Heart Transplantation, Rejection Heart Transplant
Conditions
Keywords
heart transplantation, donor-derived cell-free DNA, non-invasive biomarker, allograft rejection, risk stratification
Brief summary
The goal of this observational study is to assess the clinical added value of donor-derived cell-free DNA (dd-cfDNA) to monitor cardiac allograft rejection. The main question it aims to answer is whether dd-cfDNA is independently associated with rejection and if it allows a significant improvement in individual risk stratification of rejection on top of a robust predictive model based on standard clinical and biological predictive variables.
Detailed description
Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation. International guidelines recommend performing routine endomyocardial biopsies (EMB) to detect allograft rejection with the goal of identifying rejection at a subclinical state. However, this invasive strategy suffers from major limitations, making an improvement in individual risk stratification of rejection highly needed. Major advances in the field of non-invasive biomarkers of cardiac rejection have been made. Strong associations between donor-derived cell-free DNA (dd-cfDNA) and cardiac rejection have been reported, including in properly designed prospective observational studies with a longitudinal follow-up. However, the independent nature of this association and the improvement in individual risk stratification with dd-cfDNA on top of routine parameters have not yet been demonstrated. The aim of our study is to challenge, in a large observational prospective cohort, the clinical added value of dd-cfDNA with a previously published robust rejection predictive model including the following variables: time post-transplant, pre-transplant sensitizing event, circulating anti-HLA donor-specific antibodies (DSA) with mean fluorescence intensity ≥ 3,000, acute graft dysfunction and prior history of rejection.
Interventions
None listed
Sponsors
Paris Translational Research Center for Organ Transplantation
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* heart transplant recipients, * heart transplantation performed for more than 30 days, * clinical indication of an endomyocardial biopsy, either protocol or for cause, * informed consent
Exclusion criteria
* multiorgan transplantation * refusal to participate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with biopsy proven rejection and / or acute allograft dysfunction | 12 months | * acute cellular rejection ≥ 2R according to the international society for heart and lung transplantation working formulation * antibody-mediated rejection ≥ pAMR1 according to the international society for heart and lung transplantation working formulation * acute allograft dysfunction defined as an unknown left ventricular ejection fraction - LVEF \< 0.50 and/or acute drop in LVEF ≥ 0.15 compared to baseline evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Independent association between donor-derived cell-free DNA and allograft ejection | 12 months | \- test the independent association between dd-cfDNA and rejection after adjustment for important clinical and biological predictive variables or rejection that were included in a previously published predictive model (time post-transplant, pre-transplant sensitizing event, circulating anti-HLA donor-specific antibodies (DSA) with mean fluorescence intensity ≥ 3000, acute graft dysfunction and prior history of rejection). The association between %dd-cfDNA and rejection was tested using a three-level mixed-effect logistic regression with a random intercept (random effects: subject-level nested in the center-level, integration method = adaptive Gauss-Hermite quadrature, number of integration points = seven) to account for the clustering of patients within a center and the clustering of samples from the same subject. |
| Individual risk stratification | 12 months | \- test the improvement of individual risk stratification of rejection with dd-cfDNA on top of the baseline risk model: discrimination (area under the ROC curve), calibration (graphical evaluation), reclassification indices (net reclassification index - NRI, integrated discrimination index - IDI). |
Countries
France
Outcome results
None listed