Metabolic Reprogramming in Renal Tubular Cells in Acute Kidney Injury Following Severe Trauma (METAKIT)

Severe trauma remains the leading cause of death in people under 50, and is associated with high morbidity, including severe disability, with a substantial socio-economic impact. Secondary to trauma, multiple mechanisms (inflammatory, ischemic, oxidative, etc.) setting in rapidly, leads to organ failure, one of the three first cause of death. Vascular damage, with vasoplegia, renal damage, with acute kidney injury (AKI), and pulmonary damage, with acute respiratory distress syndrome (ARDS), are the most frequently observed but all organs can be affected whatever the type of trauma. For these reasons, identifying the pathophysiological pathways involved in organ failure induced by severe trauma is a major step towards limiting the morbidity and mortality induced by trauma, and proposing therapies to prevent them.

Because of the variability of lesions in these patients, and the multiplicity of pathways activated, the mechanisms involved and their causality with organ failure following severe trauma, are still poorly understood. Given their frequency and importance in terms of morbidity and mortality, the investigators decided to take a particular interest in the mechanisms leading to renal and pulmonary injury. The investigators' hypothesis is that the study of urinary and blood markers not performed as part of clinical routine would provide a better understanding of the pathophysiological mechanisms leading to organ failure secondary to severe trauma, and more specifically to renal and pulmonary injuries. With TRAUMATEC study, the investigators will explore mechanisms leading to AKI and ARDS through blood and urine samples of 60 severe trauma patients sampled over the first 48 hours after ICU admission and a reference of 20 healthy volunteers.

Study Overview

• Status: Not yet recruiting
• Conditions: Multi-organ Failure After Severe Trauma

Detailed Description

The investigators plan to include 60 patients over 18 years old with severe trauma, defined with an ISS≥9 and 20 healthy volunteers 18 years old as a reference group.

Blood and urine samples will be collected at ICU arrival, 12-, 24- and 48- hours after ICU admission. Specific dosages will then be realized on blood and urines to study metabolic and hormonal pathway leading to AKI and ARDS.

The primary objective of the study is to explore the association between renal metabolic changes and renal function impairment following severe trauma.

Secondary objectives are (1) to explore mitochondrial changes observed at the renal cellular level, on in vitro renal culture cells after exposure to trauma patient serum (2) to explore the association between plasma metabolic changes and renal and pulmonary function impairment following severe trauma (3) to explore the association between hormonal metabolic changes and renal and pulmonary function impairment following severe trauma (4) to explore the association between red blood cell-induced oxidative stress and renal function impairment following severe trauma (5) to explore the association between changes in the hemoglobin recycling (chelation) system and impaired renal function following severe trauma (6) to explore renal tubular damage secondary to severe trauma (7) to explore the pathophysiological mechanisms associated with pulmonary damage following severe trauma (8) to describe mortality at day 30.

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94250
    • Bicetre Hospital
    • Contact: Laurent Becquemont; Phone Number: 01 47 10 77 87; Email: laurent.becquemont@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

polytrauma patients : a population of severe trauma patients at risk of failure secondary organs.

healthy volonteers

Description

Inclusion Criteria:

Trauma patients :

• Adult patients (age ≥ 18 years)
• Patient admitted for suspected severe trauma (1 Vittel criteria)
• Injury Severity Score ≥ 9
• Health insurance
• Written consent obtained from the patient or trusted support person / family member / close friend, or inclusion in an emergency situation and written consent obtained from the patient (trusted support person / family member / close friend if necessary) as soon as possible (article L1122-1-2 of the CSP).

Healthy volunteers :

• Adult patients (≥ 18 years)
• Affiliated with health insurance
• Written informed consent́
• Patient respecting matching

Exclusion Criteria:

Trauma patients :

• Pregnant patient
• Minor patient
• Adult under guardianship, curatorship or safeguard of justice
• Patient under Aide Médicale d'État
• Chronic renal failure on dialysis
• Chronic respiratory disease
• Patient with chronic cardiac insufficiency
• Systemic inflammatory disease

Healthy volunteers :

• Pregnant patient
• Minor patient
• Adult under guardianship, curatorship or safeguard of justice
• Patient under Aide Médicale d'État
• Patient with chronic renal failure on dialysis
• Chronic respiratory disease
• Patient with chronic cardiac insufficiency
• Systemic inflammatory disease

