Advanced CKD Linked With Cognitive Impairment

A more advanced stage of chronic kidney disease (CKD) is associated with greater cognitive impairment, according to a new report that offers more detail into the complex links between CKD and cognitive impairment.¹

The study was published in JAMA Network Open.

The authors explained that associations between kidney disease and cognitive function are well established. For instance, one registry-based study found that lower kidney function and steeper kidney-function decline were risk factors for the development of dementia.² Cross-sectional studies have also shown that cognitive impairment is more common among people with advanced disease, the authors said.

“However, only a few population-based studies have prospectively examined kidney function across the CKD range with cognitive phenotypes, and fewer evaluated both the estimated glomerular filtration rate (EGFR) and urinary protein,” they said.

The existing evidence suggests urinary protein might be the more important factor, partly because it could be associated with small vessel disease in the brain. However, the authors said there is a research gap for more data evaluating EGFR and proteinuria and their relationships with cognition phenotypes.

In the new report, they looked at 5607 patients who were enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study (NCT00304148), an ongoing study tracking patients with CKD. The patients in this analysis were enrolled between 2003 and 2008 and between 2013 and 2015. The mean age of the cohort was 59.6 years at baseline, and 56.3% were men.

The investigators used a variety of tests to evaluate patients’ global cognition, as well as their verbal memory and delayed recall, attention and processing speed, and executive function. After performing a multivariate-adjusted analysis, the investigators found that each SD higher log-transformed urinary protein-to-creatinine ratio (UPCR) was associated with a 21% increased risk of impairments in attention and processing speed (HR, 1.21; 95% CI, 1.05-1.41; P = .01), as well as a 16% increased risk of executive function impairment (HR, 1.16; 95% CI, 1.02-1.31; P = .02). Lower EGFR was also linked with an increased risk of impaired attention and processing speed, with a 21% increased risk for every SD lower EGFR (HR, 1.21; 95% CI, 1.05-1.38; P = .006).

However, when the investigators adjusted each factor for the other, they found that UPCR remained “nominally” significant after adjustment for EGFR, but the inverse did not.

“Although a decreased EGFR was also associated with attention and processing speed, proteinuria largely explained this association,” the investigators explained.

When they looked at patients with both a low EGFR (less than 60 mL/min/1.73m²) and a high UPCR (150 mg/g or higher), those patients had a 38% increased risk of impairment in global cognition compared with those without both risk factors (HR, 1.38; 95% CI, 1.05-1.82; P = .003).

“In total, our results suggested that increased risk of cognitive impairment was associated with more advanced CKD stage, providing important clues for risk stratification in this high-risk population,” the investigators said.

They said a number of “credible” hypotheses about potential pathophysiological mechanisms could explain the link. One is related to the similar anatomical and functional microvasculature in the kidney and the brain.

“With both organs susceptible to microvascular injury caused by risk factors including hypertension and diabetes, CKD and cognitive impairment may share underlying mechanisms,” they said.

Scientists have also suggested that uremic toxins that accumulate in patients with CKD could affect cognitive function.

The investigators said more research into such questions is needed. However, they said their findings support the hypothesis that CKD severity is a notable risk factor for cognitive decline.

References

1. Huang Z, Yaffe K, Li C, et al. Chronic kidney disease severity and risk of cognitive impairment. JAMA Netw Open. 2026;9(2):e2559834. doi:10.1001/jamanetworkopen.2025.59834
2. Xu H, Garcia-Ptacek S, Trevisan M, et al. Kidney function, kidney function decline, and the risk of dementia in older adults: a registry-based study. Neurology. 2021;96(24):e2956-e2965. doi:10.1212/WNL.0000000000012113