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Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial

Peter Pickkers1*, Suzanne Heemskerk12, Jeroen Schouten3, Pierre-François Laterre4, Jean-Louis Vincent5, Albertus Beishuizen6, Philippe G Jorens7, Herbert Spapen8, Michael Bulitta9, Wilbert HM Peters10 and Johannes G van der Hoeven1

Author Affiliations

1 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

2 Department of Pharmacology and Toxicology, Institute for Genetic and Metabolic Disease, Geert Grooteplein Noord 21, Nijmegen, 6525 EZ, Radboud University Nijmegen Medical Center, The Netherlands

3 Department of Critical Care Medicine, Canisius Wilhelmina Ziekenhuis, Weg door Jonkerbos 100, Nijmegen, 6532 SZ, The Netherlands

4 Department of Intensive Care Medicine, Cliniques Universitaires Saint Luc-UCL, Avenue Hippocate 10, Brussels, 1200, Belgium

5 Department of Intensive Care Medicine, Hopital Erasme, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium

6 Department of Intensive Care Medicine, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1007 MB, The Netherlands

7 Department of Intensive Care Medicine, University Medical Center Antwerp, Wilrijkstraat 10, Edegem, 2650, Belgium

8 Department of Intensive Care Medicine, University Hospital VUB, Laarbeeklaan 101, 1090, Jette, Belgium

9 CRM Biometrics GmbH, Weiherstrasse 19, Rheinbach, 53359, Germany

10 Department of Gastroenterology, Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 8, Nijmegen, 6525 GA, The Netherlands

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Critical Care 2012, 16:R14  doi:10.1186/cc11159

Published: 23 January 2012

Abstract

Introduction

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.

Trial Registration

www.clinicaltrials.gov: NCTNCT00511186

Keywords:
sepsis; systemic inflammatory response syndrome; septic shock; acute renal failure; therapy