NIH – Chronic Kidney Disease in Children Central Biochemistry Laboratory (U24)

The purpose of this FOA is to support the Central Biochemistry Laboratory for The Chronic Kidney Disease in Children (CKiD) consortium. The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in collaboration with the National Heart, Lung, and Blood Institute (NHLBI), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) invites applications for this open competition FOA from eligible applicants.

The investigators will collect study data according to the CKiD Protocol; collect and transmit biologic, genetic and other samples as delineated in the Protocol and Manual of Operations.  The overarching goals of this study have expanded somewhat from those delineated in the original FOA, which were to: to determine the risk factors for decline in renal function; the incidence of, and risk factors for, impaired neurocognitive development and function; the prevalence of risk factors for cardiovascular disease; and the long-term effects of growth failure and its treatment. This will now be a study of the treated history of chronic kidney disease (CKD), causes and consequences of different types of CKD, the relationship of CKD to acute kidney injury (AKI), cardiovascular disease, growth, and development, including discerning important subgroups/sub-phenotypes of CKD.

Background 

In response to a competitive FOA issued in 2002, and subsequent limited competition, awards to CKiD investigators were approved. CKiD is a consortium composed of two Clinical Coordinating Centers (CCC), a Data Coordinating Center (DCC), and a Central Biochemistry Laboratory (CBL).

The original FOA called for creation of a Consortium of collaborating investigators to recruit a cohort of 540 children with mild to moderate CKD, and to follow these children in a prospective fashion to define factors that impact on their well-being. They were to follow a common protocol to allow for a coordinated, multi-disciplinary approach to meet the goals described above. The FOA also specified the creation of a central repository of data and biologic samples for subsequent hypothesis based research. It was envisioned that the information obtained from this prospective cohort study of chronic kidney disease would establish natural history and outcome measures for future intervention/prevention trials. It was also envisioned that the data and biosamples obtained would be available to the broader scientific community for retrospective analyses.

CKiD has succeeded in establishing a collaborative, multi-disciplinary consortium composed of pediatric nephrologists, cardiologists, psychologists, and epidemiologists. The consortium eventually exceeded the original recruitment target, enrolling 891 participants, and has collected data in the major domains described in the goals of the original FOA. The data collected has revealed novel information about the cohort of children being studied and informed the goals of this competition. Additionally, pilot clinical trials will be initiated shortly that build on the information gathered from CKiD (RFA-DK-16-018 and RFA-DK-16-035). The Consortium developed a compelling multi-disciplinary, multi-institutional, clinical research protocol that provides pertinence, validity, reliability, and generalizability to an extent not possible with previous studies of pediatric CKD patients. The Consortium has established a broad and effective collaborative base of ongoing relationships providing expanded sources of relevant idea, including several ancillary studies and collaboration with other projects, including the European ESCAPE trial, the NIDDK-funded CKD BioCon and the European 4C study.

In June 2016, the NIDDK convened a meeting of an external expert panel to review the past performance and future plans of both CKiD and the NIDDK-sponsored Chronic Renal Insufficiency Cohort (CRIC) study. Based on study findings to date, and recommendations of the expert panel, the NIDDK would like to continue the CKiD study for an additional five years, with some modifications to the current protocol.

Objectives and Scope

The overall objective of this FOA is to invite the CKiD CBL investigators to extend the follow-up of the participants recruited to date, recruit a new cohort with very early congenital disease, and modify some aspects participant evaluations. The specific goals of the CKiD consortium include:

(1) To encourage novel approaches to identification of risk factors for CKD progression, including further work on some of the preliminary environmental exposure findings, and continuing the ongoing genetic analyses.

(2) To encourage the use of novel and innovative analyses of the CKiD data in all domains of the study.

(3) To limit measurement of iohexol GFR to a subset of participants early in their disease course to aid in validation of eGFR formulae in children with normal GFR levels.

(4) To propose validation of predictive biomarkers through collaboration with other cohorts (e.g. CKD BioCon, the European ESCAPE and 4C studies).

(5) to consider the use of, and validation of, noninvasive devices that can provide clinically relevant data gathered outside the usual clinical setting (e.g. at home / school) and,

(6) To provide a broad data resource to the scientific community for further advancing chronic kidney disease research.

Study Design

The individual CCCs, the DCC and Central Biochemistry Laboratory participating in the cooperative study have jointly developed the standardized protocol, and will modify it to meet the new project goals.

The Consortium will jointly analyze data from its study populations. The consortium has developed a mechanism to solicit ancillary research applications from investigators both within and outside the consortium.  CKiD is collecting specimens that include sufficient material for measurements to be made based on hypotheses developed by the Steering Committee and for storage of sufficient specimens that material will be available in the future when new technology or approaches may be applied to hypothesis testing.

Study Components

1.  Central Biochemistry Laboratory (CBL)

The CBL will be responsible for providing participating sites with the reagents and protocol needed for the iohexol glomerular filtration rate (GFR) measurements.  GFR measurement will be limited to just a subset of participants – new participants older than 5 years, and current participants with GFR >90ml/min/1.73m2. The plasma samples collected during the iohexol GFR measurements will be sent to the CBL for analysis and results will be sent to the DCC. In addition, all central chemistry measurements dictated by the study protocol will be performed at the CBL. The Principal Investigator and study team for the CBL must demonstrate expertise in the measurement of GFR in pediatric populations and have a track record of successful management of such measures into pediatric longitudinal cohorts.

2. Clinical Coordinating Centers (CCCs)

Up to two awards will be made for CCCs that are responsible for the recruitment, evaluation and the long-term follow-up of study participants.

3. Data Coordinating Center (DCC)

This center will be responsible for the collection, management and analysis of the laboratory and clinical data, and coordinating communication and research with the Clinical Centers. In addition, the DCC will continue the data acquisition and transfer and continue to use procedures for ensuring participant confidentiality, procedures for quality control, training, and certification, update the manual of operations, and supervise the orderly collection and transmission of data. The DCC will continue to oversee implementation and adherence to the study protocols, and assure quality control of the data collected.

4. Steering Committee

A Steering Committee composed of the program director(s)/principal investigator(s) (PDs/PIs) of the CCCs, the DCC, the CBL, and the NIDDK Project Scientist will be the main governing body of the study. Representatives from the NHLBI and NICHD will also participate at all steering committee meetings for input regarding research interests and topics specific to their respective institutes.  The Steering Committee will have primary responsibility for the general organization of the study, finalizing common protocols, facilitating the conduct and monitoring of the studies, and reporting study results.

5. Project Scientist

The NIDDK Project Scientist will continue to assist the Steering Committee in carrying out the proposed studies (described in detail under Terms and Conditions).  The Project Scientist will provide scientific support to awardees activities, including quality control, interim data monitoring, final data analysis and interpretation, preparation of publications, and overall performance monitoring.

6. Observational Study Monitoring Board

An independent Observational Study Monitoring Board (OSMB) was established by the NIDDK, NHLBI and NICHD including experts in areas such as pediatric nephrology, pediatric cardiology, biostatistics, epidemiology and ethics, who are not otherwise involved in the study.  The OSMB will continue to monitor protocol performance and participant safety at least annually.

Deadline:  November 3, 2017

URL:  https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-17-034.html