Reducing Acute Kidney Injury Occurence by Administering Angiotensin II (AIDED)

Biomarker-guided Implementation of Angiotensin-II (AT-II) to Reduce the Occurrence of Kidney Damage After Cardiac Surgery

The aim of this study is to evaluate whether adding angiotensin II to the standard of care is superior compared to the standard of care alone with respect to kidney damage (personalized approach) after cardiac surgery.

Study Overview

• Status: Completed
• Conditions: Cardiac Surgery; Vasoplegia; Hyperreninemia
• Intervention / Treatment: Drug: Angiotensin II; Drug: Control

Detailed Description

Vasoplegic syndrome is a form of distributive shock that is characterized by low arterial pressure with reduced systemic vascular resistance and normal or elevated cardiac output that occurs in 5 to 25% of patients undergoing cardiac surgery. Patients with vasoplegic shock after cardiac surgery are at higher risk of organ failure, including acute kidney injury (AKI). Postsurgical AKI is associated with several adverse outcomes. Attempts to prevent AKI have largely been futile so far. Prior studies often started with the interventions after an AKI event, when a decline of kidney function (i.e. glomerular filtration rate) was already established. Application of norepinephrine is currently considered as the first-line therapy for vasoplegic shock, but all catecholamines have adverse effects, including myocardial ischemia and arrhythmias. In a recent observational trial, we demonstrated that there is a dysregulation in the renin-angiotensin-aldosterone system (RAAS) likely caused by a reduced angiotensin-converting enzyme (ACE) activity after cardiac surgery. Elevated renin levels identified patients at risk for AKI and were associated with cardiovascular instability and increased AKI rate after cardiac surgery. Furthermore, elevated renin levels could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention with angiotensin II that could improve their outcomes. Therefore, the application of angiotensin II to treat a postoperative hypotension would mean a hormone substitution.Shock after cardiac surgery is associated with increased mortality. Cardiopulmonary bypass (CPB) represents a common clinical setting of sympathetic nervous system activation and cardiovascular instability. Vasoplegia is a form of distributive shock that is characterized by low arterial pressure with reduced systemic vascular resistance and normal or elevated cardiac output. It occurs in 5 to 25% of patients undergoing cardiac surgery. Patients with vasoplegia after cardiac surgery are at higher risk of organ failure, including AKI, and have an increased mortality rate and longer hospital length of stay.

Clinical trials focusing on septic patients suggest that AT-II is a potent vasopressor. However, no human data exist whether the application of AT-II in cardiac surgery patients with y hyperreninemia high-risk patients identified by renin levels (individualized approach) reduces kidney damage and improves kidney function after cardiac surgery.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alexander Zarbock, MD; Phone Number: +49-251-8347252; Email: aki@anit.uni-muenster.de
• Study Contact Backup: Name: Melanie Meersch, MD; Phone Number: +49-251-8347255; Email: aki@anit.uni-muenster.de

Study Locations

• Germany
  • Münster, Germany, 48149
    • University Hospital Muenster

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients undergoing cardiac surgery with CPB
• Cardiac index 2.1l/min per square meter
• Written informed consent
• D-renin (difference between post- and preoperative) ≥ 3.7 micro Unit/ml 4 h after CPB
• Postoperative hypotension requiring vasopressors

Exclusion Criteria:

• Preexisting AKI (stage 1 and higher)
• Patients with cardiac assist devices
• Pregnant women, nursing women and women of childbearing potential
• Known (Glomerulo-) Nephritis, interstitial nephritis or vasculitis
• chronic kidney disease with estimated glomerular filtration rate (eGFR) < 30 ml/min
• Dialysis dependent chronic kidney disease
• Prior kidney transplant within the last to 12 months
• Emergency surgery in the context of an acute coronary syndrome
• Hypersensitivity to the active substance, or to any of the excipients of the study medication
• Bronchospasm
• Liver failure
• Mesenteric ischemia
• Participation in another intervention trial in the past 3 months
• Persons with any kind of dependency on the investigator or employed by the institution responsible or investigator
• Persons held in an institution by legal or official order

