Alkaline phosphatase: a possible treatment for sepsis-associated acute kidney injury in critically ill patients.
Acute kidney injury (AKI) is a common disease in the intensive care unit and accounts for high morbidity and mortality. Sepsis, the predominant cause of AKI in this setting, involves a complex pathogenesis in which renal inflammation and hypoxia are believed to play an important role. A new therapy should be aimed at targeting both these processes, and the enzyme alkaline phosphatase, with its dual mode of action, might be a promising candidate. First, alkaline phosphatase is able to reduce inflammation through dephosphorylation and thereby detoxification of endotoxin (lipopolysaccharide), which is an important mediator of sepsis. Second, adenosine triphosphate, released during cellular stress caused by inflammation and hypoxia, has detrimental effects but can be converted by alkaline phosphatase into adenosine with anti-inflammatory and tissue-protective effects. These postulated beneficial effects of alkaline phosphatase have been confirmed in animal experiments and two phase 2a clinical trials showing that kidney function improved in critically ill patients with sepsis-associated AKI. Because renal inflammation and hypoxia also are observed commonly in AKI induced by other causes, it would be of interest to investigate the therapeutic effect of alkaline phosphatase in these nephropathies as well.
Department of Intensive Care Medicine, Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Esther
E
Peters
Department of Intensive Care Medicine, Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Suzanne
S
Heemskerk
Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Rosalinde
R
Masereeuw
Department of Intensive Care Medicine, Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: peter.pickkers@radboudumc.nl.
Peter
P
Pickkers
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000368:Aged; D000469:Alkaline Phosphatase / Q000494:pharmacology / Q000627:therapeutic use*; D016638:Critical Illness; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D018805:Sepsis / Q000150:complications* / Q000503:physiopathology
D000469:Alkaline Phosphatase
Acute kidney injury; adenosine; alkaline phosphatase; biopharmaceutical; hypoxia; renal failure; renal inflammation; sepsis; systemic inflammation