Effect of Activated Vitamin D on Acute Kidney Injury in Critically Ill Patients

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. RNAseq on CD14+ monocytes, 2 time points(immediately prior to randomization; two days after treatment initiation), 3-arim design (oral calcifediol, n=51; oral calcitriol, n=50; placebo control, n=49), randomized, double-blinded,

活性维生素D代谢物，包括25-羟维生素D（25-hydroxyvitamin D，25D）与1,25-二羟维生素D（1,25-dihydroxyvitamin D，1,25D），具有强效免疫调节作用，且在动物模型中可减轻急性肾损伤（acute kidney injury，AKI）。本研究开展了一项由美国国立卫生研究院（National Institutes of Health，NIH）资助的II期随机双盲多剂量三臂临床试验，在罹患中重度急性肾损伤高风险的重症成年患者中，对比口服骨化二醇（calcifediol）、骨化三醇（calcitriol）与安慰剂的疗效。本研究的主要终点为死亡、肾脏替代治疗及肾损伤（血清肌酐的基线校正平均变化值）的分层复合终点，采用基于秩的检验方法，在受试者入组后7天内完成评估。此外，本研究对随机分组前即刻及随机分组后2天采集的循环CD14+单核细胞进行了RNA测序（RNA sequencing，RNAseq）转录组学分析。结果显示，骨化二醇组与安慰剂组受试者的主要终点全局秩和得分无显著差异（P=0.85），骨化三醇组与安慰剂组的该得分亦无统计学差异（P=0.58）。相较于骨化二醇，骨化三醇可在循环单核细胞中上调更多的单个基因及通路，包括干扰素（interferon，IFN）-α、干扰素-γ、氧化磷酸化、DNA修复及血红素代谢相关通路。综上，在重症成年患者中给予骨化二醇或骨化三醇治疗并未减轻急性肾损伤，但骨化三醇可上调多条涉及免疫调节、DNA修复及血红素代谢的基因与通路。本数据集包含CD14+单核细胞的RNA测序数据，共两个采集时间点（随机分组前即刻；治疗开始后2天），采用三臂设计（口服骨化二醇组n=51；口服骨化三醇组n=50；安慰剂对照组n=49），为随机双盲试验。