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

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ClinicalTrials.gov Identifier: NCT03786991
Recruitment Status : Recruiting
First Posted : December 26, 2018
Last Update Posted : April 19, 2023
Sponsor:
Collaborator:
Centre de recherche du CHUS
Information provided by (Responsible Party):
Université de Sherbrooke

Brief Summary:
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

Condition or disease Intervention/treatment
Organ Donation Liver Transplantation Kidney Transplantation Graft Dysfunction Other: No intervention

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.

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Study Type : Observational
Estimated Enrollment : 105 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: EPI-STORM Cytokine Storm in Organ Donors: A Translational Study Linking Donor Epigenetic to Transplantation Success in Recipient
Actual Study Start Date : December 16, 2018
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : December 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Organ Donation

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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)

  3. 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

  4. 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

  5. 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)


Biospecimen Retention:   Samples With DNA
Blood samples (including miRNA and buffy coat) will be drawn at 5 specific time points: following ICU admission when patient has a serious neurological lesion, as soon as possible after consent to organ donation, as well as 4 to 8 hours and 24 hours after the first sample of phase 2 has been drawn. A final draw will be made prior to transfer from the ICU to operating room for organ recovery. A substudy will be conducted in some centers and we will collect samples at time of aortic cross clamp during surgery


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Organ donors by neurologic death and liver and kidney recipients
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03786991


Contacts
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Contact: Marie-Hélène Masse, RRT, M.Sc. 819-346-1110 ext 14173 marie-helene.masse3@usherbrooke.ca
Contact: Daphnée Lamarche, PhD 819-821-8000 ext 70106 daphnee.lamarche@usherbrooke.ca

Locations
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Canada, Quebec
Hôpital Maisonneuve-Rosemont Recruiting
Montréal, Quebec, Canada, H1T 2M4
Centre Hospitalier Universitaire de Montréal Recruiting
Montréal, Quebec, Canada, H2X 3E4
Centre Hospitalier Universitaire de Québec- Université Laval Recruiting
Quebec city, Quebec, Canada, G1V 4G2
CIUSSS de l'Estrie-CHUS Recruiting
Sherbrooke, Quebec, Canada, J1H 5N4
Contact: Marie-Hélène Masse, RRT, MSc    819-346-1110 ext 14173    marie-helene.masse3@usherbrooke.ca   
Contact: Daphnée Lamarche, PhD    819-821-8000 ext 70106    daphnee.lamarche@usherbrooke.ca   
Sponsors and Collaborators
Université de Sherbrooke
Centre de recherche du CHUS
Investigators
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Principal Investigator: Dr Frédérick D'Aragon, MD FRCPC MSc Université de Sherbrooke
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Université de Sherbrooke
ClinicalTrials.gov Identifier: NCT03786991    
Other Study ID Numbers: MP-31-2019-2960
First Posted: December 26, 2018    Key Record Dates
Last Update Posted: April 19, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cytokine Release Syndrome
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock