A large study involving 5,607 participants with chronic kidney disease (CKD) has found that more severe stages of CKD are associated with a higher risk of developing cognitive impairment. The findings come from data collected through the Chronic Renal Insufficiency Cohort (CRIC) Study, an ongoing, multi-center observational study designed to examine risk factors and outcomes in patients with CKD across 12 clinical sites in United States.

Understanding Chronic Kidney Disease (CKD)

Chronic kidney disease is a long-term condition characterized by gradual loss of kidney function. Kidney function is commonly assessed using:

• Estimated glomerular filtration rate (eGFR) – measures how well the kidneys filter waste from the blood.

• Urinary protein to creatinine ratio (UPCR) – measures the amount of protein in urine, an indicator of kidney damage.

CKD is categorized into stages based on eGFR levels, with lower values indicating more advanced disease. Proteinuria (elevated protein in urine) reflects structural damage to kidney filtration units.

Globally, CKD affects approximately 10% of the population and is associated with cardiovascular disease, metabolic complications, and increased mortality.

Study Design and Method

The cohort study included 5,607 adults with CKD enrolled between 2003–2008 and 2013–2015. The mean age at baseline was 59.6 years, and participants were followed for up to 16 years depending on the cognitive test administered.

Cognitive function was assessed using standardized tools:

• Modified Mini-Mental State Examination (3MS) – global cognition

• Buschke Selective Reminding Test – verbal memory and delayed recall

• Trail Making Tests A and B – attention, processing speed, and executive function

Cognitive impairment was defined as performance at least one standard deviation worse than the baseline cohort mean.

Researchers excluded individuals with baseline cognitive impairment and used Cox proportional hazards models to assess the association between CKD severity markers (eGFR and UPCR) and incident cognitive impairment.

Key Findings: Proteinuria Strongly Linked to Cognitive Decline

• Higher Urinary Protein Associated With Cognitive Impairment

• Lower eGFR Associated With Cognitive Impairment — But Attenuated After Adjustment

• Combined Advanced CKD Markers Increased Global Cognitive Risk

Participants with:

• eGFR < 60 mL/min/1.73 m²

• UPCR ≥ 150 mg/g

had a 38% higher risk of impairment in global cognition compared with those with better kidney function and lower protein levels.

How CKD May Affect Brain Function

Although the study was observational and does not establish causation, several biological mechanisms may explain the association between kidney disease and cognitive decline:

• Vascular injury: CKD is associated with small vessel disease, which can affect brain circulation.

• Chronic inflammation: Persistent systemic inflammation may impact neuronal health.

• Accumulation of uremic toxins: Reduced filtration can allow neurotoxic substances to accumulate.

• Shared cardiovascular risk factors: Hypertension and diabetes are common in CKD and independently increase dementia risk.

This study suggests that more advanced chronic kidney disease is associated with increased incidence of cognitive impairment. Elevated urinary protein levels appear to be independently associated with impairments in attention, processing speed, and executive function, while combined advanced CKD markers were linked to global cognitive decline.

These findings highlight CKD severity as a significant risk factor for cognitive decline across the CKD spectrum and reinforce the need for integrated kidney and brain health monitoring.

Reference

1. Huang, Zhi, Kristine Yaffe, Chiung-Yu Lin, et al. 2026. “Chronic Kidney Disease Severity and Risk of Cognitive Impairment.” JAMA Network Open 9, no. 2 (2026): e2559834. https://doi.org/10.1001/jamanetworkopen.2025.59834.