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Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal CirculationMIT-CECNCT04125069

Role of Mitochondrial Dysfunction in the Occurrence of Acute Kidney Injury (AKI) in Postoperative Cardiac Surgery

An observational study of Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation, run by University Hospital Center of Martinique at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Cardiac Surgery and Acute Kidney Failure (AKI) post Surgery: AKI is a frequent complication in the immediate aftermath of cardiac surgery with an incidence varying from 5 to 40%. Read more about this study

Who is it for?
Ages 18 to 85 years
What is being tested?
Coronary Artery Bypass Graft (CABG)
Type of treatment
Surgery or procedure
How many people
27 participants
Where
1 siteFrance
Study dates
2 Oct 2019to 2 Jan 2022
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Patients undergoing coronary artery bypass graft requiring circulation extracorporeal

Who may be able to join

  • Be between 18 and 85 years old,
  • Patients undergoing coronary artery bypass graft requiring circulation extracorporeal,
  • Have been informed of the research,
  • Having defended its decision of non-opposition to the research on samples taken during the treatment and on the data medical file,
  • Patients affiliated to a social security scheme.

Who cannot join

  • Pregnant or nursing woman,
  • Diabetic type 1,
  • Emergency cardiac surgery,
  • Valvular replacement surgery,
  • Clinical heart failure or ejection fraction of the ventricle left EFVG <50%,
  • Valvular pathology,
Show all 12Show fewer
  • Left atrial dilation> 40 mm,
  • Systolic pulmonary arterial pressure> 40 mmHg,
  • BNP (Brain natriuretic peptide) level> 100 ng / L,
  • Atrial fibrillation or flutter,
  • Right coronary stenosis> 50%,
  • Chronic renal failure defined by a filtration rate Glomerular GFR (GFR) less than 60 ml / min / 1.73 m2 estimated from creatinine by the equation CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration).

Trial locations and contacts

1 site in 1 country.

France1 site
  • CHU de Martinique

    Fort-de-France, 97200

Other trials in France

About this study

Official title: Role of Mitochondrial Dysfunction in the Occurrence of Acute Kidney Injury(AKI) in Postoperative Cardiac Surgery

Cardiac Surgery and Acute Kidney Failure (AKI) post Surgery:

AKI is a frequent complication in the immediate aftermath of cardiac surgery with an incidence varying from 5 to 40%. KDIGO criteria (Kidney Disease: Improving Global Outcomes) are used to define the AKI in cardiac surgery because of their validated prognostic value in this patient population. The occurrence of a postoperative AKI, even of low severity, is accompanied by a significant increase in the duration of hospitalization and mortality. The AKI risk factors in cardiac surgery are related to the precarious clinical conditions of the patient before the surgery, to the complex surgical context, to the surgical procedures particularly the duration of extracorporeal circulation (ECC) greater than 120 min and the occurrence of a postoperative circulatory insufficiency.

Read more

AKI and inflammatory response:

The mechanisms involved in postoperative AKI in cardiac surgery, are low cardiac output, ischemia reperfusion injury (IRI), mechanical intravascular hemolysis, hypothermia, and activation of the neuroendocrine system by the ECC.

In addition, ECC triggers a secondary inflammatory response to blood contact with the ECC circuit and membranes. The secondary stimulation of immunocompetent cells accompanies secretion of many cytokines and proinflammatory mediators via the activation of nuclear transcription factors as the NFκB factor.

Of the 50 000 ECC performed per year in France, about 25% of the patients develop a Systemic Inflammatory Response Syndrome (SIRS). Although most often transient, SIRS can intensify and lead to a multi-visceral failure and to death, especially if the patient presents medical history of type 2 diabete. Increase of postoperative plasma cytokine levels has a positive predictive value on the occurrence of AKI and the risk of death.

Priming of the NLRP3 inflammasome and post ECC inflammatory response:

In addition to activation by nuclear transcription factors (NFκB), the inflammatory syndrome may develop secondarily to the activation of multi-protein platforms, called inflammasomes.

The activation of the NLRP3 inflammasome has been particularly studied in humans because of its association with multiple chronic inflammatory pathologies, infectious and cardio-metabolic diseases. Its activation is the combination of intracellular receptors like NOD-like receptors (NLR) types, ASC-like adapter proteins and pro caspase-1.

This assembly activates inflammatory caspases (caspase-1, in particular) responsible for the cleavage of pro-interleukins IL-1β and IL-18 in mature pro-inflammatory cytokines that participate in the orchestration of the inflammatory response.

