ABSTRACT: Active vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), have potent immunomodulatory effects and attenuate acute kidney injury (AKI) in animal models. We conducted an NIH-funded, phase 2, randomized, double-blind, multiple-dose, 3-arm clinical trial comparing oral calcifediol (25D), calcitriol (1,25D), and placebo among critically ill adult patients at high-risk of moderate-to-severe AKI. The primary end point was a hierarchical composite of death, kidney replacement therapy, and kidney injury (baseline-adjusted mean change in serum creatinine), each assessed within 7 days following enrollment using a rank-based procedure. We also performed transcriptomic analyses on circulating CD14+ monocytes collected immediately prior to randomization and two days later using RNA sequencing. The global rank score for the primary end point was similar among calcifediol vs. placebo treated patients (P=0.85) and for calcitriol vs. placebo-treated patients (P=0.58). Calcitriol upregulated more individual genes and pathways in circulating monocytes than did calcifediol, including pathways involving interferon (IFN)-alpha, IFN-gamma, oxidative phosphorylation, DNA repair, and heme metabolism. In summary, treatment with calcifediol or calcitriol in critically ill adults did not attenuate AKI, but calcitriol upregulated multiple genes and pathways involving immunomodulation, DNA repair, and heme metabolism.
