Chronic kidney disease (CKD) is an urgent public health problem worldwide. Children with CKD live with the consequences of abnormal renal function their entire lives. Irrespective of its primary cause, CKD will progress to kidney failure. Antiproteinuric and antihypertensive therapies slow the rates of kidney function decline, but rarely halt or reverse renal progression. While many of the genetic and molecular pathways for renal progression have been elucidated in animal models, these pathways have been difficult to translate into humans, let alone in children with CKD. Whole genome screening for associations with renal progression is now cost efficient and feasible, in part due to advances in bioinformatics and biostatistics that have enabled identification of pathways responsible for renal progression. This Pediatric investigation for genetic factors associated with renal progression (PediGFR) study is an ancillary study proposal to the ongoing Chronic Kidney Disease in Children (CKiD) Prospective Cohort Study. The objective of this study proposal is to identify the genetic determinants associated with renal function decline in children with CKD. For this international collaborative effort, we have assembled the largest pediatric CKD patient population spanning North America and Europe, with 1482 subjects among three current pediatric CKD studies. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. These studies have extensive and detailed longitudinal data for the phenotype of interest. Using the Affymetrix(R) Genome-Wide Human SNP Array 6.0 for genotyping for all subjects, we propose to perform hypothesis-driven pathway-based analyses that prioritize known risk pathways for renal progression, evaluating associations with glomerular filtration rate decline (Aim 1) and levels of proteinuria (Aim 2). With the genome-wide genotyping data, we will perform an unbiased genome-wide association study for renal progression and proteinuria (Aim 3). The results from this work are anticipated to provide insight into the mechanisms of renal progression in humans and the development of novel therapies directed toward these pathways associated with kidney function decline. This work will open new areas of scientific investigation and ongoing collaboration among the parent studies. PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease (CKD) is a growing worldwide health problem with serious complications that leads to the development of permanent kidney failure; CKD in children is especially devastating. Current treatments for CKD can slow the onset of kidney failure, but rarely can these treatments halt or reverse the process. The goals of this project are to identify the genetic factors that contribute to the progressive decline of kidney function in children with CKD, which will give us a better understanding of why kidneys fail, and provide insights for new treatments for pediatric CKD.