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Öğe Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease(Oxford University Press, 2022) Silva, Pedro H. Imenez; Unwin, Robert; Hoorn, Ewout J.; Ortiz, Alberto; Trepiccione, Francesco; Nielsen, Rikke; Pesic, Vesna; Hafez, Gaye; Fouque, Denis; Massy, Ziad A.; Zeeuw, Chris I. De; Capasso, Giovambattista; Wagner, Carsten A.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 CKDÖğe Albuminuria as a risk factor for mild cognitive impairment and dementia—what is the evidence?(Nephrol Dial Transplant, 2021) Bikbov, Boris; Soler, Maria Jose; Pesic, Vesna; Capasso, Giovambattista; Unwin, Robert; Endres, Matthias; Remuzzi, Giuseppe; Perico, Norberto; Gansevoort, Ron; Mattace-Raso, Francesco; Bruchfeld, Annette; Figurek, Andreja; (Cognitive Decline in Nephro-Neurology European Cooperative Target; Hafez, GayeKidney 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.Öğe Animal models to study cognitive impairment of chronic kidney disease(2024) Silva, Pedro H. Imenez; Pepin, Marion; Figurek, Andreja; Gutierrez-Jimenez, Eugenio; Bobot, Mickael; Iervolino, Anna; Mattace-Rosso, Francesco; Hoorn, Ewout J.; Bailey, Matthew A.; Henaut, Lucie; Nielsen, Rikke; Frische, Sebastian; Trepiccione, Francesco; Hafez, Gaye; Altunkaynak, Hande O.; Endlich, Nicole; Unwin, Robert; Capasso, Giovambattista; Pesic, Vesna; Massy, Ziad; Wagner, Carsten A.; Consortium, ConnectMild 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 life. 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 modelling 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 therapy of people with CKD and MCI.Öğe Big databases and biobanks for studying the links between CKD, cognitive impairment, and dementia(2025) Zoccali, Carmine; Mallamaci, Frances; Rosenberg, Kerry; Unwin, Robert; Silva, Pedro Imenez; Simeoni, Maria Adelina; Hafez, Gaye; Capasso, Giovambattista; Nitsch, Dorothea; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) collaboratorsResearch on cognitive function in individuals with chronic kidney disease (CKD) is critical due to the significant public health challenge posed by both CKD and cognitive impairment. CKD affects approximately 10-15% of the adult population, with higher prevalence in the elderly, who are already at increased risk for cognitive decline. Cognitive impairment is notably higher in CKD patients, particularly those with severe stages of the disease, and progresses more rapidly in those on dialysis. This review explores how data from large biobank studies such as the Alzheimer's Disease Neuroimaging Initiative, UK Biobank, and others could be used to enhance understanding the progression and interplay between CKD and cognitive decline. Each of these data sources has specific strengths and limitations. Strengths include large sample sizes and longitudinal data across different groups, and in different settings. Addressing limitations leads to challenges in dealing with heterogeneous data collection methods, and addressing missing data, which requires the use of sophisticated statistical techniques. Combining data from multiple databases can mitigate individual study limitations, particularly via the 'epidemiological triangulation' concept. Using such data appropriately holds immense potential to better understand the pathobiology underlying CKD and cognitive impairment. Addressing the inherent challenges with a clear strategy is crucial for advancing our understanding and improving the lives of those affected by both CKD and cognitive impairment.Öğe Chemotherapy-related cognitive impairment and kidney dysfunction(2025) Simeoni, Mariadelina; Mulholland, Michele M.; Workeneh, Biruh T.; Capasso, Anna; Capasso, Anna; Hafez, Gaye; Liabeuf, Sophie; Malyszko, Jolanta; Mani, Laila-Yasmin; Trevisani, Francesco; De, Ananya; Wagner, Carsten A.; Massy, Ziad A.; Unwin, Robert; Capasso, Giovambattista; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) collaboratorsCancer and kidney diseases (KD) intersect in many ways resulting in worse outcomes. Both conditions are correlated with cognitive impairment, which can be exacerbated in cancer patients by known effects of many antineoplastic drugs on cognition, leading to a phenomenon known as chemotherapy-related cognitive impairment (CRCI). This manifests as poor attention span, disturbed short-term memory, and general mental sluggishness. This literature review explores CRCI and investigates the potential impact of KD on this phenomenon. Additionally, we highlight the shared pathogenetic mechanisms (including neurotoxicity, neuroinflammation, oxidative stress, vascular disease, electrolyte, and acid-base imbalances), clinical presentation and imaging findings between cognitive impairment in KD and CRCI. The disruption of the blood-brain barrier might be a key mechanism for increased brain permeability to anticancer drugs in nephropathic patients with cancer. Based on existing knowledge, we found a potential for heightened neurotoxicity of antineoplastic drugs and a synergistic potentiation of cognitive impairment in cancer patients with KD. However, further translational research is urgently required to validate this hypothesis.