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

Abstract

BackgroundPatients 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 ResultsThis 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.

Translating Knowledge Into Therapy for Acute Kidney Injury

“…8 This was a phase 2B study that was powered properly to test the hypothesis that there is a dose-dependent protective effect of ABT-719 on the development of AKI in high-risk patients 72 hours after surgery. This study built on promising data from a small, unpublished, single-dose study of ABT-719 in cardiac surgery patients.…”

“…10,15 The required patient enrollment was reached in this large, well-conducted, multicenter clinical study, but unfortunately the study showed no effect of ABT-719 on the primary (early AKI) or secondary end points (90 days >25% reduction in estimated glomerular filtration rate, or urinary or plasma AKI biomarkers). 8 In retrospect, it is notable that despite the strong supportive preclinical data, there were no published data indicating that MRs are expressed in human kidneys, or that there is aberrant activation of MSH/MR signaling in human kidneys after AKI. Another concern is that although published preclinical data in a variety of species from different laboratories have indicated that AP214 and α-MSH are protective after IR-induced AKI, 10,16–18 it is not clear that IR injury is the mechanism of AKI after cardiac surgery with modern cardiopulmonary bypass machines.…”

“…5 For example, the clinical trial of ABT-719 to prevent AKI in patients undergoing cardiac surgery 8 was supported by preclinical research in models of sepsis-associated AKI (cecal ligation and puncture), 11 and IR-induced AKI in rodents and pigs. 9,10,14 However, at the time the clinical studies were initiated, there were no data on ABT-719 efficacy in preclinical models of cardiac surgery, and no data on the efficacy of ABT-719 in preclinical models of AKI with pre-existing CKD.…”

“…8 This weakness was mitigated by including the use of three doses of ABT-719 in the clinical trial design: even if the lowest dose had no effect, we might have expected to have seen some effects at higher doses. However, this expectation makes the assumption that any dose of ABT-719 can activate this pathway in human beings, and if it does not, how could ABT-719 have been expected to have any beneficial effects in patients with AKI?…”

“…An illustrative example of this comes from one of the more recent clinical studies of a melanocyte-stimulating hormone (MSH) agonist to prevent AKI in patients after cardiac surgery. 8 …”