Randomized trial of activated vitamin D for acute kidney injury prevention in critically ill patients

BACKGROUNDActive vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), have potent immunomodulatory effects that attenuate acute kidney injury (AKI) in animal models.METHODSWe conducted a phase 2, randomized, double-blind, multiple-dose, 3-arm clinical trial comparing oral calcifediol (25D), calcitriol (1,25D), and placebo among 150 critically ill adult patients at high risk of moderate to severe acute kidney injury (AKI). The primary endpoint was a hierarchical composite of death, kidney replacement therapy (KRT), and kidney injury (baseline-adjusted mean change in serum creatinine), each assessed within 7 days following enrollment using a rank-based procedure. Secondary endpoints included new or progressive AKI and a composite of KRT or death. Hypercalcemia was the key safety endpoint. We also performed RNA-Seq on circulating CD14+ monocytes collected immediately prior to randomization and 2 days later.RESULTSThe global rank score for the primary endpoint was similar among calcifediol- (n = 51) versus placebo- (n = 49) treated patients (P = 0.85) and for calcitriol (n = 50) versus placebo-treated patients (P = 0.58). Secondary endpoints also occurred at similar rates across groups. Hypercalcemia occurred in 1 patient in the calcifediol group (1.7%), 1 patient in the calcitriol group (2.0%), and no patients in the placebo group. Compared with placebo, calcitriol upregulated more individual genes and pathways in circulating monocytes than did calcifediol, including pathways involving IFN-α, IFN-γ, oxidative phosphorylation, DNA repair, and heme metabolism.CONCLUSIONTreatment with calcifediol or calcitriol in critically ill adults upregulated multiple genes and pathways involving immunomodulation, DNA repair, and heme metabolism, but it did not attenuate AKI.TRIAL REGISTRATIONClinicalTrials.gov (NCT02962102)FUNDINGNIH/NIDDK grant K23DK106448 (to DEL) and NIH/NHLBI grant R01HL16687 (to EYK).