Advanced Stages of CKD Linked to Increased Risk of Cognitive Impairment

A cohort study published in JAMA Network Open found that more advanced chronic kidney disease (CKD) stage was independently associated with increased incidence of cognitive impairment, reinforcing growing evidence that the kidney-brain axis represents a critical, underappreciated dimension of CKD management.¹

Key Findings

The primary exposures were estimated glomerular filtration rate (eGFR) and urinary protein-to-creatinine ratio (UPCR). In fully-adjusted models, each 1 standard deviation (SD) lower eGFR was associated with a 21% increased risk of impairment in processing speed and attention (HR, 1.21; 95% CI, 1.05-1.38; P = .006); however, this association was attenuated and lost significance after further adjustment for UPCR.¹

Compared with lower stages of CKD (grades 1 and 2), patients with higher stages (grades 4 and 5) harbored an approximate 54% increased risk of impairment (HR, 1.54; 95% CI, 1.05-2.27; P = .03).¹

Proteinuria, as determined by UPCR, emerged as the more robust independent predictor. Each 1 SD higher log UPCR was associated with a 21% increased risk of impairment in attention and processing speed (HR, 1.21; 95% CI, 1.05-1.41; P = .01) and a 16% increased risk of impairment in executive function (HR, 1.16; 95% CI, 1.02-1.31; P = .02), both of which remained significant after further adjustment for eGFR.¹

The most striking finding emerged from joint analyses. Patients with both an eGFR below 60 mL/min/1.73 m² and a UPCR of 150 mg/g or more had a significant 38% increased risk of global cognitive impairment compared with those with an eGFR of 60 mL/min/1.73 m² or higher and a UPCR below 150 mg/g (HR, 1.38; 95% CI, 1.05-1.82; P = .003). This combined group also showed a nominally significant 54% increased risk of impairment in recall and verbal memory (HR, 1.54; 95% CI, 1.08-2.19; P = .02). Findings were consistent across subgroups stratified by age, sex, race and ethnicity, and diabetes status.¹

Study Design

Investigators analyzed data from the Chronic Renal Insufficiency Cohort (CRIC) Study (NCT00304148), an ongoing multicenter prospective cohort that enrolled 5607 adults aged 21 to 79 years across a broad spectrum of CKD severity at 7 clinical centers between 2003 and 2015. Participants were predominantly male (56.3%), with a mean age of about 59.6 years, and reflected a racially diverse sample (43.1% non-Hispanic Black, 40.5% non-Hispanic White, 12.9% Hispanic). Comorbidity burden was high—which is consistent with typical presentations of patients with CKD—with hypertension present in 86.5% and diabetes in 51.4% of participants.¹

Cognitive function was assessed at baseline and longitudinally using 4 validated tools: the Modified Mini-Mental State Examination (3MS) for global cognition; the Buschke Selective Reminding Test for verbal memory and delayed recall; and Trail Making Tests A and B for attention/processing speed and executive function, respectively. Incident cognitive impairment for each test was defined as a score at least 1 SD worse than the cohort mean at baseline. Patients with cognitive impairment at baseline were excluded from longitudinal analyses, with median follow-up ranging from 4 to 6 years.¹

Broader Context: The Crucial Relationship Between the Brain and Kidney

These findings align with a growing body of evidence establishing CKD as an independent risk factor for cognitive decline. A 2024 systematic review and meta-analysis published in PLOS One, which analyzed 50 studies encompassing 25,289 patients with CKD, determined that the overall prevalence of cognitive impairment in the CKD population was approximately 40%. Attention and executive dysfunction were among the most common manifestations. Notably, prevalence was significantly higher in patients receiving hemodialysis (53%) and peritoneal dialysis (39%) compared with those not yet on dialysis (32%), suggesting that higher stages of CKD—characterized by treatments like dialysis—correspond with cognitive decline.²

Supporting these epidemiological trends, a 2025 analysis published in Nature Reviews Nephrology characterized the mechanisms underpinning the kidney-brain relationship. The investigators identified shared vascular pathways, overlapping risk factor profiles (eg, hypertension, diabetes, and metabolic syndrome), and the direct neurotoxic accumulation of uremic waste in the kidneys as likely contributors to cognitive decline across the CKD spectrum.³

Implications for Pharmacists

As frontline medication managers for patients with CKD, pharmacists are uniquely positioned to identify cognitive risk. Clinicians should be aware that patients with more advanced CKD stages, particularly those with both reduced eGFR and significant proteinuria, may be at heightened risk for impairments in attention, processing speed, executive function, and global cognition. Such deficits carry direct implications for medication adherence, self-management capability, and patient safety, particularly in complex polypharmacy regimens that are common in this population.

Routine cognitive screening and interdisciplinary communication with prescribing teams may be warranted for patients at higher CKD stages, especially as clinical guidelines continue to evolve toward a more comprehensive, patient-centered framework for CKD management.

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. Zhang J, Wu L, Wang P, et al. Prevalence of cognitive impairment and its predictors among chronic kidney disease patients: a systematic review and meta-analysis. PLoS One. 2024;19(6):e0304762. doi:10.1371/journal.pone.0304762

3. Ikram MA. Chronic kidney disease and dementia: an epidemiological perspective. Nat Rev Nephrol. 2025;21(8):525-535. doi:10.1038/s41581-025-00967-w