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
healthy volunteers
polytrauma patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Profile of urinary metabolite concentrations measured by mass spectometry	Metabolomic study of patients urine according to AKI and compared to healthy volunteers measured by mass spectometry	On admission, at 12 hours, 24 hours and 48 hours of hospital admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mitochondrial enzymatic activities of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to serum from healthy volunteers	In vitro mitochondrial function of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to healthy volunteer serum assessed by enzymatic activities by Seahorse XFe96 analyzer	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
mitochondrial membrane potential of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to serum from healthy volunteers	In vitro mitochondrial function of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to healthy volunteer serum assessed by measurement of mitochondrial membrane potential by fluorescence	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
mitochondrial Adenosine TriPhosphate (ATP) content of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to serum from healthy volunteers	In vitro mitochondrial function of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to healthy volunteer serum assessed by measurement of ATP content by spectrofluorimetry	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
expression levels of mitochondrial of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to serum from healthy volunteers	In vitro mitochondrial function of cultured Human Kidney 2 (HK2) kidney cells exposed to patient serum and exposed to healthy volunteer serum assessed by measurement of expression levels of mitochondrial by Western-blot	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
Plasma metabolite concentration profile measured by mass spectrometry	Metabolomic study of patients plasma measured by mass spectrometry according to AKI and ARDS and compared to healthy volunteers	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
advanced glycation end products (AGEs) produced by red blood cells	Measurement of oxidative stress produced by red blood cells assessed by advanced glycation end products (AGEs)	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
reactive oxygen derivatives produced by red blood cells	Measurement of oxidative stress produced by red blood cells assessed by reactive oxygen derivatives	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
erythrocyte NO production produced by red blood cells	Measurement of oxidative stress produced by red blood cells assessed by erythrocyte NO production	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
haptoglobin level	Hemoglobin recycling system assessed by haptoglobin	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
haptoglobin-hemoglobin complexes level	Hemoglobin recycling system assessed by haptoglobin-hemoglobin complexes	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
free hemoglobin level	Hemoglobin recycling system assessed by free hemoglobin	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
monocyte CD163 receptor from peripheral blood mononuclear cell (PBMC) isolation level	Hemoglobin recycling system assessed by monocyte CD163 receptor from peripheral blood mononuclear cell (PBMC) isolation	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
Heme oxygenase-1 (HO-1) enzyme catabolizing heme level	Hemoglobin recycling system assessed by Heme oxygenase-1 (HO-1) enzyme catabolizing heme	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
renin-angiotensin-aldosterone (RASS) profile	Measurement of RASS	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
Antidiuretic hormone (ADH) profile	Measurement of ADH	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
cortisol profile	Measurement of cortisol	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
leptine profile	Measurement of leptine	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
Intensity of renal tubular injury	Renal tubular injury assessed by standard urinary markers: neutrophil gelatinase-associated lipocalin (NGAL), Kidney injury molecule 1 (KIM-1), IGFB-7, tissue inhibitor of metalloproteinases-2 (TIMP-2), cystatin C	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
hypoxemia level	Pulmonary injury during hospitalization in intensive care evaluated by hypoxemia assessed by the PaO2/FiO2 ratio	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
use of mechanical ventilation	Pulmonary injury during hospitalization in intensive care evaluated by use of mechanical ventilation	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
Radiographic Assessment of Lung Edema (RALE) score	Pulmonary injury during hospitalization in intensive care evaluated by Radiographic Assessment of Lung Edema (RALE) score	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
alveolar epithelial lesions	Pulmonary injury during hospitalization in intensive care evaluated by evaluation of alveolar epithelial lesions by circulating soluble Receptor for Advanced Glycation Endproducts (sRAGE) assay.	On admission, at 12 hours, 24 hours and 48 hours of hospital admission
Death	Vital status at day 30	Day 30

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: November 21, 2023
• First Submitted That Met QC Criteria: December 4, 2023
• First Posted (Actual): December 12, 2023

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Acute respiratory distress syndrome; Severe trauma; hemorrhagic shock; Multi-organ failure; Acute kidney Injury
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Shock; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Wounds and Injuries; Acute Kidney Injury; Multiple Organ Failure
• Other Study ID Numbers: APHP231084; 2023-A01597-38 (Other Identifier: IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No