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PTH suppression by calcitriol does not predict off‐target actions in experimental CKD
Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25‐(OH)(2)D(3)) is a former first‐line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC). An experimental CKD model was use...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283992/ https://www.ncbi.nlm.nih.gov/pubmed/32519465 http://dx.doi.org/10.1002/prp2.605 |
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author | Svajger, Bruno A. Pruss, Cynthia M. Laverty, Kimberly J. Zelt, Jason G. E. Jones, Glenville Kaufmann, Martin Petkovich, Martin Holden, Rachel M. Adams, Michael A. |
author_facet | Svajger, Bruno A. Pruss, Cynthia M. Laverty, Kimberly J. Zelt, Jason G. E. Jones, Glenville Kaufmann, Martin Petkovich, Martin Holden, Rachel M. Adams, Michael A. |
author_sort | Svajger, Bruno A. |
collection | PubMed |
description | Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25‐(OH)(2)D(3)) is a former first‐line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC). An experimental CKD model was used to determine whether altering the calcitriol delivery profile to obtain different PTH suppression levels could improve vascular health outcomes. High adenine diet (0.25%) was used to generate experimental CKD in rats. CKD rats were treated using different calcitriol dosing strategies: (a) 20 ng/kg SD (n = 8), (b) 80 ng/kg SD (n = 8), (c) 5 ng/kg QID (n = 9), or (d) 20 ng/kg QID (n = 9). Multiple targets of calcitriol were assessed which include arterial calcium and phosphate as well as circulating calcium, phosphate, PTH, FGF‐23, VWF, and vitamin D metabolome. PTH suppression occurred dose‐dependently after 1‐week calcitriol treatment (P < .01), but the suppressive effect was lost over time. Both VC and circulating FGF‐23 increased > 10× in all calcitriol‐treated rats (P < .05 and P < .001, respectively); similarly, circulating VWF increased at all time points (P < .05). Ad‐hoc analysis of CKD morbidities in treated rats indicated no differences in negative outcomes based on PTH suppression level (minimal‐, target‐, and over‐). Comparing different calcitriol dosing strategies revealed the following: (a) despite initial calcitriol‐influenced PTH suppression across all treatments, the ability to continually suppress PTH was markedly reduced by study conclusion and (b) PTH suppression level is not an adequate proxy for improvements in overall CKD morbidity. These findings show (a) a more holistic approach to evaluate CKD treatment efficacy aside from PTH suppression is needed and (b) that other VDRA therapies should be examined in CKD treatment. |
format | Online Article Text |
id | pubmed-7283992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-72839922020-06-11 PTH suppression by calcitriol does not predict off‐target actions in experimental CKD Svajger, Bruno A. Pruss, Cynthia M. Laverty, Kimberly J. Zelt, Jason G. E. Jones, Glenville Kaufmann, Martin Petkovich, Martin Holden, Rachel M. Adams, Michael A. Pharmacol Res Perspect Original Articles Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25‐(OH)(2)D(3)) is a former first‐line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC). An experimental CKD model was used to determine whether altering the calcitriol delivery profile to obtain different PTH suppression levels could improve vascular health outcomes. High adenine diet (0.25%) was used to generate experimental CKD in rats. CKD rats were treated using different calcitriol dosing strategies: (a) 20 ng/kg SD (n = 8), (b) 80 ng/kg SD (n = 8), (c) 5 ng/kg QID (n = 9), or (d) 20 ng/kg QID (n = 9). Multiple targets of calcitriol were assessed which include arterial calcium and phosphate as well as circulating calcium, phosphate, PTH, FGF‐23, VWF, and vitamin D metabolome. PTH suppression occurred dose‐dependently after 1‐week calcitriol treatment (P < .01), but the suppressive effect was lost over time. Both VC and circulating FGF‐23 increased > 10× in all calcitriol‐treated rats (P < .05 and P < .001, respectively); similarly, circulating VWF increased at all time points (P < .05). Ad‐hoc analysis of CKD morbidities in treated rats indicated no differences in negative outcomes based on PTH suppression level (minimal‐, target‐, and over‐). Comparing different calcitriol dosing strategies revealed the following: (a) despite initial calcitriol‐influenced PTH suppression across all treatments, the ability to continually suppress PTH was markedly reduced by study conclusion and (b) PTH suppression level is not an adequate proxy for improvements in overall CKD morbidity. These findings show (a) a more holistic approach to evaluate CKD treatment efficacy aside from PTH suppression is needed and (b) that other VDRA therapies should be examined in CKD treatment. John Wiley and Sons Inc. 2020-06-09 /pmc/articles/PMC7283992/ /pubmed/32519465 http://dx.doi.org/10.1002/prp2.605 Text en © 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Svajger, Bruno A. Pruss, Cynthia M. Laverty, Kimberly J. Zelt, Jason G. E. Jones, Glenville Kaufmann, Martin Petkovich, Martin Holden, Rachel M. Adams, Michael A. PTH suppression by calcitriol does not predict off‐target actions in experimental CKD |
title | PTH suppression by calcitriol does not predict off‐target actions in experimental CKD |
title_full | PTH suppression by calcitriol does not predict off‐target actions in experimental CKD |
title_fullStr | PTH suppression by calcitriol does not predict off‐target actions in experimental CKD |
title_full_unstemmed | PTH suppression by calcitriol does not predict off‐target actions in experimental CKD |
title_short | PTH suppression by calcitriol does not predict off‐target actions in experimental CKD |
title_sort | pth suppression by calcitriol does not predict off‐target actions in experimental ckd |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283992/ https://www.ncbi.nlm.nih.gov/pubmed/32519465 http://dx.doi.org/10.1002/prp2.605 |
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