Patients with both a reduced estimated glomerular filtration rate and urinary protein to creatinine ratio of 150 mg/g or more had a 38% higher risk of global cognitive impairment, according to a recent study.

In a prospective cohort of 5,607 adults with chronic kidney disease (CKD), each 1–standard deviation increase in log-transformed urinary protein to creatinine ratio (UPCR) was linked to a 21% greater likelihood of impaired attention and processing speed and a 16% greater likelihood of executive dysfunction. A 1–standard deviation decrease in estimated glomerular filtration rate (eGFR) was also associated with a 21% increased likelihood of impaired attention and processing speed; however, this association was attenuated after adjustment for UPCR. Joint modeling demonstrated complementary associations between filtration decline and UPCR in relation to global cognitive impairment.

The analysis was conducted within the CRIC Study, which enrolled participants during two time periods: from 2003 to 2008 and 2013 to 2015. The researchers then followed them longitudinally with repeated cognitive assessments. Kidney function was evaluated at baseline using eGFR calculated with the 2021 race-neutral creatinine–cystatin C equation and UPCR derived primarily from 24-hour urine collections. The eGFR was categorized according to established CKD stages, and UPCR was grouped as less than 150 mg/g, 150 to 500 mg/g, and greater than 500 mg/g. The participants with cognitive impairment at baseline were excluded from the longitudinal analyses.

Cognitive outcomes included global cognition measured by the Modified Mini-Mental State Examination and domain-specific performance assessed by the Buschke Selective Reminding Test and Trail Making Tests A and B. Incident cognitive impairment was defined as performance at least 1 standard deviation below the baseline cohort average on a given cognitive test. The models were sequentially adjusted for demographic characteristics, lifestyle factors, and clinical variables, with additional analyses evaluating the joint effects of eGFR and UPCR and testing for nonlinear associations.

Limitations included the use of UPCR rather than the urinary albumin to creatinine ratio in primary analyses because albumin data were limited to a subsample. Although sensitivity analyses yielded similar findings, UPCR thresholds aren't fully aligned with CKD guideline staging, and misclassification is possible. The exclusion of patients with end-stage kidney disease may have limited generalizability to the most advanced CKD stages. Repeated cognitive testing may have introduced practice or ceiling effects that attenuated observed changes, and differential loss to follow-up could have biased results. Residual confounding cannot be excluded despite comprehensive adjustment for measured covariates.

“These findings underscore CKD severity as a risk factor for cognitive decline across the CKD spectrum,” noted lead study author Zhijie Huang, PhD, of the Department of Epidemiology at the Tulane University School of Public Health and Tropical Medicine, and colleagues.

Co–study author Anand Srivastava, MD, reported personal fees from CVS Caremark, Novo Nordisk, and AstraZeneca and grant funding from Bayer; co–study author Manjula Kurella Tamura, MD, reported advisory work with the Kidney Disease Aging Research Collaborative and editorial service for the Journal of the American Society of Nephrology; and co–study author Matthew R. Weir, MD, reported personal fees from AstraZeneca, Bayer, Corcept, MineraLys, Novo Nordisk, CSL Vifor, and Vera, with no additional disclosures reported.

Source: JAMA Network Open