Patients with chronic kidney disease (CKD) face increased risk of cognitive decline, and more advanced stages of CKD are associated with more severe cognitive decline. Results of previous studies have suggested an association between measures of kidney function and brain atrophy, cerebrovascular pathologies, and white matter abnormalities. Those studies characterized the brain damage as primarily driven by vascular causes and having a functional rather than structural nature.
There are no data available on the effects of CKD on structural outcomes. Further, most studies based estimates of glomerular filtration rate (GFR) on creatinine, which can be influenced by non-GFR determinants of creatinine such as unusual muscle mass, a diet rich in protein, or supplement intake.
Johannes B. Scheppach, MD, and colleagues recently conducted a cross-sectional study nested in a cohort study to evaluate the association of estimated GFR (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). The researchers also sought to determine whether this association was altered when different filtration markers were used to estimate GFR. Results were reported in the American Journal of Kidney Diseases.
The Atherosclerosis Risk in Communities (ARIC) study recruited 15,792 participants 45 to 64 years of age from four communities in the United States (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota). Participants with evidence of cognitive impairment and a stratified random sample of the remaining participants were invited for a brain MRI scan at study visit 5 (2011-2013) as part of the ARIC Neurocognitive Study (NCS). The current cross-sectional analysis included all White or Black participants with complete data for brain MRI, eGFR, UACR, and covariates.
The outcomes of interest were brain volume reduction, infarcts, microhemorrhages, and white matter lesions. Predictors were log (UACR) and eGFR based on cystatin-C, creatinine, cystatin-C and creatinine in combination, or ß2-microglobulin (B2M). The analysis utilized multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value.
The analysis included 1527 ARIC participants. Mean age was 76.4 years, 879 (57.6%) were women, and 417 (27.3%) were Black. Among all participants, 25.6% (n=391) had one and 2.6% (n=40) had two apolipoprotein E (APOE) e4 risk alleles. At the cognitive status assessment at the study visit, 60.6% (n=926) of the participants had no cognitive impairment, 34.4% (n=525) had mild impairment, and 5.0% (n=76) had dementia.
There was an association between lower eGFR and a higher prevalence of hypertension, diabetes, heart failure, and previous stroke. Those with an eGFR <30 mL/min/1.73 m2 also had higher levels of albuminuria compared with the rest of the study cohort. Mean brain volume was 1016.0 cm3, and cortex volume was 399.1 cm3. Results of brain MRI scans revealed infarcts in 26.1% of participants (n=398) and microhemorrhages in 24.3% of participants (n=371).
There was an association between lower cystatin C-based eGFR and lower brain cortex volume, with a regression coefficient of –0.07 (95% CI, –0.12 to –0.02) per 1-IQR lower eGFR (equivalent to 26.10 mL/min/1.73 m2). The association of decreased eGFR with brain atrophy in temporal lobe meta-regions of interest, which identify regions of the cortex usually susceptible to neurodegenerative disease, had a regression coefficient of –0.05 (95% CI, –0.11 to 0.1) per 1-IQR lower eGFR. Results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M.
In assessing cortex volume according to standard eGFR categories, there was an association between lower eGFR with brain cortex atrophy; the association was only statistically significant for participants with eGFR <30 mL/min/1.73 m2 compared with the reference group with an eGFR of 60 to <90 mL/min/1.73 m2. Higher levels of albuminuria were also related to lower brain volume; the regression coefficients per 1-IQR-fold greater value were similar to the regression coefficients per 1-IQR lower eGFR.
Associations of albuminuria with macrovascular damage were expressed in adjusted odds ratio (aOR) per 1-IQR-fold greater log(UACR). Participants with higher levels of albuminuria were more likely to have prevalent macrovascular brain damage, such as brain infarcts (aOR, 1.31; 95% CI, 1.13-1.52). This was also seen for the two types of brain infarcts examined in this study: cortical infarcts (aOR, 1.27; 95% CI, 1.05-1.53) and lacunar infarcts (aOR, 1.18; 95% CI, 1.00-1.39).
Higher levels of albuminuria were also associated with increased odds of brain microhemorrhages in general (aOR, 1.30; 95% CI, 1.12-1.51) and subcortical microhem-orrhages in particular (aOR, 1.32; 95% CI, 1.13-1.54). The effect estimate was similar in direction and magnitude but not statistically significant for lobar microhemorrhages.
Similar associations between reduced eGFR and greater albuminuria and microvascular white matter pathologies were seen in conventional MRI and diffusion tensor imaging. The volume of white matter hyperintensities, a sign of brain small vessel damage, was higher in participants with lower eGFR (regression coefficient, 0.07; 95% CI, 0.01-0.15) and higher log(UACR) (regression coefficient, 0.09; 95% CI, 0.03-0.15).
White matter fractional anisotropy (FA) is a measurement for the directional constrain of water diffusion with a unitless range from 0 to 1. In analysis of standard eGFR categories, white matter FA was lower in participants with eGFR <30 mL/min/1.73m2 than in those in the reference group (regression coefficient,–0.30; 95% CI, –0.59 to –0.01).
The researchers cited some limitations to the study, including the cross-sectional design that did not allow for inference regarding longitudinal effects, the inability to assess the rate of brain atrophy over time, and the possibility of selection bias due to conducting MRI scans on only a part of the ARIC cohort at study visit 5.
In summary, the authors said, “A principal objective of ARIC-NCS is to characterize the morphological manifestations of dementia and cognitive decline. This study builds upon previous reports, which linked kidney function measures to dementia and cognitive decline and confirms the association of UACR and eGFR with structural brain damage while also providing new information about its etiology as well as its localization in the brain. Future studies need to collect longitudinal data and confirm predictors as risk factors in increased clinical applicability.”
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