In CKD-induced cognitive impairment, vascular hypothesis includes systemic hypertension, arteriosclerosis, and uremic toxin-related pathways. Schematic representation of the potential mechanism of cognitive impairment in patients with CKD and treatment strategies. In the context of AD, neuron-specific expressed Aβ can cause BACE-mediated kidney damage. These anti-anemia drugs exhibit beneficial effects on CDK-induced cognitive impairment. ![]() Roxadustat (FG-4592) is a PHD inhibitor that can stimulate endogenous EPO production. For risk factors such as anemia, rHuEPO is the standard therapy and also acts as a neuroprotective agent. Recombinant klotho proteins are used to treat and/or prevent CKD by reducing inflammation and injury. The antioxidant drug 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl shows potential to improve cognitive dysfunction in the CKD model. Therapies and interventions include inflammasome-targeted RNA interference approaches such as NLRP3 siRNA. Increased FGF23 directly impacts hippocampal neurons or interferes with the immune system. Oxidative stress leads to the cleavage of APP and Aβ production. Purine nucleotides alter the activity of AChE which is associated with cognitive impairment. Activation of AhR leads to BBB disruption and subsequently increases the transportation of inflammatory immune cells and proteins into the brain. Accumulation of uremic toxins, including phosphate, IS, and PCS, is agonists of the transcription factor AhR in endothelial cells. Specifically, CKD-related vascular damage can contribute to cognitive impairment by inducing impaired cerebral hemodynamics, altered brain microcirculation, or leakage of hemoglobin (HbA1c) and fibrinogen from vessels. These hypotheses together with other known factors such as albuminuria or anemia contribute to cognitive impairment. The nonvascular hypothesis contains purine nucleotides, oxidative stress, and FGF23-related pathways. Risk Factors Leading to Cognitive Impairment in CKD These basic scientific findings will provide translational values for developing new therapeutic strategies to prevent, treat, or reverse CKD-related cognitive impairment. ![]() Understanding kidney-brain interplay is a multidisciplinary issue in the scientific field. However, the intricate pathogenic relationship and exact modulation mechanisms between CKD and cognitive impairment remain unclear and require in-depth clarification. In fact, an 11-year follow-up study elucidated that albuminuria and microalbuminuria, as early markers of endothelial damage of the renal glomeruli, could help predict cognitive decline. It is especially worth noting that CKD is closely related to Alzheimer’s disease (AD), stroke, and cerebrovascular disease. Hence, CKD is deemed as one of the strongest risk factors for mild cognitive impairment and dementia. A substantial number of patients with CKD suffer from cognitive dysfunction. ![]() Cognitive impairment begins early in the course of the CKD and parallels kidney function decline. At the end stage of renal disease, which requires hemodialysis, 85% of patients endure memory loss, difficulty in execution, or language deficits. Cognitive impairment and deficits in one or more key brain functions, such as learning, memory, and sensory processing, have often been observed as accompanying symptoms of CKD, with a prevalence that depends on the stage of CKD among 16% and 38%. ![]() CKD-related complications include kidney disease progression, acute kidney injury, anemia, mineral and bone disorders, increased all-cause and cardiovascular mortality, and especially cognitive impairment. Global prevalence and incidence of CKD were shown to be 9.37% and 0.05%, respectively, in 2019. According to the 2019 Global Burden of Disease, 697.29 million people worldwide suffered from CKD, which caused about 1.427 million deaths. As an important risk factor for morbidity, CKD is a major health burden world-widely. Chronic kidney disease (CKD), also known as chronic kidney failure, is a gradual loss of kidney function that manifests in a decrease in the glomerular filtration rate or an increase in urinary albumin excretion.
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