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

Abstract

Introduction: To 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.

Methods: Thirty-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.

Results: There 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.

Conclusions: The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI.

Trial registration: www.clinicaltrials.gov: NCT00511186.

Figures

Figure 1

Flow chart of patients.

Figure 2

Progression of renal parameters. (A) Endogenous creatinine clearance is expressed as mean ± SEM (one-side depicted) and analyzed by ANOVA with repeated measurements over the complete curve (P = 0.01). Missing values were imputed from last-observation-carried forward (LOCF) from Day 7 to Day 28. (B) Renal replacement therapy (RRT) requirement is expressed as percentage in total treatment group; analyzed by Fisher's exact test (P = 0.29). (C) RRT duration: hours per total number of patients in group (cumulative for multiple interventions) over study period, expressed as mean ± SEM; analyzed by independent t-test (P = 0.08). *: Primary variable analyzed by the Hartung method [22].

Figure 3

Urinary biomarkers of renal injury. (A) Kidney injury molecule-1 (KIM-1); (B) neutrophil gelatinase-associated lipocalin (NGAL); (C) glutathione S-transferase A1-1 (GSTA1-1); (D) GSTP1-1; and (E) IL-18 levels in urine; measured at various times points for placebo and alkaline phosphatase treatment during the first seven days. Urinary excretion of KIM-1 and IL-18 was lower in AP-treated patients relative to placebo-treated patients. Data are expressed as mean ± SEM (one-side depicted) and analyzed by ANOVA with repeated measurements over the complete curve with baseline as covariate.

Figure 4

Systemic inflammatory markers. (A) LBP: Lipopolysaccharide-binding protein; (B) IL-6: interleukin-6; (C) CRP: C-reactive protein; (D) PCT: procalcitonin. Data are expressed as mean ± SEM (one-side depicted); analyzed by ANOVA with repeated measurements over the complete curve with baseline as covariate.