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    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) collaborators
    Research 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.
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    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.
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    Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review
    (2024) Barbieri, Michelangela; Chiodini, Paolo; Di Gennaro, Piergiacomo; Hafez, Gaye; Liabeuf, Sophie; Malyszko, Jolanta; Mani, Laila-Yasmin; Raso, Francesco Mattace; Pepin, Marion; Perico, Norberto; Simeoni, Mariadelina; Zoccali, Carmine; Tortorella, Giovanni; Capuano, Annalisa; Remuzzi, Giuseppe; Capasso, Giovambattista; Paolisso, Giuseppe; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) collaborators
    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.
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    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) collaborators
    Chronic 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.