Acute Calcitriol‐Mediated PTH Suppression is Attenuated by High Phosphate Diet in Experimental Model of CKD

Abstract

BackgroundChronic kidney disease (CKD) patients have impaired phosphate and calcium excretion as well as vitamin D deficiency, which exacerbates secondary hyperparathyroidism (SHPT). A decrease in renal CYP27B1 conversion of calcifediol leads to reduced levels of calcitriol. SHPT leads to increased bone resorption and is a risk factor for vascular calcification and cardiovascular disease in the CKD population. The effectiveness of calcitriol in managing SHPT is problematic, as significant resistance develops with chronic therapy; a condition that can lead to parathyroidectomy.AimDetermine the time course and impact of increasing dietary phosphate on calcitriol‐induced suppression of PTH in experimental CKD.MethodsIn Sprague Dawley rats (N=10), a 0.25% adenine 0.5% phosphate diet was fed for 4–5 weeks to generate stable CKD. A single oral calcitriol dose (160ng/kg) was given pre‐CKD, and at 1, 3, and 5 (off adenine) weeks of CKD induction (0.5% dietary phosphate). From 7–8 weeks rats were given increased dietary phosphate (1.0%) and the response to calcitriol was re‐assessed. Changes in circulating PTH, fibroblast growth factor 23 (FGF‐23), calcium and phosphate in response to the biweekly sham or calcitriol dosing were assessed at 0, 4, 8 and 24 hours.ResultsIn CKD rats, PTH increased from 80±25.8 pg/mL to 221±66.7 pg/mL (week 5) and FGF‐23 from 421±26.0 pg/mL to 6803±1510.2 pg/mL (week 5). The two week 1% phosphate markedly increased PTH to 1342±310 pg/mL (8 weeks) and FGF‐23 to 14490±4980.8 pg/mL (7 weeks). In CKD rats on a low phosphate diet, the biweekly calcitriol dose reduced PTH by up to 44% and raised FGF‐23 by 82% whereas in rats on high dietary phosphate PTH was no longer responsive to calcitriol suppression.ConclusionResponses to calcitriol therapy were attenuated with increasing dietary phosphate and increasing CKD severity. This study supports the importance of dietary phosphate restriction in the CKD population to limit the impact of PTH responsiveness and mineral bone disease in this population.SignificanceCharacterization of calcitriol resistance will help to develop new dosing strategies for vitamin D receptor agonists in this population and prevent SHPT and parathyroidectomies.Support or Funding InformationFunded by the Canadian Institutes of Health ResearchThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.