Randomized controlled trial of calcitriol in severe sepsis

Abstract

Rationale: Vitamin D and its metabolites have potent immunomodulatory effects in vitro, including up-regulation of cathelicidin, a critical antimicrobial protein.

Objectives: We investigated whether administration of 1,25-dihydroxyvitamin D (calcitriol) to critically ill patients with sepsis would have beneficial effects on markers of innate immunity, inflammation, and kidney injury.

Methods: We performed a double-blind, randomized, placebo-controlled, physiologic study among 67 critically ill patients with severe sepsis or septic shock. Patients were randomized to receive a single dose of calcitriol (2 μg intravenously) versus placebo. The primary outcome was plasma cathelicidin protein levels assessed 24 hours after study drug administration. Secondary outcomes included leukocyte cathelicidin mRNA expression, plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2), and urinary kidney injury markers.

Measurements and main results: Patients randomized to calcitriol (n = 36) versus placebo (n = 31) had similar plasma cathelicidin protein levels at 24 hours (P = 0.16). Calcitriol-treated patients had higher cathelicidin (P = 0.04) and IL-10 (P = 0.03) mRNA expression than placebo-treated patients 24 hours after study drug administration. Plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2) and urinary kidney injury markers were similar in calcitriol- versus placebo-treated patients (P > 0.05 for all comparisons). Calcitriol had no effect on clinical outcomes nor were any adverse effects observed.

Conclusions: Calcitriol administration did not increase plasma cathelicidin protein levels in critically ill patients with sepsis and had mixed effects on other immunomodulatory markers. Additional phase II trials investigating the dose and timing of calcitriol as a therapeutic agent in specific sepsis phenotypes may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 01689441).

Trial registration: ClinicalTrials.gov NCT01689441.

Keywords: 1,25-dihydroxyvitamin D; cathelicidin; critical illness; innate immunity; vitamin D.

Figure 1.

Enrollment flow chart. The slight imbalance in number of patients randomized to calcitriol versus placebo resulted from a clerical error in one of the permuted blocks generated by the research pharmacy. This error did not affect blinding, and all patients received the drug to which they were randomized. AKI = acute kidney injury (defined in the Methods); ESRD = end-stage renal disease; ICU = intensive care unit; RRT = renal-replacement therapy.

Figure 2.

Change in plasma 1,25-dihydroxyvitamin D (1,25D) levels, placebo versus calcitriol. 1,25D levels represent the sum of 1,25D₂ and 1,25D₃. *P < 0.001, comparison of 1,25D levels in calcitriol- versus placebo-treated patients at 6 hours. n = 36 (calcitriol), n = 31 (placebo). Thin lines represent individual patients. Thick lines represent median levels.

Figure 3.

Effect of calcitriol on plasma levels of immune and inflammatory markers. No significant between-group differences were detected in plasma protein levels of (A) human cathelicidin antimicrobial peptide (hCAP)-18, (B) IL-6, (C) tumor necrosis factor (TNF)-α, (D) IL-10, (E) IL-1β, or (F) IL-2. n = 36 (calcitriol) and n = 31 (placebo). Bars represent median (25th–75th interquartile range).

Figure 4.

Effect of calcitriol on leukocyte mRNA expression of immune and inflammatory markers. (A) mRNA fold elevation at 24 hours for hCAP-18, IL-6, tumor necrosis factor (TNF)-α, and IL-10. (B) Fold-elevation in 1,25-dihydroxyvitamin D (1,25D) levels (0–6 h) versus fold-elevation in human cathelicidin antimicrobial peptide (hCAP)-18 mRNA expression (0–24 h). n = 32 (calcitriol) and n = 26 (placebo). Bars represent median (25th–75th interquartile range). 1.0-fold elevation is equivalent to no change.

Figure 5.

Effect of calcitriol on urinary biomarkers. No significant between-group differences were detected for (A) urinary NGAL or (B) urinary KIM-1. n = 36 (calcitriol), n = 26 (placebo). NGAL = neutrophil gelatinase-associated lipocalin; KIM-1 = kidney injury molecule-1. Bars represent median (25th–75th interquartile range).