Application of integrative omics to identify mechanistic pathways of adverse outcomes in children with chronic kidney disease
openNIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Chronic kidney disease (CKD) in children is associated with high mortality rates and negatively impacts bone
accrual and linear growth. Current treatments for pediatric CKD are limited, and many children progress to kidney
failure. Our prior work leading the pediatric investigations in the NIDDK CKD Biomarkers consortium identified
biomarkers of CKD progression in the Chronic Kidney Disease in Children (CKiD) cohort using targeted protein
and untargeted metabolomic approaches. We identified metabolites, metabolomic signatures, and six targeted
proteins which were each independently associated with CKD progression. Recent advances in proteomic
technologies enable the measurement of thousands of proteins concurrently with high specificity and sensitivity.
Integrating large-scale, proteomics, metabolomics, and genomics provides unprecedented opportunities to
define the molecular basis of CKD etiology and generate novel insights into CKD-related outcomes. With
proteomic and metabolomic measurements supported by this award, and existing genomic, metabolomic, and
targeted biomarker measurements, we hypothesize that an unbiased examination of the plasma and urine
proteome will identify proteins and pathways involved in CKD progression and complications, expanding on our
prior research to understand underlying tubular injury and dysfunction, inflammation, and repair mechanisms.
This retrospective cohort study will leverage stored samples and existing data from >1,100 children in CKiD and
the Cardiovascular Comorbidity in Children with CKD (4C) study, the two largest prospective cohort studies of
pediatric CKD worldwide. Proteomic analysis will be performed on paired baseline plasma and urine samples.
Untargeted metabolomic profiling of baseline 4C samples will be performed on the same platform used
previously in CKiD. In Aim 1, we will: identify plasma and urine proteins that are biomarkers of CKD progression
(50% decline in eGFR or kidney replacement therapy) and determine whether these protein markers differ by
CKD etiology; identify novel biological pathways involved in CKD progression; and develop a multi-protein
prognostic model that is highly predictive for CKD progression. In Aim 2, we will utilize the newly generated
proteomic data to identify plasma and urine proteins and novel biological pathways associated with linear growth
failure and mineral bone disease. Statistical analyses for Aims 1 and 2 will include Cox regression analysis, high
dimensional regularization Cox regression with elastic net penalty, and consensus clustering analysis. In Aim 3,
we will combine existing genomic and metabolomic data with newly generated proteomic and metabolomic data
to apply novel integrative approaches to analyze multi-omic data. This is the first pediatric CKD study to couple
high-throughput proteomic measurements with multi-omic data integration. The completion of these aims will:
provide new insights into mechanisms of CKD progression and CKD-associated mineral bone disease and linear
growth failure; contribute to the identification of non-invasive biomarkers; and generate a large repository of
multi-omic data that can be leveraged to expand the project’s impact in future pediatric CKD research.
Up to $934K
health research