title: Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury.
abstract: Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated. In a second model, rats (n=18) received a 30min infusion of lipopolysaccharide (LPS; 2.5mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000U/kg) was administered intravenously (15min before reperfusion, or 90min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial.
authors.affiliation: Department of Intensive Care Medicine, Radboud university medical center, PO Box 9101, Internal Mailbox 710, 6500 HB, Nijmegen, The Netherlands; Department of Pharmacology and Toxicology, Radboud university medical center, PO Box 9101, Internal Mailbox 149, 6500 HB, Nijmegen, The Netherlands. Electronic address: esther.peters@radboudumc.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: Peters
authors.affiliation: Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Electronic address: b.ergin@amc.uva.nl.
authors.forename: Bülent
authors.initials: B
authors.lastname: Ergin
authors.affiliation: Department of Biology, Faculty of Science, Istanbul University, PK 34134, Vezneciler, Istanbul, Turkey. Electronic address: aslikandil@istanbul.edu.tr.
authors.forename: Asli
authors.initials: A
authors.lastname: Kandil
authors.affiliation: Department of Biology, Faculty of Science, Istanbul University, PK 34134, Vezneciler, Istanbul, Turkey. Electronic address: egurelgurevin@gmail.com.
authors.forename: Ebru
authors.initials: E
authors.lastname: Gurel-Gurevin
authors.affiliation: AM-Pharma, Rumpsterweg 6, 3981 AK, Bunnik, The Netherlands. Electronic address: a.vanelsas@am-pharma.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: van Elsas
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, PO Box 80082, 3508 TB Utrecht, The Netherlands. Electronic address: r.masereeuw@uu.nl.
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.affiliation: Department of Intensive Care Medicine, Radboud university medical center, PO Box 9101, Internal Mailbox 710, 6500 HB, Nijmegen, The Netherlands. Electronic address: peter.pickkers@radboudumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Electronic address: c.ince@amc.uva.nl.
authors.forename: Can
authors.initials: C
authors.lastname: Ince
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D000469:Alkaline Phosphatase / Q000494:pharmacology*; D000818:Animals; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D000469:Alkaline Phosphatase; D010100:Oxygen
keywords: Acute kidney injury; Alkaline phosphatase; Inflammation; Ischemia-reperfusion; Lipopolysaccharide; Therapy