Chronic kidney disease (CKD), characterized by a gradual loss of kidney function over time, affects approximately 10% of the global population (1–3). This high prevalence of CKD can be attributed to an increasingly aging population, along with a growing prevalence of type 2 diabetes mellitus, obesity, hypertension, and cardiovascular diseases, all of which significantly contribute to CKD development and progression (4). The progression of CKD is linked to several severe complications, such as a higher incidence of anemia, metabolic bone disease, cardiovascular events, increased mortality, and greater utilization of healthcare resources (5, 6). In addition, major depression is also a common complication in patients with CKD, with an overall prevalence of 34.0% (7). This high prevalence of depression not only impairs quality of life but also contributes to adverse health outcomes, including increased hospitalization rates, reduced treatment adherence, and higher mortality risk (8–11). Notably, depression has been identified as a risk factor for accelerated decline in kidney function (11–13), creating a detrimental cycle in which depression and CKD progression may exacerbate each other. Recent studies have suggested that depression-associated inflammation, medication non-adherence, and unhealthy behaviors may contribute to the faster deterioration of kidney function (12, 14, 15), highlighting the critical importance of early depression prevention in patients with CKD.

The kidneys play a crucial role in vitamin D metabolism by converting 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D (16). As kidney function declines, this conversion is impaired, leading to decreased vitamin D levels.

The prevalence of vitamin D deficiency (VDD) was high among patients with CKD, progressively increasing from 40.7% in stage 3 to 61.5% in stage 4, and reaching 85.7% in stage 5 as renal function declined (17). Beyond its well-known role in bone and mineral metabolism, recent evidence suggests that vitamin D may play a role in mood regulation, with low vitamin D levels being associated with depression (18–22).

The extremely high prevalence of VDD among patients with CKD, along with their inherently increased risk of depression, presents a potentially modifiable risk factor that deserves thorough investigation. Therefore, we conducted a large-scale cohort study using real-world data to investigate whether VDD is associated with an increased risk of depression in patients with CKD who have elevated baseline depression risk. These findings could have important implications for depression prevention strategies in patients with CKD and might suggest new therapeutic approaches for this vulnerable population.

Among 17,955 matched pairs of patients with CKD, those with VDD showed a significantly higher risk of developing major depression than those with normal vitamin D levels. At one-year follow-up, depression occurred in 1.06% of VDD patients vs. 0.59% of controls (HR: 1.929; 95% CI: 1.52–2.448; p < 0.0001). This association remained significant through 3 years of follow-up. Subgroup analyses revealed that males with VDD had a notably higher depression risk (HR: 2.264) than females (HR: 1.761). This association was consistent across all CKD stages. Even patients with vitamin D insufficiency (20–30 ng/mL) showed an elevated depression risk compared to those with normal levels (HR: 1.667). In patients with both CKD and VDD, cerebrovascular disease (adjusted OR 2.701) and malnutrition (adjusted OR 2.004) emerged as the strongest independent risk factors for depression.

Our findings demonstrate a robust association between VDD and an increased risk of major depression in CKD patients, consistent with a previous meta-analysis in the general population that linked low vitamin D levels to depression (19). However, the strength and nature of this association may differ among patient populations. A recent meta-analysis studying stroke patients found that VDD in the acute phase was associated with an increased risk of post-stroke depression (OR: 3.59) (23), suggesting an even stronger association than observed in our CKD cohort (HR: 1.929). Interestingly, while the study (23) found no significant association between vitamin D insufficiency and depression, our study demonstrated that even insufficient vitamin D levels increased depression risk in patients with CKD. This difference suggests that the relationship between vitamin D and depression may be disease-specific and context-dependent. These findings have several important clinical implications. First, they suggested that vitamin D screening and monitoring should be considered as part of comprehensive depression prevention strategies in CKD patients, although optimal target levels may differ from other populations. Second, the identification of risk factors (i.e., cerebrovascular disease and malnutrition) may help clinicians target preventive interventions more effectively.

The definition of VDD and appropriate threshold values warrant careful consideration. In our study, we used the widely accepted cutoff of <20 ng/mL (i.e., 50 nmol/L) for VDD, aligning with guidelines established by the Endocrine Society Task Force on Vitamin D (24). However, the optimal vitamin D levels may vary across different populations and ethnicities (25). For instance, individuals with darker skin typically require greater sun exposure to produce the same amount of vitamin D as those with lighter skin, and genetic variations in vitamin D binding protein can affect bioavailable vitamin D levels (26). Our study population included diverse ethnic groups, but we applied uniform thresholds across all ethnicities. This approach, while consistent with current clinical practice guidelines, may not fully account for ethnic-specific vitamin D requirements. Therefore, our findings should be interpreted with consideration of these ethnic variations in vitamin D metabolism and the ongoing debate about population-specific threshold values for defining VDD.

Our sex-stratified analysis revealed a notably stronger association between VDD and depression risk in male CKD patients (HR: 2.264) than in females (HR: 1.761). This finding aligns partly with a recent study of hemodialysis patients that found that VDD was independently associated with depression only in males (OR: 8.207), while this association was not significant in females (27). Similarly, a cross-sectional study of 612 patients with CKD found that male sex itself was an independent risk factor for depression (OR 1.3), regardless of vitamin D status (28). The stronger association between VDD and depression in males suggests that vitamin D might be a particularly important modifiable risk factor in this population. Several reasons might explain this stronger association in males. First, males with CKD might be less likely to seek mental health care or report depressive symptoms, leading to delayed diagnosis and potentially more severe cases when finally detected. Second, hormonal interactions between vitamin D and sex hormones could differ in the context of CKD (29), possibly affecting mood regulation differently in males and females.

