Lower estimated glomerular filtration rate relates to cognitive impairment and brain alterations

Abstract

Introduction: Chronic kidney disease (CKD) is associated with cognitive decline and changes in brain structure. However, their associations remain unclear, particularly the selective vulnerability characteristics that make some brain regions more vulnerable.

Methods: We investigated the baseline association between estimated glomerular filtration rates (eGFR) and cognitive function in 15,897 individuals from the CARTaGENE cohort. We performed vertex-based magnetic resonance imaging (MRI) analyses between eGFR and longitudinal cortical thickness in the 1397 participants who underwent brain MRI after 6 years. Imaging transcriptomics was used to characterize the gene expression and neurodegenerative features associated with this association.

Results: Lower eGFR correlated with reduced cognitive performance and brain structure. Brain regions associated with eGFR were enriched for mitochondrial and inflammatory-related genes. These associations occurred independently from age, sex, education, and body mass index (BMI), Framingham risk score, and white matter lesion volume.

Discussion: This study highlights the link between reduced eGFR, cognitive impairment, and brain structure, revealing some of the kidney-brain axis mechanisms.

Highlights: Lower eGFR is associated with reduced cognitive abilities.Structural brain changes are mediated by eGFR levels.Specific gene expression patterns correlate with lower eGFR and brain changes.Mitochondrial and inflammation-related genes were enriched in these patterns.

Keywords: MRI; atrophy; brain; chronic kidney disease; cognition; glomerular filtration rate.

FIGURE 1

Flowchart of the baseline and follow‐up steps of the study. eGFR, estimated glomerular filtration rate; QC, quality control

FIGURE 2

Associations between eGFR, brain structure, and cognitive performance. The eGFR is significantly associated with brain structure. (A) Vertex‐wise analyses of eGFR against cortical thickness, with red areas representing the association between lower eGFR and thinning and blue areas the association with thickening. The uncorrected z maps and corrected FDR maps are shown. The FDR color bar indicates significance on a logarithmic scale of p‐values (–log10). (B) Vertex‐wise analyses of eGFR against performance on the reasoning and reaction time tasks, with red areas representing positive relationships and blue areas negative relationships. (C) Vertex‐wise analyses showing where the association between reasoning performance and cortical thickness differed as a function of eGFR levels. The scatterplot shows the association between residualized reasoning performance and average thickness in the significant cluster. The asterisks represent the significant correlations, and the arrow indicates that the difference in the slopes between the G1 and G3 groups was significant. eGFR, estimated glomerular filtration rate; FDR, false discovery rate

FIGURE 3

Regional gene expression patterns of the eGFR‐thickness association. Regional gene expression patterns underlie the association between eGFR and cortical thickness. (A) Brain maps showing the spatial patterns of regional t‐values between thickness and eGFR, BMI, Framingham risk score, and white matter lesion volume independently from the effects of age, sex, and respective confounders. A positive t value represented the effect of decreased eGFR on thinning and a negative t value for the other variables represented the effect of an increase on thinning. (B) Two components explained significantly more variance in the eGFR‐thickness spatial pattern than 10,000 spatial null models. (C) Scatterplot of the first component showing that regions where decreased eGFR associated with thinning (positive t‐values) are positively associated with the component. (D) Brain map of the first component's regional weights showing that regions positively associated with the component locate in the frontal, parietal, and occipital areas. BMI, body mass index; C, component; eGFR, estimated glomerular filtration rate; ROI, region of interest

FIGURE 4

Gene set enrichment analysis of eGFR‐thickness associations. Specific gene enrichments underlie the eGFR‐thickness association in the brain. (A) Gene set enrichment analysis on the first component reveals biological processes enriched in regions where lower eGFR associated with thinning (blue) or thickening (yellow). Darker bars represent significance after FDR correction. (B) Scatterplot of the second component showing that regions where lower eGFR is associated with thinning (positive t‐values) are positively correlated with the component. (C) Brain map of the second component's regional weights showing that regions where lower eGFR associates with thinning (red areas) locate in the frontal and parietal regions. C, component; eGFR, estimated glomerular filtration rate; FDR, false discovery rate; RNA, ribonucleic acid; ROI, region of interest; pri‐miRNA, primary microRNA