Clinical trial NCT03786991: EPI-STORM: Cytokine Storm in Organ Donors
Official title: EPI-STORM Cytokine Storm in Organ Donors: A Translational Study Linking Donor Epigenetic to Transplantation Success in Recipient
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Organ Donation
Liver Transplantation
Kidney Transplantation
Graft Dysfunction
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Centre de recherche du CHUS
First posted: 2018-12-26
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Organ donors by neurologic death and liver and kidney recipients

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

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.

Eligibility 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

Primary outcomes:
measure: Kidney delayed graft function
timeFrame: 7-days post-transplantation
Secondary outcomes:
measure: Liver early graft dysfunction
timeFrame: 7-days post-transplantation
measure: Quantification of circulatory cytokines
timeFrame: 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).
measure: Identification of inflammatory-related miRNA targets using micro-transcriptome analyses
timeFrame: 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).
measure: Validation of inflammatory-related miRNA targets using targeted quantification
timeFrame: 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).
measure: Validation of circulatory cytokines
timeFrame: 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).
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: Hôpital Maisonneuve-Rosemont
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire de Montréal
state: Quebec
city: Quebec city
country: Canada
facility: Centre Hospitalier Universitaire de Québec- Université Laval
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie-CHUS
state: Quebec
Study officials:
affiliation: Université de Sherbrooke
name: Dr Frédérick D'Aragon, MD FRCPC MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Clement AA, Lamarche D, Masse MH, Legare C, Tai LH, Fleury Deland L, Battista MC, Bouchard L, D'Aragon F. Time-course full profiling of circulating miRNAs in neurologically deceased organ donors: a proof of concept study to understand the onset of the cytokine storm. Epigenetics. 2022 Nov;17(11):1546-1561. doi: 10.1080/15592294.2022.2076048. Epub 2022 May 21.