Chronic Kidney Disease and Cardiac Remodeling Potentiate Cognitive Impairment Progression: Disentangling the Sex-Specific Crosstalk of Kidney-Heart-Brain Axis

Chronic kidney disease (CKD)-mediated oxidative stress, uremic toxicity, inflammation, and cardiovascular (CV) damage connect the kidney-heart-brain axis that contributes to cognitive impairment (CI) and progression to major neurological disorders. Although the sex disparity has a profound impact on CKD epidemiology, its role in the progression of CI needs to be elucidated in detail. The present study aims to unravel the sex-specific crosstalk of the kidney-heart-brain axis in CKD. CKD and control subjects, equally represented by both sexes, were included in a cross-sectional study that involved a community-dwelling rural population. CV and CKD parameters, mini-mental state examination (MMSE), markers of fibrosis and neurodegeneration were assessed. We elucidated the sex-specific associations among these factors through linear regression and structural equation modeling (SEM), or Path, analyses. CKD patients have higher blood pressure vs. controls, and men with CKD exhibited a decline in cardiac function vs. sex- and age-matched controls. Both men and women with CKD had lower MMSE scores vs. controls, although cognitive performance in CKD-women was significantly better than that of CKD-men. Path analysis revealed a direct association of the plasma phosphorylated Tau protein (pTau) and the ratio of amyloid β-42 to amyloid β-40 with MMSE scores in women only. Pro-brain natriuretic peptide and pTau were associated with short-term memory, a part of the MMSE assessment, also in women only. Our findings will broaden the current understanding and clinical consequences of the pathophysiological interactions between kidney and CV damage with brain function in a sex-dependent manner that could prompt innovative pharmacological interventions.