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

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.

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.

Study Overview

• Status: Completed
• Conditions: Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation
• Intervention / Treatment: Procedure: Coronary Artery Bypass Graft (CABG)

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).

• Study Type: Observational
• Enrollment (Actual): 27

Contacts and Locations

Study Locations

• France
  • Fort-de-France, France, 97200
    • CHU de Martinique

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing coronary artery bypass graft requiring circulation extracorporeal

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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,
• 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).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients aged from 18 to 85 years; Cardiac surgery patients aged from 18 to 85 years,programmed for Coronary artery bypass graft requiring ECC.

Procedure: Coronary Artery Bypass Graft (CABG); 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	15 months
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.	15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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%.	15 months
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.	15 months

Collaborators and Investigators

• Sponsor: University Hospital Center of Martinique
• Investigators: Study Director: Rémi NEVIERE, PhD, CHU de Martinique

Publications and helpful links

General 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 2, 2019
• Primary Completion (ACTUAL): July 12, 2021
• Study Completion (ACTUAL): January 2, 2022

Study Registration Dates

• First Submitted: October 9, 2019
• First Submitted That Met QC Criteria: October 10, 2019
• First Posted (ACTUAL): October 14, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 24, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Mitochondrial dysfunction; Inflammatory response; Extracorporeal circulation; Acute Kidney Injury (AKI); Type 2 diabete; Coronary Artery Bypass Graft (CABG) Surgery
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury
• Other Study ID Numbers: 18_RIPH3-24

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