Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial

Abstract

IntroductionTo evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed.MethodsThirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety.ResultsThere was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 mL/minute (mean ± SEM) for the AP group; and from 40 ± 37 to 65 ± 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial.ConclusionsThe improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI.Trial Registrationwww.clinicaltrials.gov: NCTNCT00511186

Challenges and Advances in the Treatment of AKI

“…In a phase II randomized controlled trial, infusion of bovine alkaline phosphatase within 48 hours of diagnosis of AKI secondary to sepsis resulted in a significant reduction in the systemic markers C-reactive protein and IL-6, and urinary excretion of kidney injury molecule-1 and IL-18, but not neutrophil gelatinaseassociated lipocalin (NGAL). 23 In addition, endogenous creatinine clearance was significantly higher up to day 28 in the treated group relative to placebo. 23 RRT requirement decreased, but this did not reach significance.…”

“…22 Alkaline Phosphatase Alkaline phosphatase is an endogenous enzyme that acts by detoxification of proinflammatory substances, such as LPS and extracellular ATP. 23 Alkaline phosphatase dephosphorylates ATP to produce adenosine, which promotes anti-inflammatory properties and prevents tubular damage. Additionally, dephosphorylated LPS produced by the action of alkaline phosphatase acts as an antagonist for the LPS receptor TLR4 and prevents an inflammatory response and renal damage.…”

A test of vitamin D benefits on respiratory health mediated through inflammatory markers

“…It has been proposed as a possible therapeutic agent for such conditions as sepsis, acute kidney injury, or brain injury. [28][29][30] It has also been examined as a diagnostic tool for pulmonary tuberculosis 31 and as a marker of fibrosis in chronic interstitial lung disorders. 17 Our evidence suggests that AP is elevated in persons who report more frequent respiratory symptoms or COPD and that vitamin D may operate to help control serum levels of this enzyme.…”

Inflammation in AKI

“…Especially for relatively small phase 2 trials with compounds that show promising data in animal studies, a combination of study drug-induced effects on these end points may facilitate the design of larger trials. 61 Currently, a cutoff level of 25% or 50% decrease in GFR is the most commonly used outcome measure in clinical trials of intervention for AKI, and this degree of GFR decrease is accepted by the FDA and the EMEA as a clinical end point. An alternative end point with clinical relevance, however, is requirement for initiation of RRT.…”