Chronic kidney disease and cardiac remodeling potentiate cognitive impairment progression: disentangling the sex-specific cross talk 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 cross talk 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 (SE), or Path, analyses. Patients with CKD have higher blood pressure versus controls, and men with CKD exhibited a decline in cardiac function versus sex- and age-matched controls. Both men and women with CKD had lower MMSE scores versus controls, although cognitive performance in women with CKD was significantly better than that of men with CKD. 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.<b>NEW & NOTEWORTHY</b> To our knowledge, the present study explored, for the first time, the direct sex-specific association of chronic kidney disease, cardiovascular disease, and cognitive function with a panel of fluid biomarkers of oxidative stress, inflammation, fibrosis, and neurodegeneration, including the novel profibrotic marker marinobufagenin. The study shows that dysregulated cardiac and neurodegeneration biomarkers, along with hypertension and cardiac remodeling, aggravate the progression of cognitive impairment in patients with chronic kidney disease (CKD) in a sex-specific manner.