|Human recombinant alkaline phosphatase failed to improve creatinine clearance during first 7 days in patients with sepsis-associated acute kidney injury|
|Sepsis induces acute kidney injury with a variety of mechanism, including inflammation, toxin, and ischemia. Alkaline phosphatase exerts detoxifying functions by dephosphorylation of many chemicals such as bacterial toxins and adenosine triphosphate released from cells, which support development of acute kidney injury during sepsis. It has been evident that administration of alkaline phosphatase increased survival rates via alleviating systemic inflammation in animal models of sepsis. It has been reported that supplement of bovine alkaline phosphatase improved renal functions in sepsis patients in small trials. To test the efficacy of a human recombinant alkaline phosphatase with a long half-time in sepsis patients, the team led by Dr. Peter Pickkers executed this phase randomized, double-blind, placebo-controlled, multiple-centre 2a/2b trial (STOP-AKI trial), which is published in a recent issue of JAMA (here).
This trial was conducted with two stages in critically ill adults with sepsis-associated non-prerenal acute kidney injury. During the first stage, patients were randomly assigned to receive either placebo or one of three doses of alkaline phosphatase (0.4, 0.8, or 1.6 mg/kg) once daily for three days. The primary endpoint was the mean daily endogenous creatinine clearance for days 1 through 7 (AUC1-7 ECC), and the adverse event rate. The median AUC1-7 ECC was 47.0 ml/min, 63.5 ml/min, and 60.7 ml/min, in the 0.4-mg/kg group, 0.8-mg/kg group, and 1.6-mg/kg group, respectively; whereas, AUC1-7 ECC was 46.2 ml/min in the placebo group. Subsequently, the dose of 1.6 mg/kg was selected for the second stage of the trial, which was composed of the placebo group and the 1.6-mg/kg group. The final analysis showed that AUC1-7 ECC was 55.1 ml/min in the 1.6-mg/kg group, and 45.6 ml/min in the placebo group, yielding no statistical significance (p=0.47). Although the primary endpoint was not met, patients in the 1.6-mg/kg group showed improved AUC1-7 ECC at days 21 and 28 compared to individuals in the placebo group (mean difference: 16.3 ml/min, p=0.02 at day 21; 18.5 ml/min, p=0.006 at day 28). More importantly, patients in the 1.6-mg/kg group had lower mortality rates at day 28 (14.4% v.s. 26.7%, p=0.02) and day 90 (17.1% v.s. 29.3%, p=0.03) compared to those in the placebo group. No agent-specific or dose-related adverse effects were found in the trial.
Human recombinant alkaline phosphatase failed to improve short-term kidney functions. Given the observations where long-term kidney function was improved and the mortality rate was reduced in the treatment group, further investigations are warranted.