EPI-STORM: Cytokine Storm in Organ Donors (EPI-STORM)

March 28, 2025 updated by: Université de Sherbrooke

EPI-STORM Cytokine Storm in Organ Donors: A Translational Study Linking Donor Epigenetic to Transplantation Success in Recipient

Kidney and liver transplantation are the treatment of choice and are often the last therapeutic option offered to patients with chronic renal and liver failure. More than 70% of kidneys and liver available for transplantation are obtained from donors following neurological death. Unfortunately, compared to living donation, transplant function, graft survival, and recipient survival are consistently inferior with kidneys and liver from neurologically deceased donors. This difference lies with the exacerbated pro-inflammatory state characteristic of deceased donors. Indeed, when neurologic death occurs, the immune system releases substances in the blood that could harm organs and particularly the liver and the kidneys. We believe that achieving a better understanding of the inflammatory processes of organ donors could be greatly informative to design future randomized controlled trial assessing the effect of personalized immunosuppressive therapy on organ donors to ultimately improve the care provided to donors so as to increase the number of organs available for transplantation and enhancing the survival of received grafts

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Severe neurological injuries, such as those observed in neurologically deceased donors, trigger a pro-inflammatory state that activates the immune system, increases vascular permeability, and recruits and activates immune cells in solid organs. The rapid and intense increase in circulating pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) following neurological death, has been referred to as the cytokine storm, one condition that is not seen among living donors. Interestingly, increased expression of TNF-α in the kidney and liver at the time of transplantation has been associated with reduced graft survival and acute rejection. Moreover, numerous studies have suggested that miRNA biomarkers can be targeted as diagnostic or therapeutic molecules in the field of organ transplantation. However, current models of graft injury fail to consider the epigenetic effects of physiological stressors that occurred in neurologically deceased donors. Although several biomarkers have been associated with graft dysfunction, the changes within the donor's inflammatory state, the mechanism underlying these events in donors, and the impacts on recipients are only poorly understood.

The investigators propose a multicenter prospective cohort study with the main objective of assessing the pro-inflammatory status of neurologically deceased donors by examining both miRNAs and circulatory cytokines and investigating its association with graft function in the recipient. Blood specimens will be collected at various time points in neurologically deceased liver and kidney donors in 5 organ recovery centres. The investigators hypothesize that in donors, Peak plasma concentration of pro-inflammatory cytokines and inflammatory-associated miRNAs targets (between consent and recovery) are associated with an increase in kidney delayed graft function and liver early graft dysfunction in the recipients. Considering that there is a therapeutic arsenal for treating donor cytokine storms( e.g., immunosuppressants) and that new targets based on a highly personalized mechanism could be developed we believe that the knowledge acquired in this research program will make it possible to improve the rate of livers and kidneys recovered from potential donors as well as enhance graft function in recipients.

Study Type

Observational

Enrollment (Estimated)

105

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Quebec
      • Montréal, Quebec, Canada, H1T 2M4
        • Recruiting
        • Hôpital Maisonneuve-Rosemont
      • Montréal, Quebec, Canada, H2X 3E4
        • Recruiting
        • Centre hospitalier universitaire de Montréal
      • Quebec city, Quebec, Canada, G1V 4G2
        • Recruiting
        • Centre Hospitalier Universitaire de Québec- Université Laval
      • Sherbrooke, Quebec, Canada, J1H 5N4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Organ donors by neurologic death and liver and kidney recipients

Description

Phase 1 of the study:

Inclusion Criteria:

  • Patient admitted to the intensive care unit with a serious neurologic lesion
  • Glasgow Coma Scale score ≤ 4
  • Absence of sedation for the last 6 hours
  • Age ≥ 18 years old

Exclusion Criteria:

  • S. aureus bacteremia
  • Active neoplasia
  • Receiving immunosuppressive therapy (including steroids) for > 3 months

Specific to potential liver donors:

  • Hepatic insufficiency defined as i) INR > 1.5, ii) hepatic encephalopathy, iii) AST, ALT > 2 times normal value

Specific to potential kidney donors:

  • Polycystic kidney disease
  • Chronic renal failure (i.e., eGFR < 60 ml/min)

Phase 2 of the study:

Inclusion Criteria:

  • Organ donor after neurologic death (DND) declaration as determined by the attending physician
  • Consent to organ donation obtained

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Organ donors
Organ donors after neurologic death (NDD) of 18 years old and older for whom consent to organ donation has been obtained.
Other: No intervention
No intervention
Liver and kidney Recipients
Liver and kidney recipients of 18 years old and older.
Other: No intervention
No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Kidney delayed graft function
Time Frame: 7-days post-transplantation
Requirement for renal replacement therapy within the first 7 days following transplantation or decrease of < 10% of creatinine after 3 days after transplantation, or creatinine > 250 µmol/l at day 5 with evidence of delayed graft function by renal scintigraphy
7-days post-transplantation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Liver early graft dysfunction
Time Frame: 7-days post-transplantation
Presence of one of the following three criteria: (i) peak AST or ALT > 2000 U/L during the first 7 days, (ii) bilirubin ≥ 10 mg/dL on day 7 postoperatively, or (iii) INR ≥ 1.6 on day 7 postoperatively
7-days post-transplantation
Quantification of circulatory cytokines
Time Frame: From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 25 donors).
Quantification of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 (p70), IL-13, IFN-γ, and TNF-α by Luminex (Multiplex human cytokine panel, Millipore)
From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 25 donors).
Identification of inflammatory-related miRNA targets using micro-transcriptome analyses
Time Frame: From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room) ;25 donors).
Sequencing on an Illumina NovaSeq 6000 sequencing platform
From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room) ;25 donors).
Validation of inflammatory-related miRNA targets using targeted quantification
Time Frame: From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).
Quantification by RT-qPCR using TaqMan Advanced miRNA Assays
From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).
Validation of circulatory cytokines
Time Frame: From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).
Quantification of identified cytokines (in the 25 donors cohort) by Luminex (Multiplex, Millipore)
From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Université de Sherbrooke

Collaborators

Centre de recherche du CHUS

Investigators

  • Principal Investigator: Dr Frédérick D'Aragon, MD FRCPC MSc, Universite de Sherbrooke

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 16, 2018

Primary Completion (Actual)

March 24, 2025

Study Completion (Estimated)

December 1, 2025

Study Registration Dates

First Submitted

November 30, 2018

First Submitted That Met QC Criteria

December 19, 2018

First Posted (Actual)

December 26, 2018

Study Record Updates

Last Update Posted (Actual)

April 2, 2025

Last Update Submitted That Met QC Criteria

March 28, 2025

Last Verified

May 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MP-31-2019-2960

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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