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    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 CKD
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    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, Connect
    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 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.
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    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) collaborators
    Cancer 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.
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    Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor
    (2023) Liabeuf, Sophie; Pesic, Vesna; Spasovski, Goce; Maciulaitis, Romaldas; Bobot, Mickael; Farinha, Ana; Wagner, Carsten A.; Unwin, Robert J.; Capasso, Giovambattista; Bumblyte, Inga Arune; Hafez, Gaye
    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.
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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.