Renal Transplantation
Conditions
Keywords
renal transplantation rejection, non-invasive biomarker (dd-cfDNA ), risk evaluation, randomized trial, Gene expression
Brief summary
The investigator hypothesizes that the combined use of (1) Donor-derived cell-free DNA (dd-cfDNA) in peripheral blood predicting anti-donor immunological activation or quiescence (2) interactive and actionable data analytics delivered at the bedside will promote safe clinical follow-up of kidney transplant patients with less need for invasive biopsy and less induced risk surveillance by allograft protocol biopsies to assess allograft rejection in clinically stable kidney transplant patients. In addition, the evaluation of the transcriptional changes in tissue samples in selected patients using automated processing of digital slide images and intragraft gene expression profiles will provide a better diagnosis of the rejection mechanisms to provide the best therapeutic approach as compared to current clinical practice. We therefore propose a French, multicenter, prospective randomized trial comparing two strategies of follow-up: in the first group, a biopsy is performed at M3, M12 and for clinical indication whenever considered necessary by the clinician during the first 18 months of follow-up after transplant. In the second group, patients will have the same follow-up as in the first group, but reports providing dd-cfDNA results and relevant medical parameters will be provided to the physician to help him in the decision to perform a biopsy or not.
Detailed description
The main objective of the study is to assess whether the use of donor-derived cell-free DNA (dd-cfDNA) as an immunological biomarker combined with clinical data to decrease the number of allograft biopsies during the first 18 months after transplantation. 500 new transplanted patients in 6 French clinical transplant sites will be included in the prospective multicenter AI-CARE trial. Recruitment of patients will start on the day of transplantation (or 8 days before for transplantations with living donor) and data/samples collected at 3 months and 12 months after transplantation and during visits for clinical indication within the first 18 months of follow-up. Realization of all the acts for the research are representing the usual medical practice (Standard Of Care: SOC) except one additional blood sample for dd-cfDNA analyses that will be collected and analyzed specifically for the research. The paraffin-embedded core dedicated to SOC histology will be used for gene expression profiling and digital pathology imaging after SOC procedures. Using the newest information derived from dd-cfDNA analyses combined with clinical data, dd-cfDNA will allow us to identify kidney transplant patients at low- and high-risk of rejection. using non-invasive dd-cfDNA levels combined with clinical data, preventing unnecessary allograft biopsies which are invasive, with and present a potential risk of complications for the patients and costly burden to the healthcare
Interventions
BIOLOGICALdd-cfDNA-guided
In groups I and II, the blood sample for dd-cfDNA assay will be taken on D0, just prior to transplantation, for all patients. in addition, for patients following a dd-cf DNA-guided strategy based on dd-cf DNA ; samples for dd-cf DNA assay will be taken at M3 and M12 visits and at visits for clinical indication (5 maximum) and the blood will be sent to the PARCC technical platform of INSERM UMR 970. By combining the dd-cfDNA level and relevant medical data, an integration report will be sent to the centers to stratify patients into high-risk or low-risk rejection profiles. If the patient is classified in the low risk of rejection subgroup, he may decide not to perform the biopsy. If the patient is classified in the high risk of rejection subgroup, he may decide to perform the biopsy within 15 days of the sample being taken. the decision to perform the biopsy is left to the discretion of the physician.
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
This is a 18-months follow-up national, multicenter, prospective , randomized, biomarker strategy design trial, whereby kidney transplant patients will be randomized 1:1 at the time of transplantation in 2 study groups. * Group I (routine group): during the first 18 months after transplantation, patients will follow a standard clinical follow-up based on kidney allograft function (serum creatinine, estimated glomerular filtration rate (eGFR), proteinuria). Allograft biopsies will be performed according the clinical practice of the center and the medical decision during the visits at M3, M12 or for clinical indication (CI). * Group II (dd-cfDNA-guided): As in the routine group at M3, M12 and at CI visits, patients will have clinical follow-up based on the investigators' routines. In addition, physicians will receive a report containing dd-cfDNA results and relevant medical parameters to help them decide whether or not to perform a biopsy.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All men and women, age ≥18 years old. * Subject must be a recipient of a non-combined renal transplant from a deceased or living donor. It can be a re transplantation after a graft loss of function or graft rejection * Subject is willing and able to provide signed written informed consent and willing to comply with study procedures * Women of Childbearing Potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.
Exclusion criteria
* Subjects who are legally detained in an official institution or under legal protection * Any condition that, in the opinion of the investigator, might interfere with the patient 's participation in the study, poses an added risk for the patient, or confounds the assessment of the patient * History of multi-organ transplant (interference with rejection natural history).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| compare levels of eGFR measured by CKD-EPI equation in both arms | 18 months | Comparison of the levels of eGFR (mL/min/1.73m2) in both arms estimated by glomerular filtration rate (CKD-EPI eGFR) at 18 months' post-transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| modification of the immunosuppression treatment | 18 months | To assess the rate of modification of the immunosuppression treatment in both groups |
| graft survival rates | 18 months | To assess predicted graft survival rates in both groups using the iBox |
| biopsy-proven rejections | 18 months | compare the rate of biopsy-proven rejections in both groups |
| incidence of death | 18 months | compare the incidence of death and allograft loss in both groups |
| probability of kidney allograft rejection measured by gene expression in the biopsy tissue | 18 months | determine the probability of different types of rejection (ABMR, TCMR, IFTA and Banff lesions) in kidney transplant recipients' biopsies using gene expression (variance explanation modelling); |
| compare health care expenses between both groups | 18 months | compare the cost/benefit of implementing dd-cfDNA monitoring compared to follow-up with the biopsy using the French health insurance database, evaluated at 18 months after transplantation. |
| compare EQ-5D-5L questionnaire answers between both group | 18 months | compare the evolution of patient's well-being during the first 18 months after kidney transplantation using the EQ-5D-5L descriptive system and visual analog scale (VAS). |
| compare the PREMs questionnaire answer in dd-cfDNA-guided group | 18 months | Level of patient's understanding of their care with non-invasive monitoring and level of satisfaction with it (categorical scale answers from 0 up to 5) |
| compare the Generalised Anxiety Disorder Assessment (GAD-7 ) questionnaire answer between both group | 18 months | compare the evolution of patient's well-being during the first 18 months after kidney |
| compare the visual analyse scale ( VAS ) questionnaire answer between both group | 18 months | compare the evolution of patient's well-being during the first 18 months after kidney |
| quantity of lesion patterns between both groups | 18 months | identify and compare lesion patterns imaging that are associated with response to rejection therapy using Digital Pathology (immunosuppression dose and response). |
Other
| Measure | Time frame | Description |
|---|---|---|
| rate of biopsies | 18 months | Comparison of The mean eGFR in both Groups estimated by glomerular filtration rate (CKD-EPI eGFR) at 12 months' post-transplantation and of the number of allograft rejection. |
Countries
France
Contacts
Primary ContactLefaucheur, Carmen, PR
Backup ContactRacape Maud, PHD
Outcome results
None listed