Activation of the NLRP3 inflammasome requires prior priming which allows increase of NLRP3 and pro-cytokines IL1β and IL18 expressions. This priming is particularly intense in the presence of a mitochondrial dysfunction and of an increase in reactive oxygen species (ROS). Next, the activation of the NLRP3 inflammasome may be secondary to the presence of danger signals from cellular damages, such as cellular and mitochondrial debris (including mitochondrial DNA) recognized by NLRP3 receptors. Thus, preoperative mitochondrial dysfunction and its postoperative aggravation by ECC due to IRI induced by ECC represents powerful signals ,of the NLRP3 inflammasome activation.

Research hypothesis:

The hypothesis is that the preoperative priming of the NLRP3 inflammasome by a preoperative mitochondrial dysfunction is a factor favoring the occurrence of postoperative AKI after cardiac surgery with ECC.

For type 2 diabetic patients, the investigators think that preoperative mitochondrial dysfunction (mitochondrial respiration abnormalities and hyperpermeability of mitochondrial membranes) is accentuated worsening IRI induced by the ECC.

This increases postoperative release of cells and mitochondrial debris that maintain the activation of the NLRP3 inflammasome, exacerbating the inflammatory response and favoring the occurrence of AKI.

Read the detailed description

Primary objective of the research:

Describe the association between preoperatives mitochondrial dysfunction markers and the occurrence of AKI in postoperative cardiac surgery with ECC.

Secondary objective of research:

Describe, in preoperative cardiac surgery, the level of mitochondrial dysfunction according to type 2 diabetic status (inflammation-promoting factor).

Being tested
Coronary Artery Bypass Graft (CABG)
Keywords
Mitochondrial dysfunction, Acute Kidney Injury (AKI), Coronary Artery Bypass Graft (CABG) Surgery, Extracorporeal circulation, Inflammatory response, Type 2 diabete
Medical subject headings
Mitochondrial Diseases, Acute Kidney Injury

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Coronary Artery Bypass Graft (CABG)Procedure or surgery

    Mitochondrial function will be studied on cardiac tissue collected intraoperatively at the time of placement of the ECC cannulas by the surgeon. Fragments from auricle dissection of the right atrium of the patient will be requalified as sample residues, and will be used immediately by the surgeon to measure mitochondrial respiration (measurement of oxygen consumption by oxygenation and permeability test of the external mitochondrial membrane by the addition of cytochrome C in the oxygen chamber).

Study groups in NCT04125069
Study groupRoleWhat they receive
Patients aged from 18 to 85 yearsCardiac surgery patients aged from 18 to 85 years,programmed for Coronary artery bypass graft requiring ECC.
Receives: Procedure: Coronary Artery Bypass Graft (CABG)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Describe the correlation between preoperatives mitochondrial dysfunction markers and the occurrence of AKI in postoperative cardiac surgery with ECC.

    Frequency of postoperative onset of an AKI defined according to KDIGO criteria according to preoperative mitochondrial dysfunction (preoperative levels of oxygen consumption by the mitochondria and permeability of the external mitochondrial membrane at Cytochrome CytC in heart tissue.

    KDIGO criteria will be used for diagnosis of AKI, defined as an increase in plasma creatinine ≥0.3 mg/dl (≥26.5 μmol/l) in the 48hours (or an increase of more than 1.5 to 1.9 times the baseline) and urine output <0.5 ml/kg/h in the last 6 to 12 hours.

    Measured: 15 months

  2. Describe the correlation between preoperatives mitochondrial dysfunction markers and the occurrence of AKI in postoperative cardiac surgery with ECC.

    To measure the mitochondrial respiration and to perform the permeability test of the mitochondrial external membrane, a high resolution oxygraph that can detect levels of mitochondrial respiration on few milligrams samples will be used (O2k, Oroboros, Innsbruck, Austria). Oxygen consumption fluxes will be expressed in pmol O2*s-1*mg-1 of dry tissue.

    Measured: 15 months

Secondary outcomes (2)
  1. Describe, in preoperative cardiac surgery, the level of mitochondrial dysfunction according to type 2 diabetic status (inflammation-promoting factor).

    Diabetes will be diagnosed if the fasting blood glucose (8 hours) is equal to or greater than 1.26 g/l (7.0 mmol/l) twice or equal to or greater than 2 g/l at any time of the day.

