Acute Kidney Injury
Conditions
Brief summary
Multiple lines of evidence support a central role of iron in causing acute kidney injury (AKI), including the finding that prophylactic administration of iron chelators attenuates AKI in animal models. Patients undergoing cardiac surgery may be particularly susceptible to iron-mediated kidney injury due to the profound hemolysis that often occurs from cardiopulmonary bypass. The investigators will test in a phase 2, randomized, double-blind, placebo-controlled trial whether prophylactic administration of deferoxamine decreases the incidence of AKI following cardiac surgery.
Interventions
DRUGDeferoxamine
Deferoxamine 30mg/kg (max dose, 6g) intravenous infusion (diluted in 240mL normal saline) administered over 12 hours
DRUGNormal saline
Normal saline (240mL) intravenous infusion over 12 hours
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years 2. Undergoing coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass 3. AKI risk score ≥6 at the time of screening 4. Written informed consent from the patient or surrogate
Exclusion criteria
1. AKI, defined as any of the following: * Increase in serum creatinine ≥0.3 mg/dl in 48h * Increase in serum creatinine ≥50% in 7d (if no value available in last 7d, use most recent value in last 3 months) * Urine output ≤0.5 ml/kg/h x 6 consecutive hours (only assessed in patients with hourly monitoring via Foley catheter) * Receipt of renal replacement therapy (RRT) within 7d 2. Advanced chronic kidney disease (eGFR \<15 ml/min/1.73m2 or end-stage kidney disease receiving RRT) 3. Hemoglobin \<8 g/dL (closest value in the prior 3 months) 4. Fever (temperature ≥38⁰C) in the last 48h 5. Suspected or confirmed bacteremia, endocarditis, or pyelonephritis 6. Pneumonia, aspiration, or bilateral pulmonary infiltrates from an infectious etiology reported on chest x-ray or CT scan in the last 7d 7. Positive COVID-19 test within previous 10d 8. Chronic iron overload (including conditions such as hemochromatosis and beta thalassemia major) or previous iron chelation therapy (including prior participation in DEFEAT-AKI) 9. Known hypersensitivity to deferoxamine 10. Taking prochlorperazine 11. Severe hearing loss 12. Pregnant or breastfeeding 13. Prisoner 14. Concurrent participation in another interventional research study in which the intervention has potential interaction with deferoxamine 15. Surgery to be performed under conditions of circulatory arrest 16. Receiving extracorporeal membrane oxygenation 17. Durable ventricular assist device (VAD) prior to surgery (does not include Impella device or intra-aortic balloon pump) 18. Any condition which, in the judgement of the investigator, might increase the risk to the patient 19. Conflict with other research studies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Kidney Injury | 7 days | Composite outcome that includes any of the following: 1. Urine output \<0.5 ml/kg/h for ≥6 consecutive hours within the first 48h or until the Foley catheter is removed, whichever occurs first 2. Increase in serum creatinine ≥0.3 mg/dl within the first 48h 3. Increase in serum creatinine ≥50% within 7 days 4. Receipt of renal replacement therapy within 7 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Tubular Injury | 3 days | Urine KIM-1 standardized to urine creatinine |
| Number of Participants With Major Adverse Kidney Events | 7 days | Defined as an increase in serum creatinine ≥100%, receipt of renal replacement therapy, or death within 7 days |
| Number of Participants With Postoperative Myocardial Injury | 2 days | Defined as postoperative hs-cTnI concentration ≥ the 90th percentile of the cohort on either postoperative day 1 or 2. |
| Number of Participants With Atrial Fibrillation or Atrial Flutter | 7 days | Defined as new onset postoperative atrial fibrillation or atrial flutter (patients with atrial fibrillation or atrial flutter at baseline will be excluded) |
| Number of Participants With Prolonged Mechanical Ventilation | 24 hours | Defined as a requirement for mechanical ventilation \>24h postoperatively |
| Time to Liberation From Vasoactive Medications | 7 days | Number of hours from time of incision to liberation from all IV vasoactive medications |
| Number of Participants With Sepsis | 7 days | Defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction is defined as an acute increase in the total SOFA score ≥2 points consequent to the infection. |
| Ventilator-free Days | 28 days | 28 minus the number of days ventilated. Patients who die within 28 days will be assigned 0 ventilator-free days. |
| ICU-free Days | 28 days | 28 minus the number of days in the ICU. Patients who die within 28 days will be assigned 0 ICU-free days. |
| Hospital-free Days | 28 days | 28 minus the number of days hospitalized. Patients who die within 28 days will be assigned 0 hospital-free days. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid E. Leaf, MD, MMSc
Brigham and Women's Hospital
Participant flow
Pre-assignment details
The discrepancy between the number of patients enrolled (n=320) versus the number randomized, dosed, and included in the final analysis (n=301) was due to some patients being withdrawn from the study after enrollment but prior to randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 70 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 140 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 273 Participants |
| Sex: Female, Male Female | 45 Participants |
| Sex: Female, Male Male | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 151 | 6 / 150 |
| other Total, other adverse events | 0 / 151 | 0 / 150 |
| serious Total, serious adverse events | 23 / 151 | 25 / 150 |
Outcome results
None listed