Study for Detection of Donor-derived Cell-free DNA After Renal Transplantation Using Devysers NGS-based Chimerism Assay.

The aim of this study is to evaluate highly sensitive quantitative tests for early molecular detection of graft rejection and associated immune response from liquid biopsies in the blood from patients undergoing renal transplantation and secondly, to evaluate the evolution of de-novo HLA antibodies following renal transplantation. Furthermore, we are interested in the correlation of tissue damage caused by rejection, as measured by the presence of dd-cfDNA, and the presence of de-novo HLA antibodies.

Study Overview

• Status: Not yet recruiting
• Conditions: Cell-Free Nucleic Acids
• Intervention / Treatment: Diagnostic test: Cell free DNA analysis

Detailed Description

Each year 40-60 patients undergo renal transplant with a living donor (LD) at Karolinska University Hospital. Prior to transplantation, these patients and their donors are investigated for their immunological compatibility. This includes cytotoxic- and flow cytometric crossmatches, HLA typing as well as determination of possible presence of panel-reactive HLA antibodies (PRA). Normally these investigations are performed 2-3 months prior to renal transplantation. Once a patient has been accepted for transplantation with a given living donor, they will, prior to transplantation be asked whether they are interested in taking part of the present study. If the patient and the donor do accept, we will collect 15 mL of blood prior to transplantation using suitable sample collection tubes (Cell-Free BCT tubes). This sample will be used for screening patient and donor for specific genetic markers. Furthermore, the pretransplant samples will be used for determining the presence or absence of HLA antibodies for each patient. We aim to include up to 50 patients in the current study.

During the first 24-48 hrs after transplantation, two more samples (10 mL) from the patient will be collected to measure the potential presence of dd-cfDNA including cell-free particles such as exosomes. The cell-free DNA and RNA from all samples will be extracted, stored frozen and later sequenced. Following transplantation and initiation of the immunosuppressive therapy, samples for analysis will be obtained once every week for up to 3 months. All collected samples will be either analysed immediately or frozen for future analysis. Stored frozen samples could, at a later time point, be thawed, batched and analysed using molecular techniques including sequencing for measuring dd-cfDNA or analysis of the presence of HLA-antibodies using commercial bead-technologies (Luminex or Immucor). Results from these assays will be added to a dedicated database. The obtained laboratory results will be compared to clinical outcome including graft survival, patient survival, clinical and subclinical rejections etc. as well as other laboratory data (e.g. results from pathological examination of the graft, clinical chemistry, concentration of immunosuppressive drugs etc).

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Eytan Mor, MD; Phone Number: 052-2297779; Email: eytan.mor@sheba.health.gov.il
• Study Contact Backup: Name: Maya Mor-Cohen; Phone Number: 052-5361988; Email: Maya.MorCohen@sheba.health.gov.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing live donor or deceased donor transplantation

Description

Inclusion Criteria:

Patients older than 20 undergoing kidney transplantation -

Exclusion Criteria:

Patients included in other studies Patients a combined transplant with other donor Patients not eligible to sign an inform consent Patients with primary non-function or those that lost their graft during the first 3 months

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Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Degree of chimerism	The fraction of cell free donor DNA will be measured after transplant	According to the study protocol before and after transplantation in defined intervals up to 3 moths

Collaborators and Investigators

• Sponsor: Sheba Medical Center
• Collaborators: Dan Hauzenberger M.D., Ph.D. Assoc. Professor, Karolinska University Hospital Sweden

Publications and helpful links

General Publications

• Bloom RD, Bromberg JS, Poggio ED, Bunnapradist S, Langone AJ, Sood P, Matas AJ, Mehta S, Mannon RB, Sharfuddin A, Fischbach B, Narayanan M, Jordan SC, Cohen D, Weir MR, Hiller D, Prasad P, Woodward RN, Grskovic M, Sninsky JJ, Yee JP, Brennan DC; Circulating Donor-Derived Cell-Free DNA in Blood for Diagnosing Active Rejection in Kidney Transplant Recipients (DART) Study Investigators. Cell-Free DNA and Active Rejection in Kidney Allografts. J Am Soc Nephrol. 2017 Jul;28(7):2221-2232. doi: 10.1681/ASN.2016091034. Epub 2017 Mar 9.
• Everly MJ, Terasaki PI. Monitoring and treating posttransplant human leukocyte antigen antibodies. Hum Immunol. 2009 Aug;70(8):655-9. doi: 10.1016/j.humimm.2009.04.019. Epub 2009 Apr 15.
• Lee PC, Zhu L, Terasaki PI, Everly MJ. HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation. 2009 Aug 27;88(4):568-74. doi: 10.1097/TP.0b013e3181b11b72.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): April 1, 2022
• Primary Completion (ANTICIPATED): March 31, 2024
• Study Completion (ANTICIPATED): March 31, 2024

Study Registration Dates

• First Submitted: January 27, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (ACTUAL): February 7, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 7, 2022
• Last Update Submitted That Met QC Criteria: January 27, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 9024-21-SMC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The study is in collaboration with the transplant center in Sweden. Each study patients will be given a code and the coded information will be shared with our partners
• IPD Sharing Time Frame: The data will be available for 3 yeras from the completion of the recuitment of all patients
• IPD Sharing Access Criteria: Shared mail with an access code
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No