Our study utilized data from 133 healthcare organizations within the TriNetX network, representing diverse patient populations across different geographical locations and healthcare settings. This broad sampling enhances the external validity of our findings compared to single-center studies. However, our study population consisted of patients aged 50 years or older who had documented vitamin D measurements within 3 months after CKD diagnosis, suggesting that they may seek medical attention more aggressively and have more regular healthcare monitoring. The relatively low incidence of depression observed in our study (1.06% in the VDD group vs. 0.59% in the control group at 1 year) further indicates that our patient population might not represent CKD patients with limited healthcare access or those who seek medical attention only for acute problems. This selection bias might have led to an underestimation of the true association between VDD and depression in the broader CKD population. Additionally, the availability and implementation of mental health services can differ significantly across healthcare settings and geographical regions. While our matched cohorts included patients across all CKD stages and diverse racial/ethnic backgrounds, the effectiveness of our findings may vary in different healthcare systems with varying screening practices, diagnostic criteria for depression, and treatment protocols.

The association between VDD and depression risk in our study suggests potential therapeutic implications for vitamin D supplementation. While supplementation could theoretically help prevent depression in CKD patients, several key questions remain unanswered. The optimal type of supplementation (nutritional vitamin D vs. activated analogs), dosing regimens, and target levels specific to CKD populations are unknown. Additionally, the timing of intervention may be crucial - early supplementation might prevent depression, but its effectiveness in treating established depression is uncertain. Randomized controlled trials are needed to determine whether vitamin D supplementation could serve as a preventive strategy for depression in CKD patients and to establish evidence-based supplementation protocols.

An important methodological consideration in interpreting our findings is the potential variability in vitamin D measurement techniques across the participating healthcare organizations. While liquid chromatography-mass spectrometry (LC–MS/MS) is considered the gold standard for measuring vitamin D metabolites due to its superior sensitivity and specificity, various other assay methods are commonly used in clinical practice, including radioimmunoassay, enzyme immunoassay, and chemiluminescence immunoassay (30–33). These different methodologies can yield varying results for the same sample, with inter-method variability potentially affecting vitamin D level classifications. In our study using the TriNetX network database, which aggregates data from multiple institutions, we could not standardize or verify the specific assay methods used at each site. This analytical variability could have influenced our categorical classification of vitamin D status and potentially impacted the observed associations. However, the robust and consistent relationship between VDD and depression risk across different subgroups and the observed dose-dependent effect suggest that our main findings are unlikely to be solely attributable to assay variability.

Several significant limitations of this study should be considered when interpreting the results. First, as this was an observational study using electronic health records, we could not establish causality between VDD and depression. While we found a significant association, the relationship could be bidirectional. Depression may lead to VDD through behavioral changes including reduced outdoor activities, poor dietary habits, and decreased adherence to vitamin D supplementation. Moreover, depressive symptoms such as fatigue and social withdrawal might result in less sun exposure, further contributing to VDD. These unmeasured confounders could have influenced our findings, despite our attempts to control for multiple clinical variables through propensity score matching. Second, depression diagnosis in our study relied on clinician documentation and diagnostic codes, which may not capture the full spectrum of depressive symptoms. This approach could miss cases where patients experienced depressive symptoms but did not seek mental health care, potentially leading to an underestimation of the true association. Furthermore, cultural and socioeconomic factors affecting healthcare-seeking behaviors for mental health issues could have influenced depression diagnosis rates. Third, although we required vitamin D measurements within 3 months of CKD diagnosis, we could not account for potential changes in vitamin D levels during the follow-up period. The dynamic nature of both vitamin D status and kidney function over time may have influenced our findings. Fourth, information on vitamin D supplementation, adherence to treatment, and other medications that might affect both vitamin D metabolism and risk of depression was not consistently available in the database. Fifth, seasonal variations in vitamin D levels (34) and their potential impact on mood disorders could not be adequately assessed, owing to limitations in the temporal resolution of our data. The timing of vitamin D measurements relative to seasonal changes might have affected our results. Finally, our study did not analyze several important clinical factors that could influence depression risk, including symptom burden (e.g., dyspnea from fluid overload), frequency of follow-up visits, and complications requiring frequent monitoring such as hyperkalemia. These factors could significantly impact patients’ quality of life and mental health outcomes.

In this large-scale cohort study, VDD was significantly associated with an increased risk of major depression in CKD patients, with the effect persisting throughout the 3 years of follow-up. The association remained robust across different subgroups, with male patients showing particular vulnerability. The observed dose-dependent relationship, where even vitamin D insufficiency carried an elevated depression risk, suggests that maintaining adequate vitamin D levels may be crucial for mental health in patients with CKD. The identification of cerebrovascular disease and malnutrition as strong independent risk factors for depression in patients with vitamin D-deficient CKD highlights the complex interplay between physical and mental health in this population. These findings suggest that routine vitamin D screening and appropriate supplementation might be valuable strategies for depression prevention in CKD patients. Further randomized controlled trials are needed to determine whether vitamin D supplementation can effectively prevent or reduce risk of depression in this vulnerable population. Clinicians should remain vigilant for depression symptoms, particularly in CKD patients with VDD and additional risk factors.