Drivers and mechanisms of cognitive decline in chronic kidney disease.

Robert J Unwin, Mark D Okusa, Alessandro Tessitore, Maiken Nedergaard, Casper F M Franssen, Alessandra F Perna, Giovambattista Capasso, Carsten A Wagner, Ziad A Massy, Carmine Zoccali, Alberto Ortiz, Robert I Menzies

Journal: Nature reviews. Nephrology 2025;21(8):536-552

PMID: 40281076

Full Text on Nature Publishing Group View on PubMed

Abstract

Cognitive impairment is highly prevalent among individuals with chronic kidney disease (CKD). Despite its high prevalence, the contributing factors and mechanisms underlying brain-kidney dysfunction in CKD remain poorly understood. However, advances in neuroscience, including novel imaging techniques and cognitive assessment methods, have begun to clarify this complex relationship. Several factors contribute directly to cognitive decline in people with CKD, including accumulation of uraemic toxins, microvascular damage, malnutrition, chronic inflammation and disruptions in key neuroprotective pathways, such as those involving Klotho and the glymphatic system. These factors are also linked to the accelerated ageing observed in people with CKD, a key contributor to cognitive decline. However, most studies on cognition in people with CKD have been cross-sectional and associative, offering limited insight into causation. Research advances, such as studies on the effect of uraemic toxins on the blood-brain barrier and the role of the endothelial glycocalyx in vascular damage, offer promising new directions. Emerging data from longitudinal cohort studies are also enhancing our understanding of these processes, with potential implications for both the treatment of CKD-related cognitive decline and the broader issue of cognitive dysfunction in ageing populations. Here, we examine key mechanisms linking CKD to cognitive decline and consider potential therapeutic interventions.

Address: Biogem, Institute of Molecular Biology and Genetics, Ariano Irpino, Italy. [email protected].; Department of Translational Medical Science, University of Campania Luigi Vanvitelli, Naples, Italy. [email protected].; Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.; Department of Translational Medical Science, University of Campania Luigi Vanvitelli, Naples, Italy.; AURA (Association pour l'Utilization du Rein Artificiel dans la Region Parisienne) Paris, Department of Nephrology, CHU Ambroise Paré, AP-HP, Paris, France.; Centre for Research in Epidemiology and Population Health (CESP), University Paris-Saclay, University Versailles-Saint Quentin, Inserm UMRS 1018, Clinical Epidemiology Team, Villejuif, France.; Edinburgh Kidney, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.; Biogem, Institute of Molecular Biology and Genetics, Ariano Irpino, Italy.; Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio, Italy.; Department of Advanced Surgical and Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.; Center for Basic and Translational Neuroscience, University of Copenhagen, Copenhagen, Denmark.; Division of Nephrology, Center for Immunity Inflammation and Regenerative Medicine University of Virginia, Charlottesville, VA, USA.; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD UAM), Madrid, Spain.; Institute of Physiology and Zurich Kidney Center University of Zurich, Zurich, Switzerland.; UCL Centre for Kidney and Bladder Health, University College London, London, UK.

DOI: 10.1038/s41581-025-00963-0

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https://doi.org/10.1038/s41581-025-00963-0

MeSH Terms: Humans, Renal Insufficiency, Chronic, Cognitive Dysfunction, Blood-Brain Barrier