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

Abstract

Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25‐(OH)2D3) 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.

Where are we now? Emerging opportunities and challenges in the management of secondary hyperparathyroidism in patients with non-dialysis chronic kidney disease

“…Active vitamin D and its analogues may, therefore, also lead to surges of 1,25(OH) 2 D following administration, which can induce vitamin D catabolism via CYP24A1 (24-hydroxylase), causing excessive increases in 24,25(OH)D3 and 1,24,25(OH)D3, respectively. Importantly, active vitamin D and its analogues are also associated with an increased risk of hypercalcaemia and risk of accelerated vascular calcification [54][55][56]. Indeed, recent studies of CKD stage G3-G4 patients with SHPT treated with paricalcitol (PRIMO and OPERA studies) failed to demonstrate improvements in hard outcomes (left ventricular mass and function) but found an increase in the risk of hypercalcaemia [57,58].…”