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Abstract: FR-PO489

Impact of Modifying Calcitriol Dosing on the Vitamin D Metabolome and Vascular Calcification in Experimental CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Svajger, Bruno A., Queen's University, Kingston, Ontario, Canada
  • Pruss, Cynthia M., Queen's University, Kingston, Ontario, Canada
  • Laverty, Kimberly J., Queen's University, Kingston, Ontario, Canada
  • Zelt, Jason, Queen's University, Kingston, Ontario, Canada
  • Ward, Emilie C., Queen''s University, Kingston, Ontario, Canada
  • Turner, Mandy E., Queen's University at Kingston, Kingston, Ontario, Canada
  • Jones, Glenville, Queens University, Kingston, Ontario, Canada
  • Petkovich, Martin P., Queen's University, Kingston, Ontario, Canada
  • Holden, Rachel M., Queen's University, Kingston, Ontario, Canada
  • Adams, Michael A., Queen's University, Kingston, Ontario, Canada
Background

Calcitriol (CAL) and other vitamin D analogs are used to manage SHPT in CKD although treatment can result in PTH over-suppression and lead to vascular calcification (VC). This study sought to determine whether modifying CAL dosing frequency and magnitude could provide a better treatment profile (PTH, FGF23, VC) in experimental CKD.

Methods

Experimental CKD (e-CKD) was induced by 0.25% dietary adenine in adult male Sprague-Dawley rats (n=42). At 4 weeks (W), e-CKD rats were divided into 5 groups and treated with oral CAL as follows: 0ng/kg (e-CKD control, n=8), 5ng/kg x 4, q6h (n=9), 20ng/kg once daily (n=8), 20ng/kg x 4, q6h (n=9), or 80ng/kg once daily (n=8). After 3W treatment, rats were sacrificed, tissues and blood were collected and assessed for vitamin D metabolome, PTH, FGF-23 and VC. Sub-analysis according to PTH level: (i) over suppressed (OS), (ii) target, and (iii) mildly suppressed (MS) was performed.

Results

CAL treatment in e-CKD rats markedly increased the levels of 1,25-(OH)2D3 in a dose-dependent manner (4-6X). In contrast, both circulating 25-OH-D3 and 24,25-(OH)2D3 fell significantly (10-30%), particularly at the higher CAL dose. Sub-analysis based on PTH suppression revealed a greater fall in 25-OH-D3 and 24,25-(OH)2D3 levels in Target and OS groups compared to the MS and untreated e-CKD. Overall, in e-CKD, the CAL treatment induced markedly increased VC (94% in Tx vs. 29% of vessels in unTx) and FGF-23 (8-20 X increase in Tx vs. unTx) regardless of treatment profile.

Conclusion

CAL suppressed PTH early in e-CKD treatment as expected, but PTH became progressively refractory over the 3 weeks of treatment. Even in the absence of overt PTH over suppression, all animals in the CAL treatment group had significant vascular calcification. All CAL treatment groups induced similar changes in the circulating vitamin D metabolome, with increased 1,25-(OH)2D3 but decreased 25-OH-D3 and corresponding 24,25-(OH)2D3. The CAL treatment induced varying alterations in the vitamin D metabolome which were reflected, in part, on how PTH levels were modified in response to CAL. These findings suggest that how calcitriol is administered as well as the level of PTH suppression should be re-examined to minimize VC in CKD.