Leaf David E, Shenoy Tushar, Zinchuk Kevin, Gupta Shruti, Dias Julie-Alexia, Sanchez-Almanzar Daniel, Ginde Adit A, Athar Humra, Cheng Changde, Tamura Tomoyoshi, Kim Edy Y, Waikar Sushrut S
Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
JCI Insight. 2025 Sep 9;10(20). doi: 10.1172/jci.insight.193523. eCollection 2025 Oct 22.
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).
背景
活性维生素D代谢产物，包括25-羟基维生素D（25D）和1,25-二羟基维生素D（1,25D），具有强大的免疫调节作用，可减轻动物模型中的急性肾损伤（AKI）。
方法
我们进行了一项2期、随机、双盲、多剂量、3组临床试验，比较口服骨化二醇（25D）、骨化三醇（1,25D）和安慰剂对150例有中度至重度急性肾损伤（AKI）高风险的危重症成年患者的影响。主要终点是死亡、肾脏替代治疗（KRT）和肾损伤（血清肌酐的基线校正平均变化）的分层复合终点，在入组后7天内使用基于秩的程序进行评估。次要终点包括新发或进展性AKI以及KRT或死亡的复合终点。高钙血症是关键的安全终点。我们还对随机分组前立即采集的循环CD14+单核细胞和2天后采集的细胞进行了RNA测序。
结果
骨化二醇治疗组（n = 51）与安慰剂治疗组（n = 49）相比，主要终点的总体秩次评分相似（P = 0.85），骨化三醇治疗组（n = 50）与安慰剂治疗组相比也是如此（P = 0.58）。次要终点在各组中的发生率也相似。骨化二醇组有1例患者发生高钙血症（1.7%），骨化三醇组有1例患者发生高钙血症（2.0%），安慰剂组无患者发生高钙血症。与安慰剂相比，骨化三醇上调循环单核细胞中更多的单个基因和通路，比骨化二醇上调的更多，包括涉及IFN-α、IFN-γ、氧化磷酸化、DNA修复和血红素代谢的通路。
结论
对危重症成年患者使用骨化二醇或骨化三醇治疗上调了多个涉及免疫调节、DNA修复和血红素代谢的基因和通路，但并未减轻AKI。
试验注册
ClinicalTrials.gov（NCT02962102）
资助
美国国立卫生研究院/国立糖尿病、消化和肾脏疾病研究所拨款K23DK106448（授予DEL）和美国国立卫生研究院/国立心肺血液研究所拨款R01HL16687（授予EYK）。
