The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease

Abstract

Chronic kidney disease is characterized, in part, as a state of decreased production of 1,25-dihydroxyvitamin D (1,25(OH)2D); however, this paradigm overlooks the role of vitamin D catabolism. We developed a mass spectrometric assay to quantify serum concentration of 24,25-dihydroxyvitamin D (24,25(OH)2D), the first metabolic product of 25-hydroxyvitamin D (25(OH)D) by CYP24A1, and determined its clinical correlates and associated outcomes among 278 participants with chronic kidney disease in the Seattle Kidney Study. For eGFRs of 60 or more, 45–59, 30–44, 15–29, and under 15 ml/min/1.73m2, the mean serum 24,25(OH)2D concentrations significantly trended lower from 3.6, 3.2, 2.6, 2.6, to 1.7 ng/ml, respectively. Non-Hispanic Black race, diabetes, albuminuria, and lower serum bicarbonate were also independently and significantly associated with lower 24,25(OH)2D concentrations. The 24,25(OH)2D concentration was more strongly correlated with that of parathyroid hormone than was 25(OH)D or 1,25(OH)2D. A 24,25(OH)2D concentration below the median was associated with increased risk of mortality in unadjusted analysis, but this was attenuated with adjustment for potential confounding variables. Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)2D production and vitamin D catabolism.

Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

“…Similar to prior cross-sectional studies in CKD cohorts (15,16,26,27), our investigation demonstrated lower baseline 24,25(OH) 2 D 3 concentrations in patients with CKD, as well as a positive correlation between eGFR and baseline 24,25 (OH) 2 D 3 concentrations (Supplemental Figure 2). The lack of statistical significance between baseline 24,25(OH) 2 D 3 concentrations in the CKD and control groups was not unexpected because our power calculations were based on the anticipated variability in post-treatment 25(OH)D 3 concentrations and not differences in baseline 24,25(OH) 2 D 3 concentrations.…”

“…However, no clinical trials have prospectively tested this hypothesis. Furthermore, crosssectional data from humans and rodent models of CKD suggest that 24,25(OH) 2 D concentrations are lower in the setting of impaired kidney function (13,(15)(16)(17)26). Given the apparent disparity between these clinical observations and current theories regarding vitamin D metabolism in CKD, further in vivo investigation of the 24-hydroxylase pathway can provide valuable insight into the pathophysiology of mineral metabolism derangements in CKD.…”

“…Similarly, cross-sectional studies in humans suggest lower 24,25(OH) 2 D concentrations in patients with advanced CKD and a negative correlation with FGF23 concentrations (14)(15)(16)(17). Thus, the effect of FGF23 on the generation of 24,25(OH) 2 D following vitamin D supplementation in humans with CKD remains undefined.…”

Serum 25-Hydroxyvitamin D Level and Kidney Function Decline in a Swiss General Adult Population

“…Most studies conducted so far were crosssectional and hence subject to temporality bias. In fact, the product of 25(OH)D metabolism (24,25[OH]D) seems to be decreased in CKD, leading to a stagnating metabolism of vitamin D (11). Thus, the level of 25(OH)D could paradoxically be higher among people with early stages of CKD than among those with adequate eGFR (11).…”

“…In fact, the product of 25(OH)D metabolism (24,25[OH]D) seems to be decreased in CKD, leading to a stagnating metabolism of vitamin D (11). Thus, the level of 25(OH)D could paradoxically be higher among people with early stages of CKD than among those with adequate eGFR (11). The 1,25(OH) 2 D deficiency in CKD could be mediated via fibroblast growth factor-23 (FGF-23), a protein that is elevated in CKD and inhibits the conversions of 25(OH)D into 1,25(OH) 2 D and stimulates the catabolism of 1,25(OH) 2 D (12,13).…”