VIRTUUS Children's Study
- Conditions
- NephropathyPediatric Kidney DiseaseBK Virus (Nephropathy)Acute Cellular Graft RejectionAntibody-mediated RejectionEnd Stage Renal DiseaseRenal Transplant Rejection
- Registration Number
- NCT03719339
- Lead Sponsor
- Children's Hospital of Philadelphia
- Brief Summary
The objective of the VIRTUUS Children's Study is to adapt identified and validated adult noninvasive diagnostic and prognostic biomarkers for the characterization of allograft status in pediatric recipients of kidney allografts.
- Detailed Description
Advances in immunosuppressive regimens have significantly improved short-term allograft survival for kidney transplant recipients. Yet, long-term allograft survival remains static. For children with end-stage renal disease (ESRD), improvements in long-term outcomes are greatly needed. Children with ESRD require multiple transplants over a lifetime, incurring repeated surgical and immunological risks with each newly transplanted organ. Allograft injury occurs primarily due to acute cellular rejection (ACR) and/or antibody mediated rejection (AMR) and viral infections, such as BK virus associated nephropathy (BKVN). A major hindrance to promoting long-term allograft survival is the lack of non-invasive diagnostic and prognostic biomarkers to reliably detect early injury in the allograft before clinical manifestations arise.
The incidence of acute rejection (AR) in children in the first year post-transplant is 10-13%\[1\]. The current gold standard for diagnosing AR is core needle biopsy; however, biopsy is highly invasive, incurs risk of bleeding and graft loss, is subject to sampling error and lacks sensitivity and specificity for early injury. Since immune responses are dynamic over time, single biopsies do not adequately capture anti-allograft immunity, but repeat biopsies are impractical in children who often require sedation and hospitalization for biopsies. Other markers, such as serum creatinine, have low sensitivity and specificity for early kidney allograft damage.
The ability to identify sub-clinical kidney allograft injury using minimally invasive, robust, biomarkers with high sensitivity and specificity in pediatric recipients would represent a major advance in pediatric kidney transplant care. In the Clinical Trials in Organ Transplantation (CTOT)-04 study, a NIH-sponsored, multicenter, prospective study of adult kidney allograft recipients, members of the VIRTUUS team were able to diagnose and predict ACR using urinary cell mRNA and metabolite profiles with high sensitivity and specificity\[2, 3\]. In addition, the investigators validated a urinary cell mRNA signature that distinguishes acute rejection (AR) from acute tubular injury (ATI) and ACR from AMR as well as a urinary cell mRNA signature diagnostic and prognostic of BKVN\[3-5\]. The overarching objective of this VIRTUUS proposal is to adapt existing validated adult noninvasive diagnostic and prognostic biomarkers to characterize allograft status in pediatric recipients of kidney allografts. Specifically, the investigators will investigate 1) whether the adult urinary cell 3-gene signature is diagnostic and prognostic of ACR in pediatric recipients of kidney allografts, 2) whether the combined metabolite and the urinary cell 3-gene signature is diagnostic and prognostic of ACR in pediatric recipients of kidney allografts, 3) whether levels of BKV VP-1 mRNA in urinary cells are diagnostic of BKVN, and 4) whether urinary cell levels of plasminogen activator inhibitor -1 (PAI-1) mRNA and serum creatinine levels predict allograft failure.
Investigators propose to validate early immunologic markers that have shown to be prognostic and diagnostic in adult kidney transplant recipients in pediatric kidney transplant recipients. Investigator findings will significantly advance the field of pediatric transplantation by moving toward proactive, tailored immunosuppressive regimens that minimize morbidity and optimize long-term allograft survival.
The Investigator's primary objective is to hypothesize that: (i) the adult urinary cell 3-gene signature will be diagnostic and prognostic of ACR in longitudinally collected urine samples from children with kidney transplants; and (ii) combined metabolite and mRNA biomarkers have greater ability to diagnose ACR than the mRNA or metabolite signature alone and (iii) levels of BKV VP-1 mRNA are diagnostic of BK virus nephropathy (BKVN) and (iv) urinary cell levels of plasminogen activator inhibitor-1 (PAI-1) mRNA and serum creatinine levels predict allograft failure.
Investigators seek to:
1. Determine if the adult urinary cell 3-gene signature is diagnostic and prognostic of ACR in pediatric kidney allograft recipients,
2. Evaluate whether a combined metabolite and the 3-gene urinary mRNA signature is diagnostic and prognostic of ACR and
3. Test the hypothesis that BKV-VP-1 mRNA levels in urinary cells are diagnostic of BKVN, and to test the hypothesis that a two variable prediction model composed of urinary cell level of PAI-1 mRNA and serum creatinine levels, both measured at the time of BKVN biopsy diagnosis, predict future graft failure
Secondary objectives include the following:
1. Create a repository of DNA samples from urine, saliva, discarded blood and tissue, and deceased donor blood and tissue to use for future research studies that will examine genome-wide associations with rejection and viral infections in pediatric kidney transplant recipients and
2. Create a biobank of samples of left-over blood and deceased donor blood to later examine associations between urine and blood proteomics and metabolomics.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 445
- Males or females between 2 to 18 years at the time of recruitment
- Receiving the first, or additional, incident kidney transplants.
- Have an existing/prevalent transplant with a scheduled kidney allograft biopsy.
- Parental/guardian permission (informed consent) and, if appropriate, child assent.
• Patient's primary medical team feels the subject's participation is not safe.
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Amount of CXCL10 (chemokine C-X-C motif ligand 10) 48 months The amount of mRNA observed in urinary sample biopsy.
Amount of 18s rRNA 48 months The amount of mRNA observed in urinary sample biopsy.
Amount of CD3E mRNA (CD3-epsilon polypeptide) 48 months The amount of mRNA observed in urinary sample biopsy.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (13)
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
University of California
🇺🇸Los Angeles, California, United States
Stanford University
🇺🇸Palo Alto, California, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
CHOP
🇺🇸Philadelphia, Pennsylvania, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Joan & Sanford I. Weill Medical College of Cornelle University
🇺🇸New York, New York, United States
University of California-San Diego, Rady Children's Hospital
🇺🇸La Jolla, California, United States
Vancouver Children's Hospital
🇨🇦Vancouver, British Columbia, Canada