Chronic kidney disease (CKD) is a growing public health concern and is strongly associated with premature cardiovascular disease (1, 2). CKD affects about 10–15% of adults worldwide and may progress to end-stage kidney disease (ESKD), requiring dialysis or transplantation. As kidney function progressively deteriorates, patients develop multiple complications, with one of the most significant being disturbances in mineral and bone metabolism, notably involving vitamin D (3).

Vitamin D is a fat-soluble prohormone crucial for calcium-phosphate balance, but it also exerts numerous extra-skeletal effects on immune regulation and cardiovascular health. In the kidney, the activation of vitamin D to its hormonal form (calcitriol) occurs, meaning renal impairment can directly perturb vitamin D metabolism (4). Vitamin D deficiency (VDD) is highly prevalent in CKD patients. In fact, over 80% of individuals with CKD have insufficient 25-hydroxyvitamin D levels (5, 6). This high prevalence is partly because even early-stage CKD (e.g., estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73m²) is associated with declining vitamin D levels (6).

Patients with CKD often experience reduced sun exposure, dietary limitations, and increased urinary loss of vitamin D metabolites. Furthermore, early reductions in megalin expression impair the reabsorption of 25(OH)D from the glomerular filtrate, leading to decreased circulating levels (1). Consequently, CKD patients commonly develop secondary hyperparathyroidism and other sequelae of VDD. Beyond classical bone and mineral effects, vitamin D plays important roles in modulating the renin-angiotensin-aldosterone system (RAAS) and inflammation; VDD in CKD has been linked to faster disease progression and cardiovascular complications (7, 8).

Major Adverse Kidney Events (MAKEs) refer to a composite of critical renal outcomes, typically including sustained worsening of kidney function, initiation of renal replacement therapy (dialysis or transplantation), or kidney-related mortality (9). MAKEs are considered critical endpoints because they encompass the most serious outcomes for CKD patients and align with patient-centered clinical goals (9). While VDD has been associated with adverse outcomes in CKD (10, 11), its relationship with composite endpoints like MAKEs remains under-explored. Thus, the study aimed to examine the association between VDD and risk of MAKEs in patients with CKD.

In this study, we found a significant association between VDD and an increased risk of MAKEs in patients with CKD. This association remained robust across various subgroups, including age, sex, and CKD severity, suggesting a consistent impact of VDD on renal outcomes. Additionally, VDD was linked to increased risks of all-cause mortality and hospitalization. These findings underscore the clinical importance of maintaining adequate vitamin D levels in CKD management, highlighting VDD as a potentially modifiable risk factor for adverse renal outcomes.

Our results align with previous reviews, demonstrating that VDD contributes to CKD progression and adverse outcomes (5, 31). A notable strength of our study is that we used MAKEs as the primary endpoint, offering a robust and clinically relevant composite metric (i.e., ESKD, urgent dialysis, or dialysis dependence) for evaluating the cumulative burden of advanced renal events. By capturing both progression to ESKD and the need for dialysis in one measure, MAKEs provide a comprehensive hard outcome that underscores the real-world impact of VDD on kidney disease severity.

Nonetheless, minimal associations between VDD and adverse renal outcomes have been reported in certain cohorts. For example, Lunyera et al. (32), focusing on Black Americans from the Jackson Heart Study, found that vitamin D–binding protein (DBP) genotypes and other racial or genetic modifiers might confound the link between 25(OH)D and CKD progression. That study highlights how race-specific or genotype-specific factors can obscure or weaken the observed relationship between VDD and kidney function decline. Our current analysis, by contrast, drew on a large, mixed population from multiple centers, supporting a more consistent association between VDD and worse CKD outcomes overall. Given the variability noted in genetically diverse cohorts, additional research on DBP genetic variants and ancestry-specific differences in vitamin D metabolism is warranted to further clarify the nuanced interplay between VDD and kidney disease risk.

Several biological mechanisms could explain why VDD in CKD is associated with higher MAKEs. Vitamin D is biologically active in multiple organ systems, and its absence may exacerbate pathophysiological processes in CKD. One important mechanism involves the RAAS. Active vitamin D normally suppresses renin expression; when vitamin D is deficient, this suppression is removed, leading to heightened RAAS activity, hypertension, and glomerular hyperfiltration injury (33, 34). Chronic RAAS overactivity contributes to progressive nephron damage and fibrosis, promoting CKD progression to ESKD. As a result, VDD could accelerate MAKEs by worsening blood pressure control and intraglomerular pressure, hastening renal function decline (35).

Another mechanism centers on pro-inflammatory and immune dysregulation. Vitamin D has immunomodulatory effects, partly by inhibiting the nuclear factor kappa B (NF-κB) pathway and reducing inflammatory cytokine release (36, 37). In deficiency states, there may be increased inflammation within the kidneys, as immune cells in VDD patients can adopt a more pro-inflammatory profile and potentially cause ongoing renal injury. Elevated inflammation and oxidative stress can scar renal tissues, thus linking low vitamin D to an increased risk of MAKEs via inflammatory kidney damage (38).

