title: Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial.
abstract: BACKGROUND
  To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed.
  
  
  METHODS
  Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety.
  
  
  RESULTS
  There was a significant (P=0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50±27 to 108±73 mL/minute (mean±SEM) for the AP group; and from 40±37 to 65±30 mL/minute for placebo; P=0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial.
  
  
  CONCLUSIONS
  The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI.
  
  
  BACKGROUND
  www.clinicaltrials.gov: NCT00511186.
authors.affiliation: Department of Intensive Care, Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 10, Nijmegen, 6525 GA, The Netherlands. p.pickkers@ic.umcn.nl
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Suzanne
authors.initials: S
authors.lastname: Heemskerk
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schouten
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Laterre
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Albertus
authors.initials: A
authors.lastname: Beishuizen
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Jorens
authors.forename: Herbert
authors.initials: H
authors.lastname: Spapen
authors.forename: Michael
authors.initials: M
authors.lastname: Bulitta
authors.forename: Wilbert H M
authors.initials: WH
authors.lastname: Peters
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018805:Sepsis / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000469:Alkaline Phosphatase