title: Randomized controlled trial of calcitriol in severe sepsis.
abstract: BACKGROUND
  Vitamin D and its metabolites have potent immunomodulatory effects in vitro, including up-regulation of cathelicidin, a critical antimicrobial protein.
  
  
  OBJECTIVE
  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.
  
  
  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).
authors.affiliation: 1 Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: David E
authors.initials: DE
authors.lastname: Leaf
authors.forename: Anas
authors.initials: A
authors.lastname: Raed
authors.forename: Michael W
authors.initials: MW
authors.lastname: Donnino
authors.forename: Adit A
authors.initials: AA
authors.lastname: Ginde
authors.forename: Sushrut S
authors.initials: SS
authors.lastname: Waikar
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control / Q000652:urine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002117:Calcitriol / Q000627:therapeutic use*; D003422:Critical Care / Q000379:methods*; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000652:urine; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000652:urine; D016896:Treatment Outcome; D014815:Vitamins / Q000627:therapeutic use*; D055815:Young Adult; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; D016207:Cytokines; D014815:Vitamins; D002117:Calcitriol; D054804:Cathelicidins
keywords: 1,25-dihydroxyvitamin D; cathelicidin; critical illness; innate immunity; vitamin D