    A measurement of glycated hemoglobin (HbA1c) will help to know the glycemic balance of two to three months before the patient inclusion. Diabetes will be considered balanced if the HbA1c level is between 6 and 8%.

    Measured: 15 months

  2. Describe, in preoperative cardiac surgery, the level of mitochondrial dysfunction according to type 2 diabetic status (inflammation-promoting factor).

    To measure the mitochondrial respiration and to perform the permeability test of the mitochondrial external membrane, a high resolution oxygraph that can detect levels of mitochondrial respiration on few milligrams samples will be used (O2k, Oroboros, Innsbruck, Austria). Oxygen consumption fluxes will be expressed in pmol O2*s-1*mg-1 of dry tissue.

    Measured: 15 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Oct 2019
  2. Study start2 Oct 2019
  3. Primary completion12 Jul 2021
  4. Study completion2 Jan 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04125069
Sponsor's protocol ID
18_RIPH3-24
Acronym
MIT-CEC
Status last verified
Feb 2022
First submitted
9 Oct 2019
Last updated
24 Feb 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Zakkar M, Ascione R, James AF, Angelini GD, Suleiman MS. Inflammation, oxidative stress and postoperative atrial fibrillation in cardiac surgery. Pharmacol Ther. 2015 Oct;154:13-20. doi: 10.1016/j.pharmthera.2015.06.009. Epub 2015 Jun 24.

    PubMed 26116810
  • Corral-Velez V, Lopez-Delgado JC, Betancur-Zambrano NL, Lopez-Sune N, Rojas-Lora M, Torrado H, Ballus J. The inflammatory response in cardiac surgery: an overview of the pathophysiology and clinical implications. Inflamm Allergy Drug Targets. 2015;13(6):367-70. doi: 10.2174/1871528114666150529120801.

    PubMed 26021321
  • Hoste EAJ, Vandenberghe W. Epidemiology of cardiac surgery-associated acute kidney injury. Best Pract Res Clin Anaesthesiol. 2017 Sep;31(3):299-303. doi: 10.1016/j.bpa.2017.11.001. Epub 2017 Nov 8.

    PubMed 29248137
  • Wang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol. 2017 Nov;13(11):697-711. doi: 10.1038/nrneph.2017.119. Epub 2017 Sep 4.

    PubMed 28869251
  • Patel SS, Palant CE, Mahajan V, Chawla LS. Sequelae of AKI. Best Pract Res Clin Anaesthesiol. 2017 Sep;31(3):415-425. doi: 10.1016/j.bpa.2017.08.004. Epub 2017 Sep 6.

    PubMed 29248147
  • O'Neal JB, Shaw AD, Billings FT 4th. Acute kidney injury following cardiac surgery: current understanding and future directions. Crit Care. 2016 Jul 4;20(1):187. doi: 10.1186/s13054-016-1352-z.

    PubMed 27373799
  • Ortega-Loubon C, Fernandez-Molina M, Carrascal-Hinojal Y, Fulquet-Carreras E. Cardiac surgery-associated acute kidney injury. Ann Card Anaesth. 2016 Oct-Dec;19(4):687-698. doi: 10.4103/0971-9784.191578.

    PubMed 27716701
  • Rheinheimer J, de Souza BM, Cardoso NS, Bauer AC, Crispim D. Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review. Metabolism. 2017 Sep;74:1-9. doi: 10.1016/j.metabol.2017.06.002. Epub 2017 Jun 11.

    PubMed 28764843
  • Prochnicki T, Latz E. Inflammasomes on the Crossroads of Innate Immune Recognition and Metabolic Control. Cell Metab. 2017 Jul 5;26(1):71-93. doi: 10.1016/j.cmet.2017.06.018.

    PubMed 28683296
  • Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev. 2015 Nov;24(Pt A):29-39. doi: 10.1016/j.arr.2015.01.003. Epub 2015 Jan 29.

    PubMed 25641058
  • Traba J, Sack MN. The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome. Cell Mol Life Sci. 2017 May;74(10):1777-1791. doi: 10.1007/s00018-016-2431-7. Epub 2016 Dec 10.

    PubMed 27942750

Questions about this trial

What is this clinical trial studying?

An observational study of Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation, run by University Hospital Center of Martinique at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Describe the correlation between preoperatives mitochondrial dysfunction markers and the occurrence of AKI in postoperative cardiac surgery with ECC. (time frame: 15 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04125069, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2022.

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