Kenneth Newell | Emory University | Atlanta, GA

Laurence Turka | Harvard Medical School | Boston, MA

Anil Chandraker | Harvard Medical School | Boston, MA

Beth Israel Deaconess Medical Center | Boston, MA

Brigham and Women's Hospital | Boston, MA

Cleveland Clinc | Cleveland, OH

Emory University | Atlanta, GA

Mt. Sinai Medical Center | New York, NY

Northwestern University | Chicago, IL

University of Alabama | Birmingham, Birmingham, AL

University of California, San Francisco | San Francisco, CA

Background and Introduction

While two decades of advances in immunosuppression have led to vast improvements in short-term graft survival in renal transplantation, long-term outcomes have not significantly improved and concerns over the morbidity of life-long regimens of immunosuppressive drugs remain. Allograft tolerance - long-term allograft acceptance without the requirement for continuous immunosuppression – is therefore a highly desirable therapeutic goal in kidney transplantation.

As an initial step in addressing the issue of tolerance, the Immune Tolerance Network (ITN) and NIAID carried out a registry trial (ITN507ST) aiming to identify a signature from kidney recipients with functional tolerance as defined by stable renal function while remaining off immunosuppression. In a training set which included 19 tolerant patients, increased expression of multiple B-cell differentiation genes was observed when compared to renal transplant recipients with stable function on immunosuppression. Three B-cell differentiation genes were able to distinguish the tolerant from non-tolerant recipients in a separate test set which included 6 tolerant patients with a positive predictive value of 100% and a negative predictive value of 83%. Flow cytometric analyses revealed statistically elevated numbers of naïve and transitional B cells in peripheral blood of tolerant participants as compared to transplant recipients receiving immunosuppression and healthy controls.

The objective of the current study is to  examine a large group of renal transplant recipients in order to prospectively determine the frequency and stability of this tolerance signature in patients still on immunosuppression. Understanding how commonly this signature occurs in a relatively broad population of transplant recipients, and whether it is stable, will give insight into how useful this signature might be for use in future clinical trials. The presence of this tolerance signature may be indicative of underlying allograft tolerance and could be used in the future as a basis for the design of prospective immunosuppression withdrawal trials.

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Study Design

This is a multi-center observational study of adult renal transplant recipients. Each participant will be asked to provide consent for the collection of demographic and clinical information, medical history and blood and urine samples at specified time points. Blood samples will be used to perform specific assays to assess the presence of the tolerance signature. All individuals who sign informed consent will be considered participants. The study will recruit 250 participants who are determined to be eligible and will include 104 weeks of participation.

• Primary Objective: To assess the frequency of a previously defined tolerance signature in a broad population of renal transplant recipients.

• Secondary Objectives:

1) To evaluate whether the tolerance signature changes over time.

2) To investigate other biomarkers in renal transplant recipients.

3) To align the tolerance signature and other biomarkers with selected clinical events.

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This is an observational assay trial, and no treatment will be provided.