulation (EFS; 0.5-32 Hz), carbachol (10(-8)-10(-3) mol/L; cumulative dosage-response curves) and KCl (120 mmol/L) were used for the evaluation of the contractile responses. All responses were expressed as mg tension developed per mg of bladder tissue. Weights of rats and of their bladders, blood glucose levels, and frequency- and concentration-response curves were compared using anova, the paired t-test and the independent t-test. Differences were considered significant at P<0.05. RESULTS: Although no differences related to the weight of bladders of the control and diabetic groups were observed, there were differences in blood glucose levels and body weights between the two groups. Similarly, although there were no differences between the data obtained with EFS and KCl from tissues with intact and denuded strips in the control group, carbachol responses significantly differed between intact and denuded strips in the non-diabetic group. These differences were not observed in the diabetic group. In the control groups, in the presence of additional strips with intact urothelium placed in the medium containing denuded tissue, the differences in contractile responses between the intact control strip and the denuded strip disappeared. CONCLUSIONS: Diabetes possibly changes the interaction between the relaxant factors that are released from urothelium and muscarinic stimulation, but these interactions are not completely understood yet. Consequently, the response of the bladder to contractile stimulants is also affected. Further studies are required to reveal the mechanism by which diabetes influences the urothelium.

Short-term effects of arsenic sulfur in deficits of contractile and relaxant responses on urinary bladder: pharmacological and structural changes.

INTRODUCTION: Our goal was to investigate the effects of arsenic sulfur (AsS) on the detrusor smooth muscle reactivity. MATERIAL AND METHODS: AsS (100 ppm microg/g) in drinking water was administered for 2 weeks to two groups of female Wistar rats. The contractile responses of urinary bladders to electrical field stimulation, carbachol, ATP and KCl, and the relaxant responses to ATP, adenosine and isoproterenol were examined. Urinary bladder strips were collected for light microscopic examination. RESULTS: Our results demonstrate that oral inorganic AsS exposure induced enhanced contractile and reduced relaxant responses in rats. We hypothesize that AsS is involved in deficiencies of isolated urinary bladder in rats. CONCLUSION: These functional and morphological changes may be important as an intermediate link in urinary bladder oncogenesis induced by AsS.