Severe Vitamin D Deficiency Linked to Cognitive Decline, Mortality in CKD

New research is shedding light on a significant association between vitamin D status and cognitive outcomes in patients with chronic kidney disease (CKD), highlighting a heightened risk of cognitive decline and mortality with severe deficiency.1

Leveraging data from the TriNetX Global Health Research Network database, the study found that while moderate vitamin D deficiency was not associated with cognitive impairment risk, severe vitamin D deficiency, defined as <10 ng/mL, was linked to a significantly increased risk of both mild cognitive impairment and mortality.1

“Although associations between vitamin D deficiency and cognitive impairment have been established in the general population, evidence specific to individuals with CKD remains scarce. CKD patients represent a unique at-risk population due to overlapping metabolic and vascular pathologies, higher baseline prevalence of vitamin D deficiency, and disease-specific contributors to cognitive decline such as uremic toxins and chronic inflammation,” Kuo-Chuan Hung, of the department of anesthesiology at Chi Mei Medical Center, and colleagues wrote.1 “These differences may modify the neurocognitive impact of vitamin D levels in ways not observed in the general population.”

Some research suggests up to 80% of patients with advanced CKD exhibit vitamin D insufficiency or deficiency, making it one of the most common metabolic abnormalities in this population.2 Given this heightened prevalence and known association with cognitive impairment in other populations, investigators outlined the need for research specific to individuals with CKD.1

To investigate whether vitamin D deficiency increases the risk of mild cognitive impairment in patients with CKD and the impact of deficiency severity on outcomes, investigators assessed data from the TriNetX Global Health Research Network database for adults ≥50 years of age with a diagnosis of CKD ≥ 3 years prior to the index date, defined as the date of the patient’s first recorded vitamin D level measurement. Patients were categorized into a vitamin D deficiency group, which included those with a 25-hydroxyvitamin D level < 20 ng/mL, and a control group at index.1

To reduce selection bias and effectively control for potential confounding variables, investigators employed a 1:1 propensity score matching approach, calculated using a multivariable logistic regression model accounting for demographics, race, comorbidities, and severity of CKD. After matching, participants were followed for 3 years after a 1-year lag period to assess the primary outcome of mild cognitive impairment risk and the secondary outcome of all-cause mortality.1

After applying inclusion and exclusion criteria to the TriNetX Global Health Research Network database, investigators initially identified 18,261 and 43,567 patients in the vitamin D deficiency and control groups, respectively. Following propensity score matching, the final study cohort consisted of 17,545 patients in each group.1

In the main analysis comparing patients with vitamin D deficiency to those with normal levels, mild cognitive impairment occurred in 0.8% of the vitamin D deficiency group compared with 0.7% of the control group (hazard ratio [HR], 1.25; 95% CI, 0.98–1.58; P = .074). For all-cause mortality, the vitamin D deficiency group experienced significantly higher rates (9.6% vs 7.6%; HR, 1.33; 95% CI, 1.24–1.43; P <.001).1

Investigators additionally conducted a sensitivity analysis to investigate the specific impact of severe vitamin D deficiency on cognitive function, defining severe deficiency as a 25-hydroxyvitamin D level < 10 ng/mL. In this analysis, patients with severe vitamin D deficiency exhibited a significantly increased risk of mild cognitive impairment compared with the control group (0.9% vs 0.5%; HR, 1.97; 95% CI, 1.19–3.30; P = .007). Similarly, investigators noted mortality risk was markedly elevated in the severe deficiency group (10.9% vs 7.5%; HR, 1.58; 95% CI, 1.39–1.81; P < .001).1

Investigators noted vitamin D levels were assessed only at the index date and not longitudinally, meaning their classification of vitamin D deficiency reflects baseline levels and does not account for potential changes in vitamin D status over time due to supplementation, seasonal variation, or disease progression.1

“In this large-scale propensity-matched cohort study, we found that severe VDD at baseline (<10 ng/mL) was significantly associated with an increased risk of mild cognitive impairment and mortality in patients with CKD, while moderate deficiency was not related to adverse cognitive outcomes,” investigators concluded.1 “While these findings may support the rationale for screening and monitoring, they should be interpreted cautiously due to methodological limitations. Future interventional studies are needed to determine whether correcting severe VDD can improve cognitive and survival outcomes in this vulnerable group.”

References

1. Li YY, Weng HL, Lai YC, Hung KC. Severe vitamin D deficiency and risk of mild cognitive impairment in patients with chronic kidney disease: A cohort study. Medicine (Baltimore). doi:10.1097/MD.0000000000043235

2. Franca Gois PH, Wolley M, Ranganathan D, Seguro AC. Vitamin D Deficiency in Chronic Kidney Disease: Recent Evidence and Controversies. International Journal of Environmental Research and Public Health. 2018; 15(8):1773. https://doi.org/10.3390/ijerph15081773