This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Research has inadequately addressed the high risk posed for Blacks regarding the development of chronic kidney disease (CKD), rapid disease progression, and the high incidence of atherosclerotic-related deaths. We suggest a more robust inflammatory and oxidative response from physiological stressors may occur in Black children (BLK) and adults, when compared to non-Blacks (NBLK). These responses may be further exaggerated in Blacks with CKD. In addition, ethnic differences in circadian BP are known to exist in Black adults and children. Therefore, it is plausible that a higher incidence of hypertension in Blacks may lead to a chronic pro-oxidative state, a problem that is observed in children with hypertension. It is conceivable that systemic vascular and end organ changes may begin at an early age in Black children and are further exacerbated in CKD. Therefore, we hypothesize, regardless of CKD etiology: (1) oxidative and inflammatory markers will be higher in BLK versus NBLK children, adolescents, and young adults with CKD, compared to healthy sibling controls, throughout the 9-month study. To control for differences due to disease etiology, subject cohorts will be based upon ethnicity and CKD etiology: [uropathy (UP) or glomerulopathy (GP)] and ethnicity (BLK or NBLK). The 4 cohorts are: (1) BLK/UP; (2) NBLK/UP (3) BLK/GP; and (4) NBLK/GP. Cohorts will be matched by Glomerular Filtration Rate (GFR), age, BMI, and gender. Two additional cohorts of healthy siblings of the CKD patients (BLK and nBLK) will be studied as normal control subjects.
Aims : In order to demonstrate whether differences in an oxidative state exist in BLK with CKD versus NBLK, and compared to healthy controls, we will measure plasma ADMA/arginine ratio (by HPLC-tandem mass spectrometry), and urinary F2 isoprostanes (by EIA), the primary study endpoints. This will permit us to obtain a picture of circulation and elimination of by-products of the oxidative state. To assess inflammation, we will measure basal TNF-a (by ELISA), a multi-functional regulatory cytokine and our secondary study endpoint. We will also examine differences, in other variables of interest: lipoprotein profile and particle size (by NMR spectroscopy), adhesion molecules (VCAM-I and ICAM-1), which are increased with LDL oxidation (measured by ELISA) and 24-hour ambulatory blood pressure monitoring (ABPM), to address whether differences exist in lipid particle sizes, which is important to risk for augmented oxidative modification. Data will be analyzed for circadian BP rhythm, patterns of SBP and DBP during activity, quiescence, sleep, the nocturnal dip, and day and/or nocturnal hypertension. Since juvenile hypertension is associated with an increased pro-oxidative state, increased renovascular resistance may be involved in acceleration of CKD and vascular atherosclerotic changes, in conjunction with the pro-oxidative and inflammatory state initiated by metabolic perturbations as renal function declines. Thus, our aims are focused upon an initial determination of whether ethnicity and CKD etiology elicit differences in markers reflective of a pro-atherogenic state in Black children, adolescents, and young adults with stage II-III CKD, compared to normal healthy sibling controls.
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