title: Alkaline phosphatase as a treatment of sepsis-associated acute kidney injury.
abstract: Currently there are no pharmacological therapies licensed to treat sepsis-associated acute kidney injury (AKI). Considering the high incidence and mortality of sepsis-associated AKI, there is an urgent medical need to develop effective pharmacological interventions. Two phase II clinical trials recently demonstrated beneficial effects of the enzyme alkaline phosphatase (AP). In critically ill patients with sepsis-associated AKI, treatment with AP reduced the urinary excretion of tubular injury biomarkers and plasma markers of inflammation, which was associated with improvement of renal function. The dephosphorylating enzyme, AP, is endogenously present in the renal proximal tubule apical membrane but becomes depleted during ischemia-induced AKI, thereby possibly contributing to further renal damage. The exact mechanism of action of AP in AKI is unknown, but might be related to detoxification of circulating lipopolysaccharide and other proinflammatory mediators that lose their proinflammatory effects after dephosphorylation. Alternatively, tissue damage associated with systemic inflammation might be attenuated by an AP-mediated effect on adenosine metabolism. Adenosine is a signaling molecule that has been shown to protect the body from inflammation-induced tissue injury, which is derived through dephosphorylation of ATP. In this Perspectives article, we discuss the clinical activity of AP and its putative molecular modes of action, and we speculate on its use to treat and possibly prevent sepsis-associated AKI.
authors.affiliation: Department of Intensive Care Medicine, Nijmegen Institute for Infection Inflammation and Immunity, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Peters
authors.forename: Andrea
authors.initials: A
authors.lastname: van Elsas
authors.forename: Suzanne
authors.initials: S
authors.lastname: Heemskerk
authors.forename: Luigi
authors.initials: L
authors.lastname: Jonk
authors.forename: Johannes
authors.initials: J
authors.lastname: van der Hoeven
authors.forename: Jacques
authors.initials: J
authors.lastname: Arend
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002986:Clinical Trials as Topic; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D018805:Sepsis / Q000150:complications*
chemical_list: D008070:Lipopolysaccharides; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase