Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Rationale & objective: Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR.

Study design: Cross-sectional study nested in a cohort study.

Setting & participants: 1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study.

Predictors: Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or β₂-microglobulin (B2M).

Outcomes: Brain volume reduction, infarcts, microhemorrhages, white matter lesions.

Analytical approach: Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value.

Results: Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient: -0.07 [95% CI, -0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient: -0.08 [95% CI, -0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex.

Limitations: No inference about longitudinal effects due to cross-sectional design.

Conclusions: We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

Keywords: Albuminuria; Atherosclerosis Risk in Communities (ARIC) Study; brain infarcts; cerebral small vessel disease; chronic kidney disease (CKD); creatinine; cystatin C; diffusion tensor imaging; estimated glomerular filtration rate (eGFR); magnetic resonance imaging (MRI); microhemorrhages; neurodegeneration; urinary albumin-creatinine ratio (UACR); white matter lesions; β(2)-microglobulin (B2M).