Vitamin D Receptor Agonists for Patients Undergoing Hemodialysis

Abstract

Cardiovascular disease (CVD) is the leading cause of death among patients with end-stage kidney disease (ESKD) who are undergoing hemodialysis, yet many standard cardioprotective therapies have not been effective in reducing CVD in this patient population. 1 This reality has motivated the quest to identify dialysis-related and kidney disease-specific factors that promote CVD.Based on observations from the past 2 decades, deficiency of active vitamin D has been a prime candidate for CVD reduction. In patients with ESKD, activity of the 1-α-hydroxylase enzyme is substantially diminished. This enzyme is primarily expressed in the kidney and converts 25-hydroxyvitamin D to active 1,25 dihydroxyvitamin D (1,25[OH]2D). As a consequence of low 1,25[OH]2D levels, parathyroid hormone (PTH) is stimulated in a feedback loop that attempts to restore 1,25[OH]2D activity and correct abnormal calcium and phosphate levels. In the untreated state, this pathophysiology results in severe secondary or tertiary hyperparathyroidism, which is associated with highly morbid skeletal complications, including fracture, deformity, and growth failure in children. 2 To interrupt this cascade, 1,25[OH]2D is often prescribed to patients with ESKD in the form of vitamin D receptor agonists (VDRAs). As evidence supporting the potential cardiovascular benefits of vitamin D supplementation in the general population increased, the treatment of 1,25[OH]2D deficiency to prevent CVD in patients with ESKD became a prominent area of investigation, and observational studies demonstrated potential benefits. 3,4 However, with the already widespread use of VDRAs to control PTH levels and prevent bone complications in patients with ESKD, clinical trials confirming the potential cardiovascular benefits of this therapy have not been performed.In this issue of JAMA, Shoji et al report the findings of the Japan Dialysis Active Vitamin D (J-DAVID) trial, 5 the most recent trial of VDRAs in patients receiving hemodialysis. Specifically, the J-DAVID trial tested the hypothesis that the VDRA alfacalcidol reduces the risk of cardiovascular events in patients undergoing hemodialysis who do not have overt secondary hyperparathyroidism. In this open-label, blinded end point study conducted from 2008 to 2015 across 108 dialysis centers in Japan, 976 patients were randomly assigned to receive alfacalcidol (n = 495) or usual care without VDRAs (n = 481). At enrollment, eligible participants were adults receiving hemodialysis for at least 90 days, with intact PTH levels less than or equal to 180 pg/mL, serum calcium