We conducted an analysis of various MBDs and vitamin D biomarkers according to the CGA classification. Generally, iPTH, FGF-23, and 25(OH)D are the most important biomarkers for monitoring MBDs in patients with CKD. Evaluating the vitamin D status is crucial in patients with CKD as it is an essential treatment option for MBDs. Vitamin D exists in different forms within the human body, and its metabolism undergoes various changes in patients with [25]. Our study is the first to analyze not only 25(OH)D but also 24,25(OH)D, VMR, bioavailable 25(OH)D, and free 25(OH)D simultaneously in patients with CKD. By analyzing these markers according to the CGA classification, we aimed to determine the significance of each type of vitamin D in different clinical conditions in patients with CKD. We found that levels of vitamin D markers are independently altered according to the CGA classification.
25(OH)D levels may be decreased in patients with diabetes mellitus [26]. In our study, there were no significant differences in all MBD markers according to the presence or absence of diabetes mellitus. However, in patients with DKD, 24,25(OH)2D and bioavailable 25(OH)D levels were significantly lower in those with DN. Therefore, it can be hypothesized that the presence of nephropathy secondary to diabetes mellitus may impact vitamin D synthesis. Although the mechanisms remain unknown, insulin sensitivity and various metabolic issues related to synthesis may be involved [27, 28]. In patients with poor blood glucose control, chronic hyperglycemia can decrease vitamin D hydroxylation in the kidneys [29]. Thus, decreased 24,25(OH)2D levels in DN may be a result of impaired 25(OH)D hydroxylation. Total 25(OH)D consists of 25(OH)D bound to VDBP, 25(OH)D bound to albumin, and free 25(OH)D. Bioavailable 25(OH)D refers to the combination of albumin-bound 25(OH)D and free 25(OH)D [30]. Hence, bioavailable 25(OH)D levels may decrease when albuminuria worsens in patients with DN or when serum albumin levels are low. However, there is insufficient evidence to explain the relationship between these factors.
Increased levels of urinary VDBP may be a potential marker for early DN [31, 32]. When bound to 25(OH)D, VDBP is reabsorbed by tubular epithelial cells through receptors such as megalin and cubulin. When albuminuria worsens, the impairment of receptor-mediated uptake can worsen urinary excretion of VDBP [33]. However, the increase in urinary VDBP levels may not be directly related to vitamin D deficiency in patients with CKD. In these patients with increased urinary VDBP levels, serum VDBP levels were higher than those in healthy controls [12]. Furthermore, in another study, treatment to lessen albuminuria reduced urinary excretion of VDBP but did not improve the vitamin D status [34]. As shown in Table 3, our study demonstrated that the DN group had lower serum albumin levels and more severe albuminuria compared to the nonDN group, but there was no significant difference in serum VDBP levels between the two groups. This provides evidence that serum VDBP levels may not be correlated with serum albumin levels or severity of albuminuria.
Elevated FGF-23 and iPTH levels indicate secondary hyperparathyroidism in patients with CKD. In such conditions, 25(OH)D levels tend to decrease [35]. In the KDIGO guidelines, the suggested upper normal limit of iPTH is 65 pg/mL [2]. In Table 4, FGF-23 and iPTH levels were higher in patients with a low eGFR. Particularly, the mean iPTH level in patients with and eGFR < 30 mL/min/1.73 m2 was over 65 pg/mL, suggesting hyperparathyroidism. In our study, our results showed no significant differences in total 25(OH)D, VDBP, bioavailable 25(OH)D, and free 25(OH)D levels among patients in different eGFR groups. Additionally, serum VDBP levels showed no correlation with eGFR or with the presence or absence of diabetes or albuminuria. Meanwhile, 24,25(OH)2D and VMR levels were lower in patients with an eGFR < 30 mL/min/1.73 m2. These results show that 24,25(OH)2D and VMR may be more strongly correlated with eGFR than other vitamin D markers.
The 25(OH)D level tends to decrease as albuminuria worsens in patients with diabetes [36]. As bioavailable 25(OH)D includes albumin-bound 25(OH)D, 25(OH)D may be influenced by albuminuria or hypoalbuminemia. In a study conducted on patients with end-stage renal disease, bioavailable 25(OH)D may have a stronger association with the results of bone mineral density testing compared to total 25(OH)D or free 25(OH)D. Measuring levels of bioavailable 25(OH)D considers the binding status with albumin or vitamin D binding protein, which can vary in patients with CKD. It is proposed that this approach may be more biologically reliable than simply measuring the total 25(OH)D level [37]. As shown in Table 5, in patients with DKD, total 25(OH)D, 24,25(OH)2D, bioavailable 25(OH)D, and free 25(OH)D levels significantly decreased when uPCR increased. Interestingly, even in patients without DKD, only bioavailable 25(OH)D levels showed a significant change according to the uPCR (Table 6). Therefore, our results indicate that bioavailable 25(OH)D may be a reliable vitamin D marker in patients with CKD presenting with albuminuria regardless of the presence or absence of diabetes.
Our study has two limitations. First, it was conducted at a single center, and the study population consisted only of Koreans, which may limit its generalizability to a broader CKD patient population across diverse healthcare settings and geographic regions. Additionally, although patients taking vitamin D, calcium supplements, and calcium-based phosphorus binders that could affect vitamin D levels were excluded, environmental factors, such as individual dietary vitamin D intake or differences in sunlight exposure, were not accounted for.