From Cognitive Impairment to Uremic Encephalopathy in Chronic Kidney Disease: A Proposed Pathophysiological Continuum
- 1Department of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- 2Department of Cardiovascular Physiology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
Abstract
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–brain 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–brain axis.
Related
- Follicular development impairment in polyendocrine metabolic ovarian syndrome: multidimensional pathophysiological networks and frontier therapeutic targets
- Longitudinal Changes in Structural and Functional Brain Imaging and Their Association with Cognitive and Neuropsychiatric Symptoms in Hashimoto Encephalopathy with Anti-NAE Antibody
- Harpagide alleviates neuroinflammation and cognitive dysfunction in sepsis-associated encephalopathy: Association with the MMP9/NF-κB signaling pathway
- CSF APOE Secondary Glycosylation Predicts Cognitive Decline in Mild Cognitive Impairment
- Multimodal neuroimaging and electrophysiological signatures in amnestic mild cognitive impairment with different amyloid-β deposition status: correlations with cognitive function and diagnostic value
BibTeX
@article{ostojic2026from,
title = {{From Cognitive Impairment to Uremic Encephalopathy in Chronic Kidney Disease: A Proposed Pathophysiological Continuum}},
author = {Jelena Nesovic Ostojic and Andrija Vukovic and Sanjin Kovacevic and Aleksandra Nenadovic and Danijela Karanovic and Silvio R. De Luka},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198768},
url = {https://europepmc.org/article/PMC/PMC13665095},
note = {CC BY},
}
RIS
TY - JOUR
TI - From Cognitive Impairment to Uremic Encephalopathy in Chronic Kidney Disease: A Proposed Pathophysiological Continuum
AU - Jelena Nesovic Ostojic
AU - Andrija Vukovic
AU - Sanjin Kovacevic
AU - Aleksandra Nenadovic
AU - Danijela Karanovic
AU - Silvio R. De Luka
PY - 2026
DA - 2026/09/30
JO - International journal of molecular sciences
DO - 10.3390/ijms27198768
UR - https://europepmc.org/article/PMC/PMC13665095
AB - 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–brain 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–brain axis.
SN - 1422-0067
ER -