Graft Dysfunction, Kidney Transplantation, Liver Transplantation, Organ Donation
Conditions
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.
Interventions
OTHERNo intervention
No intervention
Sponsors
Centre de recherche du CHUS
Université de Sherbrooke
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kidney delayed graft function | 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
| Measure | Time frame | Description |
|---|---|---|
| Liver early graft dysfunction | 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 |
| Quantification of circulatory cytokines | 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) |
| Identification of inflammatory-related miRNA targets using micro-transcriptome analyses | 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 |
| Validation of inflammatory-related miRNA targets using targeted quantification | 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 |
| Validation of circulatory cytokines | 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) |
Countries
Canada
Contacts
Primary ContactMarie-Hélène Masse, RRT, M.Sc.
Backup ContactDaphnée Lamarche, PhD
Outcome results
None listed