ABT-719 for the Prevention of Acute Kidney Injury in Patients Undergoing High-Risk Cardiac Surgery: A Randomized Phase 2b Clinical Trial

Abstract

Background: Patients undergoing cardiac surgeries with cardiopulmonary bypass (on-pump) have a high risk for acute kidney injury (AKI). We tested ABT-719, a novel α-melanocyte-stimulating hormone analog, for prevention of AKI in postoperative cardiac surgery patients.

Methods and results: This phase 2b randomized, double-blind, placebo-controlled trial included adult patients with stable renal function undergoing high-risk on-pump cardiac surgery in the United States and Denmark. Participants received placebo (n=61) or cumulative ABT-719 doses of 800 (n=59), 1600 (n=61), or 2100 μg/kg (n=59). Primary outcome was development of AKI based on Acute Kidney Injury Network (AKIN) criteria, measured utilizing preoperative creatinine value and maximum value within 48 hours and urine output within the first 42 hours postsurgery. Secondary outcomes included incidence of AKI based on maximal changes from baseline in novel AKI biomarkers over a 72-hour period after clamp release and length of intensive care unit stays through 90 days postsurgery. A total of 65.5%, 62.7%, and 69.6% of patients in the 800-, 1600-, and 2100-μg/kg groups, respectively, developed AKI (stages 1, 2, and 3 combined) versus 65.5% in the placebo group (for each pair-wise comparison with placebo, P=0.966, 0.815, and 0.605, respectively). Adverse events occurred at a similar rate in all treatment groups.

Conclusions: ABT-719 treatment did not lower AKI incidence using AKIN criteria, influence the elevations of novel biomarkers, or change 90-day outcomes in patients after cardiac surgery.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01777165.

Keywords: acute kidney injury; cardiopulmonary bypass; clinical trial; kidney; renal; renal function; α‐melanocyte‐stimulating hormone.

Figure 1

Disposition of patients in CONSORT flow diagram. *Reasons for exclusion were not mutually exclusive.

Figure 2

Effect of ABT‐719 treatment on AKI incidence. *AKI incidence was determined by (A) the AKIN criteria, (B) RIFLE, AKIN, and KDIGO criteria using SCr only, (C) RIFLE, AKIN, and KDIGO criteria using urine output only, and (D) RIFLE, AKIN, and KDIGO criteria using both SCr and/or urine output. Any patient receiving RRT was classified as stage 3 AKI according to the AKIN and KDIGO criteria. AKI indicates acute kidney injury; AKIN, Acute Kidney Injury Network; KDIGO, Kidney Disease: Improving Global Outcomes; PBO, placebo; RIFLE, Risk, Injury, Failure, Loss, and End‐Stage Kidney Disease; RRT, renal replacement therapy; SCr, serum creatinine. *95% CI for any stage AKI incidence.

Figure 3

Effect of ABT‐719 treatment on incidence of composite outcomes (MAKE). *Percentage of patients developing at least 1 of the composite events of death, needing RRT during the 90‐day postoperative period or ≥25% reduction in eGFR at day 90. eGFR indicates estimated glomerular filtration rate; MAKE, major adverse kidney events; RRT, renal replacement therapy. *95% CI for any composite event.

Figure 4

Effect of ABT‐719 treatment on the length of hospitalization. Length of stay in the hospital and intensive care unit (ICU) by 90 days postsurgery. Using the Kruskal–Wallis test for the comparisons between placebo and ABT‐719, P values were ≥0.06 for hospitalization and ≥0.09 for ICU stay.

Figure 5

Increase in AKI biomarkers over a 72‐hour period after clamp release. (A) Serum NGAL, (B) urine NGAL, (C) urine IL‐18, and (D) urine KIM‐1. AKI indicates acute kidney injury; IL‐18, interleukin‐18; KIM‐1, kidney injury molecule 1; NGAL, neutrophil gelatinase‐associated lipocalin.