Reducing Cardiac-surgery Associated Acute Kidney Injury Occurence by Administering Angiotensin II

Last updated: September 23, 2024
Sponsor: Universität Münster
Overall Status: Active - Not Recruiting

Phase

3

Condition

Cardiac Surgery

Renal Failure

Kidney Disease

Treatment

Angiotensin II

Noradrenalin

Clinical Study ID

NCT06615102
UniMS23_0019
542931418
  • Ages > 18
  • All Genders

Study Summary

The study intervention focuses on exploring the use of angiotensin II as a primary vasopressor compared to norepinephrine in cardiac surgery patients to investigate whether angiotensin II can reduce the occurrence of moderate/severe acute kidney injury (AKI). Despite its potential, as suggested by trials involving surgical patients, there is currently no human data confirming its effectiveness in preventing moderate/severe AKI in this context. The intervention aims to address this gap by evaluating angiotensin II's impact compared to norepinephrine.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Cardiac surgery using cardiopulmonary bypass including coronary artery bypassgrafting (CABG) surgery, valve surgery, or combined CABG/valve surgery

  2. Elevated risk of AKI as predicted by a score ≥ 1.5 on the following scale:

  3. hemoglobin < 130g/l = 2

  4. creatinine > 1.1 mg/dl = 2

  5. age > 70 years =1.5

  6. New York Heart Association Classification (NYHA) 4 =1.5

  7. Body Mass Index (BMI) > 30 =1.5

  8. Adult ≥ 18 years

  9. Written informed consent

Exclusion

Exclusion Criteria:

  1. Major aortic surgery (aortic arch replacement), transplant surgery, pulmonarythrombendarterectomy, ventricular assist device placement

  2. Already receiving inotropic/vasopressor support before surgery

  3. Dialysis dependent

  4. Pre-existing AKI within the last 30 days

  5. Pre-existing chronic kidney injury with an eGFR<20 ml/min/1.73m2

  6. Pre-existing significant hypertension (persistent SBP > 180mmHg)

  7. Significant pulmonary hypertension (ePSAP > 70mmHg, mPAP > 40mmHg) with rightventricular systolic dysfunction (graded more severe than mild)

  8. Hypersensitivity to the active substance or to any of the excipients

  9. Pregnancy (a negative pregnancy test for women of childbearing age) or breastfeedingwomen

  10. Persons with any kind of dependency on the investigator or employed by thesponsor/investigator

  11. Participation in another interventional trial within the last three months thatinvestigates kidney function

Study Design

Total Participants: 1022
Treatment Group(s): 2
Primary Treatment: Angiotensin II
Phase: 3
Study Start date:
January 01, 2025
Estimated Completion Date:
April 30, 2027

Study Description

Acute kidney injury (AKI) is defined by changes in serum creatinine and/or urine output, according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In cardiac surgical patients, the AKI rate is up to 30%, with 1-2% of the patients requiring renal replacement therapy (RRT). Cardiac-surgery associated AKI (CSA-AKI) is associated with increased short- and long-term morbidity and mortality as well as increased hospital costs.

Shock after cardiac surgery is also associated with increased mortality. In the context of cardiac surgery with the use of the cardiopulmonary bypass (CPB), sympathetic nervous system activation and cardiovascular instability are common sequelae. Vasoplegic syndrome is a form of distributive shock that is characterized by low arterial pressure, reduced systemic vascular resistance, and normal or elevated cardiac output. It occurs in 5 to 25% of the patients undergoing cardiac surgery. Patients with vasoplegic shock are at higher risk of organ failure, including AKI, and show increased mortality rates and longer hospital length of stays. Currently, norepinephrine is the established first-line vasopressor for the treatment of vasoplegic shock, but all vasopressors have adverse effects, including myocardial ischemia and arrhythmias. Moreover, in vasoplegic situations, vascular smooth muscle cells may become unresponsive to vasopressors. The underlying mechanisms are complex and include adrenoceptor desensitization, increased nitric oxide (NO) synthesis, activation of adenosine triphosphate-sensitive K+ channels, and vasopressin and corticosteroid deficiency.

Physiologically, the renin-angiotensin-aldosterone system (RAAS) is a hormone system that plays a central role in regulating blood pressure and fluid balance, glomerular filtration rate, and electrolyte levels. Renin, a proteolytic enzyme released by juxtaglomerular cells in response to hypotension, decreases sodium delivery to the distal tubule, activates the sympathetic nervous system, and cleaves angiotensinogen to angiotensin I which is a precursor of the vasoactive angiotensin II. RAAS is regulated by a biofeedback loop. Angiotensin II generation inhibits renin release, whereas renin levels increase when there is insufficient activation of the angiotensin II type 1 receptor. Administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) and reduced angiotensin II generation cause a corresponding increase in renin levels.

Despite numerous clinical trials using several interventions, a reliable means to prevent AKI remains elusive. Clinical trials focusing on surgical patients suggest that angiotensin II is a potent vasopressor. However, no human data exist whether the application of angiotensin II as a primary vasopressor reduces the occurrence of AKI in patients undergoing cardiac surgery.