Chronic Kidney Disease Severity and Risk of Cognitive Impairment

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Importance: Associations between chronic kidney disease (CKD) severity and incident cognitive impairment have not been evaluated in a cohort of patients with CKD. Objective: To investigate associations between CKD severity, based on the estimated glomerular filtration rate (eGFR) and urinary protein to creatinine ratio (UPCR), and incident cognitive impairment in a cohort of patients with CKD. Design, Setting, and Participants: This cohort study investigated 5607 participants with CKD from the ongoing Chronic Renal Insufficiency Cohort (CRIC) Study who were enrolled between 2003 to 2008 and 2013 to 2015. Statistical analysis was conducted from August 2024 to December 2025. Exposure: Estimated glomerular filtration rate and UPCR. Main Outcomes and Measures: Global cognition and domains of verbal memory and delayed recall, attention and processing speed, and executive function were evaluated using the Modified Mini-Mental Status Examination, Buschke Selective Reminding test, and Trail Making Tests A and B, respectively. For each test, impairment was defined as a score at least 1 SD worse than the baseline cohort mean. After those with cognitive impairment at baseline were excluded, Cox proportional hazards regression models tested associations of baseline eGFR and UPCR, individually and together, with time to cognitive impairment after adjusting for demographic, lifestyle, and clinical risk factors. Results: The 5607 CRIC participants included 3159 men (56.3%), the mean (SD) cohort age was 59.6 (10.8) years at baseline, and the median follow-up was 6 years (range, 0.5-16 years) for the Modified Mini-Mental State Examination, 4 years (range, 0.5-13 years) for the Buschke Selective Reminding Test, and 4 years (range, 0.5-13 years) for Trail Making Tests A and B. In multivariable-adjusted analyses, each 1 SD higher log-transformed UPCR was associated with 21% increased risk of impairments in attention and processing speed (hazard ratio [HR], 1.21; 95% CI, 1.05-1.41; P = .01) and 16% increased risk of impairment in executive function (HR, 1.16; 95% CI, 1.02-1.31; P = .02). Each 1 SD lower eGFR was associated with 21% increased risk of impairment in attention and processing speed (HR, 1.21; 95% CI, 1.05-1.38; P = .006). Findings for UPCR remained nominally significant after further adjustment for eGFR, while eGFR findings were attenuated on adjustment for UPCR. Patients with a combined eGFR less than 60 mL/min/1.73 m2 and UPCR of 150 mg/g or more had a significant 38% increased risk of impairment in global cognition (HR, 1.38; 95% CI, 1.05-1.82; P = .003) compared with those with an eGFR of 60 mL/min/1.74 m2 or more and UPCR less than 150 mg/g. Conclusions and Relevance: This cohort study of patients with CKD suggests that a more advanced CKD stage was associated with increased incidence of cognitive impairment. These findings underscore CKD severity as a risk factor for cognitive decline across the CKD spectrum.

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