Öğe Cholinergic system in patients with chronic kidney disease: cognitive and renal implications(2025) Xu, Hong; Eriksdotter, Maria; Hafez, Gaye; Sumonto, Mitra; Bruchfeld, Annette; Pesic, Vesna; Unwin, Robert; Wagner, Carden A.; Massy, Carsten; Massy, Ziad A.; Zoccali, Carmine; Pepin, Marion; Capasso, Giovambattista; Liabeuf, Sophie; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target)Cholinergic synapses are widespread throughout the human central nervous system. Their high density in the thalamus, neocortex, limbic system, and striatum suggests that cholinergic transmission plays a vital role in memory, attention, learning and other higher cognitive functions. As a result, the brain's cholinergic system occupies a central position in research on normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. In addition to its role in the brain, neuronal cholinergic pathways are essential for the physiological regulation of bodily organs, including the kidneys, through the parasympathetic branch of the peripheral nervous system. Chronic kidney disease (CKD) is a non-communicable disease with a global prevalence of approximately 10%. Cognitive impairment is common among patients with CKD, with reported prevalence rates ranging from 30% to 60%, depending on definitions and assessment methods used. Given the importance of the cholinergic system in cognitive processes, it may be a key area of focus for evaluating cognitive function in this population. In this current narrative review, we will first examine evidence linking the cholinergic system to cognitive functions; with a specific focus on drugs that affect this system. we will then discuss the potential implications of cholinergic function in patients with CKD.Öğe Drugs with a negative impact on cognitive functions (part 3): antibacterial agents in patients with chronic kidney disease(2024) Liabeuf, Sophie; Hafez, Gaye; Pesic, Vesna; Spasovski, Goce; Bobot, Mickael; Maciulaitis, Romaldas; Bumblyte, Inga Arune; Ferreira, Ana Carina; Farinha, Ana; Malyszko, Jolanta; Pepin, Marion; Massy, Ziad A.; Unwin, Robert; Capasso, Giovambattista; Mani, Laila-Yasmin; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target)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.Öğe Genetic and circulating biomarkers of cognitive dysfunction and dementia in CKD(2025) Zoccali, Carmine; Mallamaci, Francesca; Wagner, Carsten A.; Unwin, Robert; Nedergaard, Maiken; Hafez, Gaye; Malyszko, Jolanta; Pepin, Marion; Massy, Ziad; Paolisso, Giuseppe; Remuzzi, Giuseppe; Capasso, Giovambattista B.; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) collaboratorsChronic kidney disease (CKD) is commonly accompanied by cognitive dysfunction and dementia, which, in turn, increase the risk of hospitalization, cardiovascular events and death. Over the last 30 years, only four studies focused on genetic markers of cognitive impairment in CKD and kidney failure (KF), indicating a significant gap in research. These studies suggest potential genetic predispositions to cognitive decline in CKD patients but also underscore the necessity for more comprehensive studies. Seventeen reports have established connections between cognitive function and kidney disease markers such as estimated glomerular filtration rate (eGFR), Cystatin C and albuminuria. A rapid eGFR decline has been associated with cognitive deterioration and vascular dementia, and mild to moderate eGFR reductions with diminished executive function in elderly men. Various biomarkers have been associated to Alzheimer’s disease or dementia in CKD and KF. These include amyloid beta and phosphorylated tau proteins, uremic toxins, gut microbiota, metabolic indicators, hypertension, endothelial dysfunction, vitamins and inflammation. However, the causal relevance of these associations remains unclear. Overall, the available evidence points to a complex interplay between the different biomarkers and cognitive health in CKD patients, underscoring the need for more research to elucidate these relationships.
