Novel biomarkers, plasma methylated arginine derivatives (MADs) and more specifically asymmetric dimethylarginine (ADMA) offer unique insights into chronic and end stage kidney disease (CKD;ESKD). High levels of MADs have provided important data on a causal link between loss of kidney filtering function in CKD and a heightened risk for cardiovascular (CV) morbidity and mortality in adults. At present, in children with CKD, there is an insufficient understanding of factors leading to loss of kidney filtering function and abnormal CV remodeling preceding CV disease (CVD). Research in adults indicates MADs may play a role, acting as a link between CKD progression and CVD due to its tie to endothelial dysfunction. However, CKD etiology is very different in children compared to adults, and children are a chaste model for CV dysfunction and atherosclerosis, although pediatric ESKD patients have an age-specific death rate=30-100x that of healthy children with the most common cause of death from CVD. Conversely, adults develop age-and CKD/ESKD-related atherosclerosis. This proposal will demonstrate in its two specific aims if MADs are novel biomarkers in children with CKD for both disease progression and CVD burden as we have been approved by the NIH-sponsored "Chronic Kidney Disease in Children" (CKiD;UO1 DK066174) Steering Committee to use plasma specimens and data from their ongoing multi-center 8-yr. prospective observational study of children with CKD in North America (enrolled at: >1 yr. to<17 yrs. old;current N=659). CKiD data and specimen collection began in 4/2005 and ends in 7/2013.
Aim 1 examines plasma MADs, including ADMA, as prognostic biomarkers to detect a decline in CKiD's primary study endpoint, directly measured GFR (mGFR) by plasma iohexol clearance.
For Aim 1, we will model the relative risk of CKD progression to the level of MADs, determined by decline in mGFR, accounting for proteinuria of a non-nephrotic nature in CKD of glomerular and non-glomerular origin.
Aim 2 focuses on determining the association between MADs levels and abnormal CV remodeling/compliance as they change over time, using a model adjusted for mGFR, hemoglobin 24hr- ambulatory BP (ABP) loads, BL casual BP load and use of BP drug therapy (class, dose, monotherapy-or combined BP medications). CKiD CV data to be used from validated non-invasive pediatric procedures are: BP: (24-hr ABP loads;nocturnal dip;casual BP load,);cardiac structure/function changes: (LVMI;diastolic function=LV stiffness], and arterial changes: [common carotid (CC) intima-media thickness;CC and aortic stiffness]. Plasma MADs, mGFR, CV data, BP drug therapy/class and additional variables collected in CKiD will allow us to rigorously test whether MADs are useful prognostic biomarkers for CKD progression and are associated with CV burden in the pediatric CKD population. If successful, we will provide a better understanding of the role of MADs in pediatric CKD and provide rational screening strategies to test new hypotheses about changing rates of CKD progression or CV disease burden in future studies.
Chronic Kidney Disease (CKD) in children and adolescents differs in most respects from that in the adult population and especially with regard to understanding its progression and rate to end-stage kidney disease (need for dialysis and transplant), and the extent of cardiovascular (CV) disease as kidney function declines, leaving traditional markers validated in adults as under-performing in children. A non- traditional blood biomarker studied in adults with CKD is asymmetric dimethylarginine (ADMA), due to its association with abnormal blood vessel function that may lead to further kidney damage, blood vessel dysfunction and abnormal blood flow, hypertension and heart problems. This study focuses on whether ADMA (and its biochemical derivatives) are useful prognostic biomarkers in children and adolescents with CKD for: (1) predicting a rapid decline in kidney filtering function and (2) determining ADMA's biomarker relationship to CV disease burden and will be accomplished with use of stored plasma specimens and data from non-invasive measurements of kidney and heart function;blood pressure and blood vessel thickness and stiffness from an ongoing, prospective, multi-center, 8-yr observational NIH-funded study with a large, racially and ethnically diverse population, Chronic Kidney Disease in Children (CKiD).