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).
RCT Entities:
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 illpatients 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 illpatients 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 illpatients 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).
Entities:
Keywords:
1,25-dihydroxyvitamin D; cathelicidin; critical illness; innate immunity; vitamin D
Authors: Aideen C Allen; Siobhan Kelly; Sharee A Basdeo; Katie Kinsella; Keith J Mulready; Kingston H G Mills; Niall Tubridy; Cathal Walsh; Jennifer J Brady; Michael Hutchinson; Jean M Fletcher Journal: Mult Scler Date: 2012-03-28 Impact factor: 6.312
Authors: Seth I Sokol; Vankeepuram Srinivas; Jill P Crandall; Mimi Kim; George Tellides; Amir H Lebastchi; Amir Lebastchi; Yiting Yu; Alok K Gupta; Michael H Alderman Journal: Vasc Med Date: 2012-12 Impact factor: 3.239
Authors: David E Leaf; Myles Wolf; Sushrut S Waikar; Herbert Chase; Marta Christov; Serge Cremers; Leonard Stern Journal: Clin J Am Soc Nephrol Date: 2012-06-14 Impact factor: 8.237
Authors: Andrea B Braun; Augusto A Litonjua; Takuhiro Moromizato; Fiona K Gibbons; Edward Giovannucci; Kenneth B Christopher Journal: Crit Care Med Date: 2012-12 Impact factor: 7.598
Authors: An Lehouck; Chantal Mathieu; Claudia Carremans; Femke Baeke; Jan Verhaegen; Johan Van Eldere; Brigitte Decallonne; Roger Bouillon; Marc Decramer; Wim Janssens Journal: Ann Intern Med Date: 2012-01-17 Impact factor: 25.391
Authors: Peter G Barlow; Pavel Svoboda; Annie Mackellar; Anthony A Nash; Ian A York; Jan Pohl; Donald J Davidson; Ruben O Donis Journal: PLoS One Date: 2011-10-21 Impact factor: 3.240
Authors: Jenny E Han; Jessica A Alvarez; Jennifer L Jones; Vin Tangpricha; Mona A Brown; Li Hao; Lou Ann S Brown; Greg S Martin; Thomas R Ziegler Journal: Nutrition Date: 2017-02-27 Impact factor: 4.008
Authors: Ryan Gardner; Xiaowen Liu; Yanbo Wang; Andrew Cole; Stanley Heydrick; Michael W Donnino; Ari Moskowitz Journal: Resuscitation Date: 2020-09-16 Impact factor: 5.262
Authors: Kate Madden; Henry A Feldman; Rene F Chun; Ellen M Smith; Ryan M Sullivan; Anna A Agan; Shannon M Keisling; Angela Panoskaltsis-Mortari; Adrienne G Randolph Journal: Ann Am Thorac Soc Date: 2015-11
Authors: Sadeq A Quraishi; Gennaro De Pascale; Joseph S Needleman; Harumasa Nakazawa; Masao Kaneki; Ednan K Bajwa; Carlos A Camargo; Ishir Bhan Journal: Crit Care Med Date: 2015-09 Impact factor: 7.598
Authors: Renata C Pereira; Isidro B Salusky; Richard E Bowen; Earl G Freymiller; Katherine Wesseling-Perry Journal: Bone Date: 2019-08-01 Impact factor: 4.398
Authors: Adit A Ginde; Roy G Brower; Jeffrey M Caterino; Lani Finck; Valerie M Banner-Goodspeed; Colin K Grissom; Douglas Hayden; Catherine L Hough; Robert C Hyzy; Akram Khan; Joseph E Levitt; Pauline K Park; Nancy Ringwood; Emanuel P Rivers; Wesley H Self; Nathan I Shapiro; B Taylor Thompson; Donald M Yealy; Daniel Talmor Journal: N Engl J Med Date: 2019-12-11 Impact factor: 91.245