Alkaline phosphatase treatment of acute kidney injury-an update

Abstract

Through improved insights into the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (ALP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS)-induced inflammation and kidney injury in animals. However, its effectiveness as an AKI treatment has not been demonstrated definitively. Because the anti-inflammatory properties of ALP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to ALP. The re-evaluation of which properties of the ALP enzyme are responsible for the benefit seen in the lab is an important step in determining where the true potential of ALP as a treatment strategy for AKI in the clinic lies. In this review we will discuss how ALP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signalling and protect barrier tissues, which together form the basis for current knowledge of the role of ALP in the kidney. With this knowledge in mind and by analysing currently available clinical evidence, we propose directions for new research that can determine whether ALP as a treatment strategy for AKI has a future in the clinical field.

Keywords: AKI; alkaline phosphatase; barrier function; ischaemia–reperfusion injury; purinergic signalling.

Figure 1:

Initial and new hypotheses for interaction of ALP with PAMPs. In this figure, a generic inflammatory cell is depicted. PAMPs released from Gram-negative bacteria cause a potent inflammatory response through TLRs. Despite current evidence pointing away from direct detoxification of the toxic lipid A core in LPS by ALP, treatment with ALP leads to strongly reduced PAMP-induced inflammation in vivo and in vitro. These effects might be mediated through purinergic/pyrimidinergic signalling or through a yet undetermined pathway. For flagellin and CpG DNA, indirect evidence suggests reduced toxicity, which needs to be confirmed with additional testing. Arrows indicate activation; arrow with flat head indicates inhibition. Created with BioRender.com.

Figure 2:

Purinergic receptor pathway. Intracellular nucleotides (ATP and UTP) are released from damaged (active through connexin or pannexin) or necrotic cells (passive leakage). In the extracellular space, these nucleotides are potent activators of pro-inflammatory receptors. They can be dephosphorylated by membrane proteins CD39 and CD73 (not shown) one phosphate group at a time and eventually into their base molecule (adenosine or uridine). ALP is the only enzyme known to remove all phosphate groups from ATP and UTP at once, directly producing adenosine and uridine. ADP and UDP also activate pro-inflammatory signalling receptors. Adenosine activates the P1 receptors and thereby acutely reduces inflammatory damage. Long-term activation of adenosine receptors leads to inflammation and fibrosis. Anti-inflammatory effects are also attributed to uridine; however, it is unknown through which pathway these effects are induced. Exogenous ALP (exALP) releases phosphate from nucleotides to form adenosine and uridine. Arrow indicates dephosphorylating action. Created with BioRender.com.

Figure 3:

Loss of tissue ALP (tALP) is associated with a loss of intestinal barrier function and increased leakage of endotoxins. Oral and parenteral supplementation with exogenous ALP (exALP) preserves tALP activity and TJPs during (ischaemic) insults and protects intestinal epithelial barrier function. tALP offers protection against bacteria-induced inflammation whereas exALP does not. There are similarities between ALP expression in the intestinal and tubular epithelium, however, its specific functions in the latter have yet to be elucidated. Created with BioRender.com.