EPI-STORM: Cytokine Storm in Organ Donors

Kidney Transplantation Clinical Trial

— EPI-STORM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03786991
• Other study ID #: MP-31-2019-2960
• Status: Recruiting
• Start date: December 16, 2018
• Est. completion date: December 1, 2025

Study information

• Verified date: May 2024
• Source: Université de Sherbrooke
• Contact: Marie-Hélène Masse, RRT, M.Sc.
• Phone: 819-346-1110
• Email: marie-helene.masse3[@]usherbrooke.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 105
• Est. completion date: December 1, 2025
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Cytokine Release Syndrome
• Graft Dysfunction
• Kidney Transplantation
• Liver Transplantation
• Organ Donation

Intervention

Other:
• No intervention
No intervention

Locations

Country	Name	City	State
Canada	Centre Hospitalier Universitaire de Montréal	Montréal	Quebec
Canada	Hôpital Maisonneuve-Rosemont	Montréal	Quebec
Canada	Centre Hospitalier Universitaire de Québec- Université Laval	Quebec city	Quebec
Canada	CIUSSS de l'Estrie-CHUS	Sherbrooke	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Université de Sherbrooke	Centre de recherche du CHUS

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kidney delayed graft function	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	Liver early graft dysfunction	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
Secondary	Quantification of circulatory cytokines	Quantification of IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-12 (p70), IL-13, IFN-?, and TNF-a 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).
Secondary	Identification of inflammatory-related miRNA targets using micro-transcriptome analyses	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).
Secondary	Validation of inflammatory-related miRNA targets using targeted quantification	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).
Secondary	Validation of circulatory cytokines	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).