Objective: Alkaline phosphatase (AP) attenuates inflammatory responses by lipopolysaccharide detoxification and may prevent organ damage during sepsis. To investigate the effect of AP in patients with severe sepsis or septic shock on acute kidney injury.
Design and Setting: A multicenter double-blind, randomized, placebo-controlled phase IIa study (2:1 ratio).
Patients: Thirty-six intensive care unit patients (20 men/16 women, mean age 58 ± 3 years) with a proven or suspected Gram-negative bacterial infection, ≥2 systemic inflammatory response syndrome criteria (<24 hours), and <12 hours end-organ dysfunction onset were included.
Intervention: An initial bolus intravenous injection (67.5 U/kg body weight) over 10 minutes of AP or placebo, followed by continuous infusion (132.5 U/kg) over the following 23 hours and 50 minutes.
Measurements and Main Results: Median plasma creatinine levels declined significantly from 91 (73–138) to 70 (60–92) μmol/L only after AP treatment. Pathophysiology of nitric oxide (NO) production and subsequent renal damage were assessed in a subgroup of 15 patients. A 42-fold induction (vs. healthy subjects) in renal inducible NO synthase expression was reduced by 80% ± 5% after AP treatment. In AP-treated patients, the increase in cumulative urinary NO metabolite excretion was attenuated, whereas the opposite occurred after placebo. Reduced excretion of NO metabolites correlated with the proximal tubule injury marker glutathione S-transferase A1-1 in urine, which decreased by 70 (50–80)% in AP-treated patients compared with an increase by 200 (45–525)% in placebo-treated patients.
Conclusions: In severe sepsis and septic shock, infusion of AP inhibits the upregulation of renal inducible NO synthase, leading to subsequent reduced NO metabolite production, and attenuated tubular enzymuria. This mechanism may account for the observed improvement in renal function.
From the Department of Pharmacology and Toxicology (SH, RM, FGMR), Nijmegen Centre for Molecular Life Sciences; and Department of Intensive Care Medicine (OM, MPWJMB, JGH, PP), Nijmegen University Centre for Infectious Diseases (JGH), Department of Gastroenterology (WHMP), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
AM-Pharma BV funded the conduct of the study and the main statistical analysis (by SGS Biopharma; Wavre, Belgium). S. Heemskerk was supported by a grant from the Netherlands Organisation for Scientific Research (NWO); P. Pickkers is a recipient of a Clinical Fellowship grant of the Netherlands Organisation for Scientific Research (NWO-ZonMw), which supported the evaluations and analyses of renal markers.
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