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Angiotensin II; Intravenous infusion of max. 80 ng/kg/min Angiotensin II (titrated for each individual patient by effect) over 12 h after start of infusion	Drug: Angiotensin II; Patients with Delta-renin >= 3.7 micro-unit/mL are at high risk for AKI. Patients who have a high delta-renin and a postoperative hypotension requiring vasopressors ad will be randomized. After randomization patients will receive intravenous infusion with the investigational drug.
Placebo Comparator: Control; Intravenous infusion placebo (matched infusion volume) over 12 h after start of infusion	Drug: Control; Patients with Delta-renin >= 3.7 micro-unit/mL are at high risk for AKI. Patients who have a high delta-renin and a postoperative hypotension requiring vasopressors ad will be randomized. After randomization patients will receive intravenous infusion with placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
• kidney damage after cardiac surgery identified by the difference between [TIMP-2]*[IGFBP7] levels 12h after randomization and [TIMP-2]*[IGFBP7] levels at randomization	The presence of tissue inhibitor of metalloproteinases (TIMP-2) and insulin-like growth-factor binding protein 7 (IGFBP7) in the urine will be measured.	12 hours after start of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of Acute Kidney Injury (AKI) according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria		72 hours after cardiac surgery
Severity of Acute Kidney Injury	Number of patients with KDIGO stage 1, KDIGO stage 2 or KDIGO stage 3)	72 hours after cardiac surgery
Amount of volume application		12 hours after start of intervention
Fluid status		12 hours after start of intervention
Dose of vasopressor use during intervention		During intervention, an average of 12 hours
Creatinine clearance on day one after cardiac surgery		One day after cardiac surgery
Free-days through day 28 of vasoactive medications and mechanical ventilation		28 days after cardiac surgery
Renal Recovery	Renal recovery is defined as serum creatinine levels < 0.5 mg/dL higher than baseline serum creatinine	90 days after cardiac surgery
Mortality		30 days after cardiac surgery
Mortality		60 days after cardiac surgery
Mortality		90 days after cardiac surgery
Length of ICU (Intensive Care Unit) stay		up to 90 days after cardiac surgery (until discharge)
Length of hospital stay		up to 90 days after cardiac surgery (until discharge)
Use and duration of renal replacement therapy	Number of patients with renal replacement therapy	up to 90 days after cardiac surgery
Major adverse kidney events (MAKE)	Major adverse kidney events consisting of mortality, dialysis dependency, persistent renal dysfunction (defined as serum creatinine ≥ 2x compared to baseline value)	90 days after cardiac surgery
Effect of Angiotensin converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARBs) use on the effect of angiotensin II		12 hours after intervention
Correlation between the severity of hyperreninemia and the effect of angiotensin II		12 hours after intervention

Collaborators and Investigators

• Sponsor: Westfälische Wilhelms-Universität Münster
• Collaborators: German Research Foundation
• Investigators: Study Chair: Alexander Zarbock, MD, University Hospital Muenster, Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2021
• Primary Completion (Actual): December 19, 2022
• Study Completion (Actual): March 19, 2023

Study Registration Dates

• First Submitted: December 2, 2021
• First Submitted That Met QC Criteria: January 5, 2022
• First Posted (Actual): January 20, 2022

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Biomarker; Cardiac Surgery; Acute kidney injury; Renin; Angiotensin II
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Kidney Diseases; Urologic Diseases; Postoperative Complications; Renal Insufficiency; Acute Kidney Injury; Vasoplegia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Vasoconstrictor Agents; Angiotensin II; Giapreza; Angiotensinogen
• Other Study ID Numbers: WWU20_0016; 2021-003088-87 (EudraCT Number); 06-AnIt-20 (Other Identifier: Dept. of Anesthesiology, Intensive Care and Pain Medicine)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No