Clinical trial NCT00951353: Immune Development in Pediatric Transplantation (IMPACT)
Official title: Immune Development and Alloimmunity in Pediatric Renal Transplant Recipients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Kidney Failure
End Stage Renal Disease
Keywords: Transplantation
Kidney Failure
End Stage Renal Disease
Pediatric
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2009-08-04
Enrollment: 125
Sex: ALL
Minimum age (years): 1
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pediatric end-stage renal disease patients needing a kidney transplant

Brief summary: Transplantation is the preferred method of treatment for end-stage renal disease (ESRD) in children. Over the past forty years, the use of newer immunosuppressive drugs has decreased the risk for organ rejection considerably, and improved short-term outcomes. However, these costly and complicated life-long treatment regimens also cause serious side effects. This has been particularly true for children, who undergo treatment with these drugs at the same time they are transitioning, physically and emotionally, from childhood to adulthood. These factors lead to significantly reduced life-spans, decreased drug regimen adherence, and an increased need for re-transplantation, as compared with adults.

Current immunosuppressive procedures and strategies for children mimic those for adults, despite the difference between the two populations' immune systems and needs. New strategies aimed at tailoring to an individual child's needs would both reduce the risk of complications and improve outcomes. The purpose of this study is to generate information which will help to change the current practice of pediatric transplantation into one that is more individualized and preventative.

Detailed description: Over the past forty years, the use of increasingly effective immunosuppressive drugs has decreased the risk for organ rejection (acute rejection, AR) considerably, and improved short-term outcomes. However, these costly and complicated life-long treatment regimens also cause serious complications in the long-term.

While transplant recipients live significantly longer lives than patients on dialysis, transplant recipients still have much shorter life spans than their healthy counterparts. Among reasons for this difference in life-expectancy are the immunosuppressive-drug related side effects that can lead to complications such as life threatening infections, malignancies, high blood pressure, heart disease, and diabetes. Additionally, certain drugs used to prevent organ rejection are known to contribute to renal damage, leading many patients to experience graft loss within 15 years. To that end, many children undergoing successful kidney transplantation require re-transplantation as adults. Therefore, while transplantation yields high success rates in the short-term, the drugs that are responsible for this early and temporary success are also the cause of later, serious complications. This is especially true for children, who endure extended drug exposures.

The purpose of this study is to explore the impact of viral exposure on children who receive immunosuppressive medications after renal transplantation; study the cellular changes associated with these influences; monitor medication adherence; and observe how all these factors affect the outcome of kidney transplantation in children. The hope is to better understand these processes to optimize future transplant therapies for the pediatric transplant recipient.

This study is designed to observe the immune system response during the first year after kidney transplant. Cells of the immune system in the recipient's blood, urine, and transplanted kidney will be tested to observe how the drugs used to prevent rejection influence them, if these cells change over time, and if they are related to kidney rejection. The comparisons will allow researchers to study how the developing immune system interacts with the kidney transplant. Blood from the kidney donor will be requested so that researchers can study how the recipient's immune system interacts with donor cells.

This study will also look closely at how well participants take prescribed medications. Since transplant medications are known to change the immune system, tests of the immune system cells will be compared to tests designed to measure how accurately medications are taken. Medication adherence will be measured using electronic medication bottle cap records, paper survey results, and drug levels in the blood. In this way, the study team hopes to learn about the impact of children's medications on their immune system.

This study will take place at multiple transplant centers in the United States. It is observational and will involve approximately 75 pediatric renal participants. The study will last for a total of 3 years, which includes a 2 year accrual period and 12 month follow up. Clinical treatment will be determined by standard of care at each participating center. There will be Baseline assessments which will occur before and on the day of transplantation and follow-up study visits will take place at months 1, 3, 6, 9, and 12 after transplant. Study assessments and specimens will also be collected at the time of each clinically indicated biopsy. Study assessments during these follow-up visits will include vital signs; review of current medications; questions related to adverse events (infection, rejection, graft failure, malignancy); treatment adherence surveys; and specimen collection for local and central laboratory testing.

Eligibility criteria: Inclusion Criteria:

* Parent or legal guardian willing to provide informed consent, if necessary
* 1 to 20 years of age (before 21st birthday) at the time of enrollment
* Undergoing renal transplantation

Exclusion Criteria:

* Need for multi-organ transplantation
* Any prior history of organ transplantation
* Inability or unwillingness of participant of their legal guardian to give written informed consent or comply with study protocol

Primary outcomes:
measure: Incidence of biopsy proven and treated (steroid pulse, taper, immunosuppressant medication changes) acute rejection Banff grade borderline or higher
timeFrame: 6 months after transplant
Secondary outcomes:
measure: Incidence of treated, clinically suspected rejection without biopsy
timeFrame: Throughout study
measure: Incidence of biopsy proven and clinically relevant chronic allograft nephropathy
timeFrame: Throughout study
measure: Incidence of infection and malignancy
timeFrame: Throughout study
measure: Incidence of medication non-adherence in pediatric kidney transplant recipients using self report questionnaires and electronic monitoring bottle caps
timeFrame: Throughout study
measure: Clinical impact of medication non-adherence with regard to the incidence of acute and chronic rejection
timeFrame: Throughout study
measure: The degree to which a child's T Cells are predominately naïve, TEM, TCM, or TTM as measured by MFC
timeFrame: Throughout study
measure: The heterologous alloreactivity of defined viral T cells for donor and third party alloantigens using MHC tetramers with specificity for CMV and EBV
timeFrame: Throughout study
measure: The peripheral blood, urine, and allograft transcriptional phenotypes specific to the MFC-defined T cell phenotype
timeFrame: Throughout study
measure: Formation of anti-donor HLA, non HLA, and MICA antibodies after transplantation as measured using Luminex platforms and microarray
timeFrame: Throughout study
measure: Identification of specific proteins in blood and allograft as correlated with rejection
timeFrame: Throughout study
measure: Barriers to adherence as indicated by AMBS, PMBS, and BMQ questionnaires
timeFrame: Throughout study
measure: Candidate surrogate markers of immunosuppressive medication non-adherence: • Tacrolimus drug level variation • De novo immune activation using real time PCR message for perforin and granzyme B, and • Anti-HLA antibodies
timeFrame: Throughout study
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California at Los Angeles/ Mattel Children's Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center/ Lucille Packard Children's Hospital
state: California
city: Atlanta
country: United States
facility: Emory University/ Children's Healthcare of Atlanta
state: Georgia
Study officials:
affiliation: Emory University
name: Allan D. Kirk, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ettenger R, Chin H, Kesler K, Bridges N, Grimm P, Reed EF, Sarwal M, Sibley R, Tsai E, Warshaw B, Kirk AD. Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation. Am J Transplant. 2017 Jun;17(6):1549-1562. doi: 10.1111/ajt.14169. Epub 2017 Feb 1.