Abstract Body: Background: Patients with chronic kidney disease (CKD) face a disproportionate burden of dementia compared to the general population. However, prospective associations between kidney function and cognitive impairment remain inconsistent and have not been exclusively evaluated in CKD.

Methods: This analysis included 4,261 CKD patients from the Chronic Renal Insufficiency Cohort (CRIC). CKD severity was defined using standard estimated glomerular filtration rate (eGFR) and urinary protein to creatinine ratio (UPCR) thresholds. Global cognition and domains of verbal memory, attention/processing speed, and executive function were assessed longitudinally using the modified mini-mental status examination (3MS), Buschke Selective Reminding test, Trail Making Test A (TMTA), and Trail Making Test B (TMTB), respectively. For each test, impairment was defined as a score at least one standard deviation (SD) worse than the cohort mean at baseline. Cox proportional hazard models assessed associations between baseline CKD severity and time-to-cognitive impairment, adjusting for demographic and lifestyle risk factors, clinical measures, medications, and baseline cognition. Restricted cubic splines evaluated non-linear relations of both eGFR and UPCR with cognitive impairment.

Results: Among CRIC participants with a mean age 59.6 years and median follow-up of 14.7 years, we observed significant, dose-response associations between increasing CKD severity, based on both eGFR and UPCR, and incident global cognitive impairment. Compared to those with stage G2 CKD (eGFR=60-89), patients with stage G4/G5 CKD (eGFR<30) had a 36% increased risk of cognitive impairment (HR=1.36; 95% CI=1.00, 1.86; P_linear=0.03). Similarly, patients with UPCR>500 mg/g had a 26% increased risk compared to those with UPCR<150 mg/g (HR=1.26; 95% CI=0.99, 1.59; P_linear=0.04). Increased CKD severity based on eGFR was significantly associated with attention impairment (G4/G5 vs. G2 HR=1.49; 95% CI=1.03, 2.14; P_linear=0.04). Spline analyses revealed linear relationships between declining eGFR and impairment in global cognition (P=0.007) and attention (P=0.005), and between increasing UPCR and impairment in attention (P=0.015) and executive function (P=0.036; Figure). No evidence of non-linear relationships were observed.

Conclusion: More severe CKD, reflected by lower eGFR and higher UPCR, was prospectively associated with impairment in global cognition and specific cognitive domains.