Does Alkaline Phosphatase Reduce Sepsis-Associated Acute Kidney Injury?

This Phase III, international, multicenter, double-blind, randomized controlled trial did not show a reduction in 28-day all-cause mortality with ilofotase alfa (recombinant human alkaline phosphatase). However, the study showed evidence to suggest that ilofotase alfa reduced major adverse kidney events at 90 days, mainly driven by lowering the incidence of renal replacement therapy through day 90 in these patients.

By Arnaldo Lopez-Ruiz, MD

Study Overview

The REVIVAL trial was a Phase III, international, double-blind, randomized controlled study investigating the efficacy and safety of ilofotase alfa, a recombinant human alkaline phosphatase, in patients with sepsis-associated acute kidney injury (SA-AKI). This study aimed to confirm earlier Phase II findings that ilofotase alfa could reduce major adverse kidney events (MAKE90) and improve survival in patients with SA-AKI. Patients were stratified into three groups: those with SA-AKI and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m² (main population), those with moderate-to-severe chronic kidney disease (CKD, eGFR 25-45 mL/min/1.73 m²), and patients with COVID-19-induced sepsis and AKI. The drug was administered within 24-48 hours of AKI onset at a dose of 1.6 mg/kg/day for three consecutive days.

The primary endpoint was 28-day all-cause mortality, while secondary endpoints included major adverse kidney events at 90 days (MAKE90), days alive without organ support, and days alive and free from the ICU through day 28.

Key Findings

Mortality Outcomes

  • 28-day mortality was 27.9% in both the ilofotase alfa and placebo groups, indicating no difference between the treatment and control arms.
  • 90-day mortality was also similar: 33.9% in the ilofotase alfa group versus 34.8% in the placebo group.
  • The trial was stopped early for futility regarding the primary outcome, as ilofotase alfa did not demonstrate a mortality benefit.

Major Adverse Kidney Events (MAKE90)

  • Despite no difference in mortality, MAKE90 events (defined as death, > 25% decline in eGFR, renal replacement therapy (RRT) status, or rehospitalization) were lower in the ilofotase alfa group compared to placebo:
  • MAKE90A: 56.7% in ilofotase alfa vs. 64.6% in placebo.
  • MAKE90B: 37.4% in ilofotase alfa vs. 42.8% in placebo.
  • The reduction in MAKE90 events was primarily driven by a lower need for RRT at 90 days.

Other Secondary Outcomes

  • Days alive without organ support: Patients treated with ilofotase alfa had a median of 17 days (IQR 0-24) compared to 14 days (IQR 0-24) in the placebo group.
  • Days alive and free from the ICU: Patients in the ilofotase alfa group had a median of 15 days (IQR 0-22) compared to 10 days (IQR 0-22) in the placebo group.

Safety

  • Adverse events were comparable between the two groups, with 67.9% of ilofotase alfa patients and 75% of placebo patients experiencing adverse events, suggesting no major safety concerns with the drug.

Commentary

Sepsis is a leading cause of AKI in critically ill patients and is associated with poor outcomes, including higher morbidity and mortality. There are currently no approved pharmacological treatments specifically targeting SA-AKI, and management is largely supportive, involving the treatment of sepsis and prevention of further renal damage.

Comparison with Previous Studies

The findings of the REVIVAL trial are consistent with earlier studies that showed ilofotase alfa's potential reno-protective effects without improving short-term survival. For example, the Phase II STOP-AKI trial suggested that ilofotase alfa reduced MAKE events, including the need for RRT, at 90 days but did not significantly impact 28-day mortality. The REVIVAL trial builds on this by demonstrating that while ilofotase alfa did not improve mortality, it did reduce adverse kidney events, particularly by decreasing the need for RRT, which is clinically significant given the long-term implications of kidney failure and RRT dependency.

Limitations of the Study

Several limitations may have contributed to the lack of mortality benefit in the REVIVAL trial:

  1. Baseline Characteristics: The majority of patients had mild to moderate AKI and relatively preserved baseline renal function (mean eGFR of 71 mL/min/1.73 m²). This population may have been more likely to recover renal function, thus diluting the potential effect of ilofotase alfa.
  1. Lower-than-Expected Mortality: The actual mortality rate in both treatment arms (27.9%) was lower than the expected rate (35%) in the control group, which may have reduced the study’s statistical power to detect a difference in survival.
  1. Unrealistic Effect Size: The study aimed for an 8% absolute mortality reduction, which may have been overly ambitious, especially in light of the patient population’s relatively mild disease severity.
  1. CKD Population: A post hoc analysis revealed that patients with lower baseline eGFR (i.e., those with more severe CKD) might benefit more from ilofotase alfa, suggesting that future studies should focus on populations with more advanced kidney dysfunction.

Future Directions

Despite the study’s failure to show a mortality benefit, ilofotase alfa still holds promise as a treatment for SA-AKI. Its ability to reduce MAKE events, particularly RRT dependency, suggests a potential role in improving long-term renal outcomes for specific patient populations. Several avenues for future research include:

  1. Identifying Responders: Further studies should aim to identify the phenotype of patients most likely to respond to ilofotase alfa, particularly those with more severe preexisting kidney disease.
  1. Timing and Stage of AKI: Early intervention in patients with mild-to-moderate AKI (stages 1 and 2) should be explored to determine if earlier treatment leads to better outcomes.
  1. Long-Term Follow-up: While the 90-day outcomes are important, longer-term data (e.g., 180-day or 1-year follow-up) are needed to evaluate the sustained impact of ilofotase alfa on kidney function and overall survival.
  1. Broader Applications: The drug’s effects on sepsis-associated lung injury or other organ dysfunction should be investigated, given its anti-inflammatory and dephosphorylation mechanisms.

The REVIVAL trial demonstrated that while ilofotase alfa did not reduce 28-day mortality in patients with sepsis-associated AKI, it significantly decreased the incidence of major adverse kidney events, particularly reducing the need for renal replacement therapy at 90 days. Although the trial was stopped early for futility, these findings suggest that ilofotase alfa may offer renal benefits, especially for patients with preexisting kidney disease. Further research is needed to identify specific patient subgroups that could benefit from this therapy and to assess its long-term impact on kidney health and overall survival.

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