Table 1.
Overview of alkaline phosphatase related (pre)clinical research.
| AP related effects | |||||
|---|---|---|---|---|---|
| Study | Species | Model | Treatment | Sample size | Outcome |
| Yao et al. (1994) | Rats | IV LPS injection | Pretreatment with monophosphoryl lipid A (MLA; a dephosphorylated form of lipid A in LPS) 5 mg/kg for 24 | NR | LPS: 89% mortality at 48 following administration LPS + MLA: 0% mortality at 48 following administration and inhibited all of the manifestations of disseminated intravascular coagulation produced by endotoxin. |
| Poelstra et al. (1997) | Rats | Intraperitoneal E. coli/Staphylococcus aureus injection | Levamisole (inhibitor of intestinal AP) 50 mg/kg BW | 42 | Inhibition of endogenous AP by levamisole significantly reduced survival of rats intraperitoneally injected with E. coli bacteria. |
| Preclinical | |||||
| Study | Species | Model | Treatment | Sample size | Outcome |
| Bentala et al. (2002) | Mice | Intraperitoneal D-galactosamine + LPS injection | IV bolus injection of 0.1 U placental AP | 7 | Survival rate: 100% (treated) vs 57% (untreated), P = NR |
| Koyama et al. (2002) | Rats | Oral LPS administration | Oral administration of 40 mg/kg BW l-phenylalanine (inhibitor of intestinal AP) | 3 | Serum LPS levels: 180 pg/ml (treated) vs 340 pg/ml (untreated), P < 0.05 |
| Beumer et al. (2003) | Mice | Intraperitoneal E. coli injection | IV bolus injection of 1.5 U biAP | 5 | Survival rate: 80% (treated) vs 20% (untreated), P < 0.01 Body temperature decreased to: 36.2 ± 0.7°C (treated) vs 34.2 ± 0.8°C (untreated), P < 0.05 |
| Beumer et al. (2003) | Piglets | IV LPS injection | IV injection of 2,500 U biAP | 1–3 per group | Platelet counts decreased to: 41 ± 4 × 109/L (treated) vs 19 ± 1 × 109/L (untreated), P < 0.05 |
| Verweij et al. (2004) | Mice | Intraperitoneal E. coli injection | IV bolus injection of 1.5 U placental AP | 14 | Survival rate: 100% (treated) vs 58% (untreated) P < 0.01 Serum NO levels increased to: 75 μmol/L (E. coli, untreated) vs 16 μmol/L [control (no E. coli)], P < 0.01; 39 μmol/L (E. coli, treated) vs 16 μmol/L [control (no E. coli)], P = NS. |
| van Veen et al. (2005) | Mice | Cecal ligation and puncture | IV bolus injection of 0.15 U/g BW biAP | 8 | Significant reduced systemic inflammatory response defined as lower peak-plasma levels of TNF-α, IL-6 an MCP-1 and significant signs of reduced injury to liver an lung defined as reduced serum AST/ALT levels and reduced MPO activity in the lung (myeloperoxidase, indicator for tissue inflammation). No significant improvement of survival was shown. |
| Su et al. (2006) | Sheep | Intraperitoneal feces injection | IV bolus injection of 60 U/kg BW Intestinal AP followed by continuous infusion of 20 U/kg/h for 15 h | NR | Median survival significantly improved following AP administration (23.3 vs 17, p < 0.05). Plasma IL-6 level: 0.16 AU (treated) vs 0.20 AU (untreated), P < 0.05 Gas exchange (PaO2:FiO2 ratio) decreased to: 320 mm Hg (treated) vs 50 mm Hg (untreated), P < 0.05. |
| Peters et al. (2015) | Rats | IV LPS injection | IV bolus injection of 1000 U/kg BW human recombinant AP (recAP) | 18 |
In vivo: LPS administration significantly prolonged FITC-sinistrin half-life (as a measure of glomerular filtration fraction), which was prevented by recAP coadministration. RecAP prevented LPS-induced increase in proximal tubule injury markers. In vitro: LPS-induced production of TNF-α, IL-6, and IL-8 was significantly attenuated by recAP. This effect was linked to dephosphorylation, as enzymatically inactive recAP had no effect on LPS-induced cytokine production. RecAP-mediated protection resulted in increased adenosine levels through dephosphorylation of LPS-induced extracellular ATP and ADP. Also, recAP attenuated LPS-induced increased expression of adenosine A2A receptor. |
| Peters et al. (2016) | Rats | Renal ischemia (30 min) and reperfusion | IV infusion of 1,000 U/kg recAP | 18 | RecAP prevented I/R-induced alterations of renal hemodynamics immediately following reperfusion. RecAP treatment prevented I/R injury-induced renal inflammation. |
| Peters et al. (2016) | Rats | LPS infusion (30 min) | IV infusion of 1,000 U/kg recAP | 18 | LPS-induced systemic hemodynamic instability and impaired renal oxygenation was not influenced by recAP. RecAP attenuated biomarkers of renal inflammation and damage during endotoxin-induced shock. |
| Clinical | |||||
| Study | Design | Treatment | Sample size | Outcome | |
| Heemskerk et al. (2009) | Multicenter double-blind, randomized, placebo-controlled phase IIa study | Bovine AP: IV bolus injection of 67.5 U/kg BW, followed by continuous infusion of 132.5 U/kg or placebo | 36 | In sepsis patients, median creatinine clearance [IQR] increased from 54 [24–84] to 76 [25–101] ml/min in the 24 h after AP treatment, while it decreased from 80 [77–91] to 59 [45–59] in the placebo group, P < 0.05. Pathophysiology of NO production and subsequent renal damage were assessed in a subgroup of 15 patients. A 42-fold induction (vs. healthy subjects) in renal inducible NO synthase expression was reduced by 80 ± 5% after AP treatment. In AP-treated patients, the increase in cumulative urinary NO metabolite excretion was attenuated, whereas the opposite occurred after placebo. Reduced excretion of NO metabolites correlated with the proximal tubule injury marker glutathione S-transferase A1-1 in urine, which decreased by 70 [50–80]% in AP-treated patients compared with an increase by 200 [45–525]% in placebo-treated patients. |
|
| Pickkers et al. (2012) | International double-blind, randomized, placebo-controlled phase IIa study | Bovine AP: IV bolus injection of 67.5 U/kg BW, followed by continuous infusion of 132.5 U/kg/24h or placebo | 36 | In patients with SA-AKI, there was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable (progress in renal function variables (ECC, requirement and duration of renal replacement therapy) in 28 days). The improvement of ECC was significantly more pronounced in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 ml/min) for the AP group; and from 40 ± 37 to 65 ± 30 ml/min for placebo; P = 0.01). Reductions in RRT requirement and duration were not significantly different between groups. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, IL-6, LPS-binding protein, and in the urinary excretion of KIM-1 and IL-18 in AP-treated patients relative to placebo. | |
| Pickkers et al. (2018) | International double-blind, randomized, placebo-controlled, dose-finding, adaptive phase IIa/b study | Human recombinant AP: 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 111) or placebo (n = 116), once daily for 3 days |
301 | In patients with SA-AKI, from day 1 to day 7, median ECC increased with 37.4 [26–65.4] and 26 [35.9–61.9] ml/min in recAP and placebo, P = NS. Improvement in ECC over 28 days was significantly better in the recAP group compared to placebo (P = 0.04). Day 28 and day 90 mortality for recAP and placebo were 14.4 and 26.7% (P = 0.02) and 17.1 and 29.1% (P = 0.03), respectively. | |