PTH suppression by calcitriol does not predict off‐target actions in experimental CKD

摘要

Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25-(OH)2 D3 ) 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??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.? 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.