Clinical trial NCT03719339: VIRTUUS Children's Study
Official title: Validating Injury to Renal Transplant Using Urinary Signatures in Children
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Renal Transplant Rejection
Pediatric Kidney Disease
End Stage Renal Disease
Nephropathy
BK Virus (Nephropathy)
Antibody-mediated Rejection
Acute Cellular Graft Rejection
Keywords: Kidney disease
Kidney allograft
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2018-10-25
Enrollment: 445
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects 2 to 18 years of age meeting inclusion criteria will be recruited from the participating sites' Nephrology outpatient clinics or inpatient settings. All sites may choose to enroll Spanish speaking subjects pending the site has necessary resources to translate/interpret study related information. Sites choosing to enroll Spanish speaking subjects will have a native speaking translator or interpreter available to prevent any miscommunication during the consent process.

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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

• Patient's primary medical team feels the subject's participation is not safe.

Primary outcomes:
measure: Amount of CD3E mRNA (CD3-epsilon polypeptide)
timeFrame: 48 months
measure: Amount of CXCL10 (chemokine C-X-C motif ligand 10)
timeFrame: 48 months
measure: Amount of 18s rRNA
timeFrame: 48 months
Secondary outcomes:
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California-San Diego, Rady Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Joan & Sanford I. Weill Medical College of Cornelle University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: CHOP
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Vancouver
country: Canada
facility: Vancouver Children's Hospital
state: British Columbia
Study officials:
affiliation: Children's Hospital of Philadelphia and Hospital of The University of Pennsylvania
name: Brendan Keating, DPhil
role: PRINCIPAL_INVESTIGATOR
References: