Deferoxamine for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury

Study Overview
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Brief Summary
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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.

Official Title
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Deferoxamine for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury

Conditions
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Acute Kidney Injury

Intervention / Treatment
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* Drug: Deferoxamine
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Undergoing coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass AKI risk score ≥6 at the time of screening Written informed consent from the patient or surrogate Exclusion Criteria: 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 Advanced chronic kidney disease (eGFR <15 ml/min/1.73m2 or end-stage kidney disease receiving RRT) Hemoglobin <8 g/dL (closest value in the prior 3 months) Fever (temperature ≥38⁰C) in the last 48h Suspected or confirmed bacteremia, endocarditis, or pyelonephritis Pneumonia, aspiration, or bilateral pulmonary infiltrates from an infectious etiology reported on chest x-ray or CT scan in the last 7d Positive COVID-19 test within previous 10d Chronic iron overload (including conditions such as hemochromatosis and beta thalassemia major) or previous iron chelation therapy (including prior participation in DEFEAT-AKI) Known hypersensitivity to deferoxamine Taking prochlorperazine Severe hearing loss Pregnant or breastfeeding Prisoner Concurrent participation in another interventional research study in which the intervention has potential interaction with deferoxamine Surgery to be performed under conditions of circulatory arrest Receiving extracorporeal membrane oxygenation Durable ventricular assist device (VAD) prior to surgery (does not include Impella device or intra-aortic balloon pump) Any condition which, in the judgement of the investigator, might increase the risk to the patient Conflict with other research studies

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferoxamine<br>Deferoxamine 30mg/kg (max dose, 6g) intravenous infusion (diluted in 240mL normal saline) administered over 12 hours | Drug: Deferoxamine<br>* Deferoxamine 30mg/kg (max dose, 6g) intravenous infusion (diluted in 240mL normal saline) administered over 12 hours<br>|
| Placebo Comparator: Placebo<br>Normal saline (240mL) intravenous infusion over 12 hours | Drug: Normal saline<br>* Normal saline (240mL) intravenous infusion over 12 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Kidney Injury | Composite outcome that includes any of the following: 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 Increase in serum creatinine ≥0.3 mg/dl within the first 48h Increase in serum creatinine ≥50% within 7 days Receipt of renal replacement therapy within 7 days | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal tubular injury | Urine levels of NGAL and KIM-1 | 3 days | 
| Major Adverse Kidney Events | Increase in serum creatinine ≥100%, receipt of renal replacement therapy, or death within 7 days | 7 days | 
| Postoperative myocardial injury | Peak postoperative troponin I elevation >10 times the 99th percentile upper reference limit | 2 days | 
| Atrial fibrillation or atrial flutter | New onset postoperative atrial fibrillation or atrial flutter (patients with atrial fibrillation or atrial flutter at baseline will be excluded) | 7 days | 
| Prolonged mechanical ventilation | Requirement for mechanical ventilation >24h postoperatively | 24 hours | 
| Vasoactive-Inotropic Score | Validated method for integrating all IV vasoactive medications and their doses on an hourly basis into a single measure | 24 hours | 
| Time to liberation from vasoactive medications | Number of hours from time of incision to liberation from all IV vasoactive medications | 7 days | 
| Sepsis | 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. | 7 days | 
| Ventilator-free days | 28 minus the number of days ventilated. Patients who die within 28 days will be assigned 0 ventilator-free days. | 28 days | 
| ICU-free days | 28 minus the number of days in the ICU. Patients who die within 28 days will be assigned 0 ICU-free days. | 28 days | 
| Hospital-free days | 28 minus the number of days hospitalized. Patients who die within 28 days will be assigned 0 hospital-free days. | 28 days |