This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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 Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Child Health and Human Development (NICHD) and the National Heart, Lung and Blood Institute (NHLBI funded a cooperative agreement including two Clinical Coordinating Centers and a Data Coordinating Center to conduct a prospective epidemiological study of children with chronic kidney disease (CKD). The primary goals of this study are to determine the risk factors for decline in kidney function and to define how a progressive decline in kidney function impacts neurocognitive function and behavior; the risk factors for cardiovascular disease/ and growth failure and its associated morbidity.
The specific aims are to: 1. Identify novel and traditional renal disease risk factors for the progression of CKD (e.g. decline of GFR) in children, 2. Characterize the impact of a decline in kidney function on neurodevelopment, cognitive abilities, and behavior, 3. Identify the prevalence and evolution of traditional and novel cardiovascular disease risk factors in progressive CKD, and 4. Examine the effects of declining GFR on growth and the treatment of growth failure, and to assess the consequences of growth failure on morbidity in children with CKD. The study will address the following hypotheses: 1. Children with mild to moderate chronic kidney disease secondary to structural causes have slower rates of declining GFR compared to those with acquired glomerular disease. 2. Accelerated CKD progression will be associated with a positive family history of kidney disease, black race, Hispanic ethnicity, lower socioeconomic status, elevated systolic and diastolic blood pressure, high nocturnal blood pressure, anemia, periods of accelerated growth, hyperparathyroidism and hyperlipidemia. 3. When indicated early surgical intervention as well as the prescription and adherence to therapy with angiotensin converting enzyme inhibitors, angiotensin receptor blockers and aldosterone inhibitors will slow CKD progression. 4. Systematic measurements of GFR, centrally measured 'true' serum creatinine by high performance liquid chromatography (HPLC), centrally based serum Cystatin C and comprehensive clinical data will yield GFR estimating equations based on height and serum creatinine. 5. Declining GCR will be associated with measurable declines in neurocognitive function behavior and quality of life in children with CKD. The greatest deficit of CKD, the highest stage of CKD and with the lowest hemoglobin levels. 6. Progressive CKD will adversely affect central nervous system conduction pathways, and detectable anatomic changes (white matter changes) will correlate with changes in neurocognitive status and GFR. 7. The prevalence and severity of traditional cardiovascular disease (CVD) risk factors (hypertension, hyperlipidemia) and uremia-related CVD risk factors (inflammation, malnutrition, anemia, hyperparathyroidism); will be associated with the progression of CKD. 8. The prevalence and severity of systemic and nocturnal hypertension will be associated with the decline of GCR and the development of concentric left ventricular hypertrophy (LVH). The prevalence and severity of anemia will be correlated with GFR decline and the development of eccentric LVH. 9. LVH will be responsible for decreased LV diastolic function in children with CKD. 10. Decreased aortic wall compliance will be related to elevated systolic blood pressure, hyperlipidemia, biomarkers of inflammation and increased Ca x P product. 11. Growth failure will be associated with the severity of secondary hyperparathyroidism, biomarkers of inflammation, poor nutrition, extent of GFR decline and early age at onset (i.e., prolonged duration of CKD) 12. Growth failure in children with CKD will be associated with a higher rate of morbidity, including increased hospitalizations, decreased quality of life, poor neurocognitive outcome and increased cardiovascular complications. 13. The response to recombinant human growth hormone (rhGH) level and nutritional status and negatively correlated with high sensitivity C reactive protein level, severity of secondary hyperparathyroidism and severity of bone biopsy evidence of renal osteodystrophy. The proposed cohort study has been designed to measure variables in four scientific domains: kidney, neurocognition, cardiovascular and growth. The protocol was determined to optimize the power of the cohort design whereby levels and changes of exposure of interest temporally precede outcomes.
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