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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic kidney disease (CKD) is associated with neurological abnormalities ranging from subtle cognitive deficits to acute or subacute uremic encephalopathy. Although clinically distinct, these syndromes may arise from overlapping biological processes, including retained uremic solutes, cerebrovascular and blood\u2013brain barrier dysfunction, systemic and neuroinflammation, oxidative stress, mitochondrial impairment, and altered neurotransmission. This narrative review synthesizes clinical, experimental, and cellular evidence supporting the contribution of these interconnected pathways to CKD-associated brain dysfunction. We propose that chronic cognitive impairment reflects progressively reduced neuronal and neurovascular reserves. In contrast, uremic encephalopathy may emerge when severe metabolic, neurotoxic, inflammatory, or hemodynamic stress exceeds the remaining capacity for cerebral adaptation. Uremic toxins may act as CKD-specific upstream drivers of endothelial injury, glial activation, redox imbalance, and cellular metabolic dysfunction. These processes converge on impaired mitochondrial bioenergetics, disrupted synaptic homeostasis, reduced cerebrovascular responsiveness, and increased neuronal vulnerability. However, direct longitudinal evidence for a linear progression from cognitive impairment to uremic encephalopathy remains limited. We therefore propose a pathophysiological continuum linking chronic cerebral vulnerability with acute uremic decompensation, intended as a mechanistic model rather than as a diagnostic or classification framework. Clarifying their shared and distinguishing mechanisms may improve recognition of neurological vulnerability and support earlier therapeutic targeting of the kidney\u2013brain axis.<\/jats:p>","DOI":"10.3390\/ijms27198768","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:19Z","timestamp":1790773279000},"page":"8768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Cognitive Impairment to Uremic Encephalopathy in Chronic Kidney Disease: A Proposed Pathophysiological Continuum"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0172-5789","authenticated-orcid":false,"given":"Jelena","family":"Nesovic Ostojic","sequence":"first","affiliation":[{"name":"Department of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6073-2663","authenticated-orcid":false,"given":"Andrija","family":"Vukovic","sequence":"additional","affiliation":[{"name":"Department of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5905-7173","authenticated-orcid":false,"given":"Sanjin","family":"Kovacevic","sequence":"additional","affiliation":[{"name":"Department of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4970-2156","authenticated-orcid":false,"given":"Aleksandra","family":"Nenadovic","sequence":"additional","affiliation":[{"name":"Department of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5746-746X","authenticated-orcid":false,"given":"Danijela","family":"Karanovic","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Physiology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0859-9252","authenticated-orcid":false,"given":"Silvio R.","family":"De Luka","sequence":"additional","affiliation":[{"name":"Department of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Deng, L., Guo, S., Liu, Y., Zhou, Y., Liu, Y., Zheng, X., Yu, X., and Shuai, P. 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