Podocyte injury and proteinuria also represent key pathways. The vitamin D receptor is expressed in podocytes, specialized cells in the kidney’s filtering units, and vitamin D signaling helps maintain podocyte health and the glomerular filtration barrier (39). VDD is associated with a higher prevalence of albuminuria (39). Loss of vitamin D’s protective effects on podocytes can lead to worsening proteinuria, which itself is a major risk factor for CKD progression and adverse outcomes. Experimental studies have shown that active vitamin D analogs, such as derivatives of calcitriol, can reduce proteinuria and prevent podocyte apoptosis in kidney disease models (40). Therefore, in deficient patients, the lack of these renoprotective effects can contribute to a faster GFR decline and more MAKEs.

A further mechanism involves mineral and bone disorder (MBD) and vascular damage. In CKD, VDD contributes to secondary hyperparathyroidism and elevated fibroblast growth factor 23 (FGF23) levels as the body attempts to maintain mineral homeostasis (41, 42). Chronic elevation of parathyroid hormone and FGF23 can induce vascular calcification and cardiac hypertrophy, compounding cardiovascular risk in CKD (43, 44). These changes may indirectly affect kidney health as well, for instance, vascular calcifications can impair renal perfusion. Additionally, skeletal resistance and bone turnover abnormalities can release factors that negatively impact the kidneys. In this way, VDD aggravates CKD-mineral bone disorder, hastening vascular and renal deterioration and increasing the likelihood of MAKEs. These proposed mechanisms are consistent with current clinical consensus. Guidelines have highlighted the multifactorial role of vitamin D in CKD, particularly its influence on mineral metabolism, parathyroid hormone regulation, inflammation, and cardiovascular risk. Disruptions in the vitamin D axis, such as reduced 1α-hydroxylase activity, increased fibroblast growth factor 23, and early onset of secondary hyperparathyroidism, are recognized contributors to renal disease progression and adverse outcomes in CKD patients with VDD (45, 46). Our findings carry important clinical implications. VDD represents a potentially modifiable risk factor in CKD. Unlike fixed risk factors such as age or genetic predispositions, vitamin D status can be improved through supplementation or lifestyle changes. If a causal relationship is confirmed, treating VDD in CKD patients could become a straightforward strategy to reduce the risk of major adverse renal outcomes. In practice, this means clinicians should remain vigilant in screening for VDD in CKD populations and consider repletion therapy when levels are low. For example, using cholecalciferol or ergocalciferol for VDD, or active vitamin D analogs if needed for severe secondary hyperparathyroidism. Current clinical guidelines acknowledge this need, the 2017 KDIGO CKD-MBD update suggests that in CKD stages G3a–G5, VDD or vitamin D insufficiency should be corrected using the same strategies as for the general population (41). Traditionally, the motivation for vitamin D supplementation in CKD has been bone health and controlling secondary hyperparathyroidism. Our study suggests that maintaining sufficient vitamin D might also confer nephroprotective benefits, potentially lowering MAKEs risk. This strengthens the rationale for ensuring vitamin D adequacy as part of comprehensive CKD care.

This study had several strengths. First, this is a large retrospective cohort, which could enhance statistical power and generalizability, and also provide more stratified analyses and robustness findings. Second, PSM was well conducted to minimize the impact of measured confounders. Third, for those unmeasured confounders, E-values indicated that only a small effect could be affected by unmeasured confounders. Last, real-world data from EMRs were used, which reflected the true complexity and heterogeneity of patients, making the results more applicable in real-world settings. Furthermore, the selection of MAKEs as the primary composite endpoint adds clinical relevance, as it directly reflects the most critical outcomes for CKD patients. In addition, our discussion incorporated multiple plausible biological mechanisms, which strengthens the interpretability of the observed associations.

This study also had some limitations. First, the observational design precluded definitive causal inferences. Second, although propensity score matching was used to balance numerous baseline differences between the groups, certain factors, such as dietary intake, supplement use, sun exposure duration, and the timing of vitamin D measurement, could not be accounted for in our analysis. Third, reliance on EMRs and administrative billing codes may have introduced misclassification bias in both CKD diagnosis and vitamin D measurements. Nonetheless, we expect these inaccuracies were comparable across groups, resulting in estimates that tend toward the null value (47). Fourth, although focusing on one-year outcomes is clinically relevant, it may not fully capture the long-term impact of VDD on disease progression and survival. An extended follow-up period would likely yield additional insights into risk magnitude and other clinically significant endpoints. Finally, patients with vitamin D insufficiency (21–29 ng/mL) were excluded to create a clear contrast between deficiency and sufficiency. However, because this group is highly prevalent in clinical practice, our findings may have limited applicability to such patients.

The study strengthens the evidence that VDD is not merely a biochemical abnormality in CKD, but a condition with tangible impacts on patient outcomes such as MAKEs. Addressing VDD in CKD care, through vigilant monitoring and appropriate repletion, could be a step toward improving the prognosis of patients with chronic kidney disease. Future studies will be crucial to determine whether this association is causal and if vitamin D–targeted interventions can favorably alter the course of CKD.