NCT04125069: MIT-CEC

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

Completed Last updated 24 February 2022

What this trial tests

trial testing Coronary Artery Bypass Graft (CABG) in Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation in 27 participants. Completed in 2 January 2022.

Timeline

2 October 2019

Primary endpoint
12 July 2021

2 January 2022

Quick facts

Lead sponsor	University Hospital Center of Martinique
Status	Completed
Study type	OBSERVATIONAL
Enrollment	27
Start date	2 October 2019
Primary completion	12 July 2021
Estimated completion	2 January 2022
Sites	1 location across France

Drugs / interventions tested

• Coronary Artery Bypass Graft (CABG)

Conditions studied

• Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation — all drugs for Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation →

Sponsor

University Hospital Center of Martinique

Who can join

Adults 18 to 85, any sex, with Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery Requiring Extracorporeal Circulation. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Involvement of Inflammasome Components in Kidney Disease.
   Aranda-Rivera AK, Srivastava A, Cruz-Gregorio A, Pedraza-Chaverri J, et al · · 2022 · cited 24× · PMID 35204131 · DOI 10.3390/antiox11020246