Neuro-Renal Crosstalk Across the Chronic Kidney Disease Spectrum: Stage-Dependent Molecular Mechanisms of Cognitive Impairment-An Integrative Review.

Chronic kidney disease (CKD) is a major public health problem worldwide, affecting over 10% of the global population, and its prevalence continues to increase. In addition to classic comorbidities, including cardiovascular and metabolic disorders, cognitive impairment (CI) has recently been recognized as a serious complication of CKD. CI can be observed across the entire spectrum of CKD, from G1 to G5 stages, independent of age-related changes. The kidney-brain axis seems to provide a conceptual framework in which microvascular disease, blood-brain barrier disruption, uremic toxins, oxidative stress, systemic inflammation, and consequent neuroinflammation converge to promote CI. This narrative review aims to synthesize the existing evidence on stage-dependent molecular mechanisms of CI in CKD, integrating clinical observations with proposed molecular and pathophysiological mechanisms. Because most studies investigating CI in CKD rely primarily on eGFR-based staging, our analysis was structured around GFR categories, assessing early-to-moderate CKD, defined according to KDIGO as G1-G3 stages, advanced CKD stages, including G4-G5 not yet requiring kidney replacement therapies, and kidney failure treated with different modalities of kidney replacement therapy, such as peritoneal dialysis, hemodialysis, and kidney transplantation. In addition to clinical observations and the burden of CI in CKD, we describe the potential stage-dependent pathomechanisms underlying vascular-executive, uremic-toxic, inflammatory, dialysis-hemodynamic, and post-transplant medication-related profiles as a continuum of cognitive disorders in individuals with CKD.