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.

Neutrophil Extracellular Traps Promote Thrombin Generation Through Platelet-Dependent and Platelet-Independent Mechanisms

“…41,42 The therapeutic efficacy of AP has been attributed to AP-mediated dephosphorylation/detoxification of lipopolysaccharide and dephosphorylation of ATP, a proinflammatory energy molecule released by inflamed renal tissue. 40 In the present study, we have shown that the addition of AP abolished thrombin generation in PRP, suggesting that AP may also exert beneficial effects by impairing platelet polyP-dependent activation of coagulation.…”

“…Recent studies have suggested a therapeutic use for AP in the treatment of sepsis-associated organ dysfunction. 40 Two phase II studies demonstrated that parenteral administration of the dephosphorylating enzyme AP to intensive care unit patients with sepsis and associated acute kidney injury improved kidney function and reduced markers of inflammation and kidney injury. 41,42 The therapeutic efficacy of AP has been attributed to AP-mediated dephosphorylation/detoxification of lipopolysaccharide and dephosphorylation of ATP, a proinflammatory energy molecule released by inflamed renal tissue.…”

Sepsis-Induced Acute Kidney Injury

“…Alkaline phosphatase obtunds the Sepsis-Induced Acute Kidney Injury inflammatory response by detoxifying endotoxin, and by attenuating RNS production. 59 Intravenous injection of alkaline phosphatase in patients with early septic AKI significantly improved creatinine clearance with a trend toward a reduced need for RRT. 60 No large RCT has yet explored its efficacy in septic humans.…”

Cellular and Molecular Mechanisms of AKI

“…In addition, there are four potential mechanisms by which the plasma membrane can play an important role in AKI that could be fruitful subjects for further research: by alterations in (1) membrane composition, (2) membrane-associated proteins, and (3) membrane-associated enzymatic activity, and by (4) signaling by membrane-associated components. Examples for each of these potential roles for the plasma membrane in AKI include the following: (1) the composition of cholesterol-rich microdomains is altered after AKI, and lipid microdomains are important both for preventing cell injury and developing subsequent cytoresistance to further insult 1,2 ; (2) there is increased expression of FAS ligand, 3 altered caveolin-1 expression, 4,5 and decreased Na transporters after AKI 6 ; (3) decreased membrane-associated alkaline phosphatase 7 and altered expression of the zinc-dependent metalloproteinase meprin A are associated with AKI 8 ; and (4) a potential role has been suggested for microvesicles/exosomes in protection and recovery from AKI. 9,10 Recent studies have highlighted the importance of regulated necrosis or necroptosis, a receptor-interacting protein kinase-dependent necrotic cell death in AKI.…”