Role of Mitochondrial Dysfunction in the Occurrence of Acute Kidney Injury (AKI) in Postoperative Cardiac Surgery
Condition: Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation
MeSH terms: Acute Kidney Injury
Study type: Observational

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%. 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.
    

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).
    

Intervention name(s): Coronary Artery Bypass Graft (CABG)
Intervention type(s): Procedure
Intervention description(s): 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).
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients undergoing coronary artery bypass graft requiring circulation extracorporeal
      
Keywords: Mitochondrial dysfunction; Acute Kidney Injury (AKI); Coronary Artery Bypass Graft (CABG) Surgery; Extracorporeal circulation; Inflammatory response; Type 2 diabete