Study Finds CKD Accelerates Cognitive Decline in Both Male and Female Patients

Research findings published in the American Journal of Physiology – Heart and Circulatory Physiology found chronic kidney disease (CKD) accelerated cognitive decline through interconnected damage to both the heart and the brain. Specifically, CKD-mediated oxidative stress, uremic toxicity, inflammation, and cardiovascular damage connect the kidney-heart-brain axis that contributes to cognitive impairment and progression to major neurological disorders.¹

The global burden of CKD is rapidly rising, wrote the study authors, with estimated prevalence rates of about 11% to 13%. Risk factors—such as nephron loss due to increasing age and acute or chronic kidney injuries caused by hypertension and type 2 diabetes mellitus—can contribute to the development and progression of CKD. Previously, animal models demonstrated that CKD is a significant and independent somatic risk factor in the development of cognitive impairment, and in end-stage CKD (stages 4–5), the prevalence of cognitive impairment has been estimated at approximately 30% to 60%, which is twice the values observed in age- and sex-matched controls. Further, prior evidence suggested that vascular damage, uremic toxicity, oxidative stress, and systemic inflammation induced by CKD may cause cerebral endothelial dysfunction, brain lesions, and cognitive decline.¹

Although the sex disparity has a profound impact on CKD epidemiology, its role in the progression of CI needs to be elucidated in detail. For this study, the investigators aimed to determine sex-specific crosstalk of the kidney-heart-brain axis in patients with CKD. Both patients with CKD and those without (controls) were included in a cross-sectional study that involved a community-dwelling rural population. CKD and cardiovascular parameters, Mini-Mental State Examination (MMSE), and markers of fibrosis and neurodegeneration were assessed. Additionally, the sex-specific associations among these factors were elucidated through linear regression and structural equation modeling analyses. Across the CKD and control groups, male and female participants were equally represented.¹

Both men and women with CKD had lower MMSE scores versus controls, although cognitive performance in women with CKD was noticeably better than their male counterparts. Approximately 20% of the women with CKD showed an MMSE score of 24 or lower, whereas 48% of the men with CKD achieved this score. On average, both men and women with CKD exhibited worse performance in MMSE compared with their sex-matched controls, although the MMSE total score was significantly higher in women with CKD than in men with CKD, indicating better cognitive function in women with CKD than in men with CKD.¹

Further, individual MMSE test domain analyses demonstrated that Language, Attention and Calculation, Recall, and Copy Design test results were significantly lower in both men and women with CKD compared with their healthy counterparts. Notably, the Recall test, which estimates short-term memory, and Language test results were lower in men with CKD compared with women 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.¹

“These results demonstrate that the biological pathways linking the kidney, heart, and brain are distinct in men and women,” lead author Sneha S. Pillai, PhD, research assistant professor of biomedical sciences at the Joan C. Edwards School of Medicine, said in a news release.²

The authors acknowledged that their study had several limitations, including the relatively small population size, the cross-sectional design, and differences in cognitive strengths (eg, better visuospatial tasks in men and advantages in verbal fluency in women), although these were considered small in magnitude. The authors urge that future studies should overcome these limitations by enrolling a larger cohort, conducting a longitudinal follow-up, including more diverse populations, utilizing alternative cognitive assessments, and including more comprehensive and extensive clinical data.¹

“Understanding how cardiovascular stress and neurodegenerative markers interact differently in men and women with CKD could fundamentally change how we approach treatment,” principal investigator Komal Sodhi, MD, associate professor of surgery at the Joan C. Edwards School of Medicine, said in the news release. “This work underscores the urgency of tailored strategies to prevent progression to more serious neurological disorders.”²

REFERENCES

1. Pillai SS, Morrell CH, Dos Santos CR, et al. Chronic kidney disease and cardiac remodeling potentiate cognitive impairment progression: disentangling the sex-specific cross talk of kidney-heart-brain axis. Am J Physiol Heart Circ Physiol. 2025;330(1). doi:10.1152/ajpheart.00617.2025

2. Marshall University Joan C. Edwards School of Medicine. Study highlights underrecognized link between kidney disease and cognitive decline. News release. December 4, 2025. Accessed December 19, 2025. https://jcesom.marshall.edu/news/musom-news/study-highlights-underrecognized-link-between-kidney-disease-and-cognitive-decline/