Prognostic Biomarkers to Predict Progression of Pediatric Chronic Kidney Disease

预测小儿慢性肾脏病进展的预后生物标志物

• 批准号: 8675896
• 负责人: Ellen Rose Brooks
• 金额: $ 30.22万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675896
• 关键词: Accounting; Adolescent; Adult; Age; Age Specific Death Rate; Arginine; Atherosclerosis; Biochemical; Biological Markers; Blood; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cause of Death; Child; Childhood; Chronic; Chronic Kidney Failure; Combined Modality Therapy; Common carotid artery; Creatinine; Data; Data Collection; Development; Diabetes Mellitus; Dialysis procedure; Diastolic blood pressure; Disease; Disease Progression; Dose; End stage renal failure; Enrollment; Etiology; Exhibits; Fibrosis; Functional disorder; Funding; Future; Generations; Hemoglobin; Hypertension; Injury; Iohexol; Kidney; Lead; Left; Left Ventricular Mass; Life; Link; Measurement; Measures; Modeling; Morbidity - disease rate; N,N-dimethylarginine; Nature; Nitric Oxide; North America; Observational Study; Participant; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Plasma; Play; Population; Population Heterogeneity; Procedures; Prognostic Marker; Proteins; Proteinuria; Relative Risks; Renal function; Research; Risk; Role; Running; Schedule; Specimen; Staging; Structure; Testing; Thick; Transplantation; United States National Institutes of Health; Urine; aged; arterial stiffness; base; burden of illness; cardiovascular risk factor; congenital anomaly; dimethylarginine; endothelial dysfunction; heart function; hypertensive heart disease; indexing; inhibitor/antagonist; insight; intima media; masked hypertension; mortality; novel; prospective; public health relevance; sample collection; screening; time use; urinary tract obstruction

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：新型生物标志物，血浆甲基化精氨酸衍生物（MAD），更具体地说是不对称的二甲基精氨酸（ADMA），为慢性和终阶段肾脏疾病（CKD; ESKD）提供了独特的见解。高水平的MAD提供了有关CKD肾脏过滤功能丧失与成人心血管（CV）发病率和死亡率增加的因果关系的重要数据。目前，在患有CKD的儿童中，对导致肾脏过滤功能丧失的因素和CV疾病（CVD）之前的CV重塑异常的理解不足。成人的研究表明，由于其与内皮功能障碍的关系，MAD可能起作用，是CKD进展与CVD之间的联系。然而，与成年人相比，儿童的CKD病因差异很大，尽管儿科ESKD患者的患者特异性死亡率= 30-100x，但儿童是CV功能障碍和动脉粥样硬化的贞洁模型，该模型是患有最常见的CVD死亡原因的健康儿童。相反，成年人发展年龄/CKD/ESKD相关的动脉粥样硬化。如果MAD是CKD儿童的疾病进展和CVD负担的新型生物标志物，则该提议将在其两个具体目标中证明，因为我们已获得NIH赞助的“儿童慢性肾脏疾病”（CKID； UO1 DK066174）指导委员会使用Plasma标本和来自On Chought Multi-Center的数据。北美CKD儿童的前瞻性观察性研究（在：> 1年至<17年的年龄；当前n = 659）。 CKID数据和标本收集始于4/2005，并于7/2013结束。 AIM 1研究了包括ADMA在内的等离子体MAD，作为预后生物标志物，以检测CKID的主要研究终点的下降，直接测量了血浆iohexol Clearance的GFR（MGFR）。对于AIM 1，我们将模拟CKD进展到MAD水平的相对风险，该水平由MGFR的下降确定，这是肾小球和非斜体起源的CKD中非股骨性质的蛋白尿。 AIM 2专注于确定MADS水平与CV异常的CV重塑/顺应性随着时间的变化，使用对MGFR调整的模型，血红蛋白24hr-卧床BP（ABP）负载，BL休闲BP负载和BP药物治疗的使用（类，剂量，剂量，单疗法，单疗法 - OR组合BP Medications）。从经过验证的非侵入性小儿程序中使用的CKID CV数据为：BP ：（ 24小时ABP负载；夜间倾斜；休闲BP负载，）；心脏结构/功能的变化：（ LVMI；舒张功能= LV刚度]，动脉变化：[常见的颈动脉（CC）内膜膜厚度； CC和主动脉僵硬]。血浆MADS，MGFR，MGFR，CV数据，BP药物治疗和CKID中的其他变量是否可以使CKID中的其他变量能够进行CCKID，是否对CKID进行了有用的MADS，是否可以进行CCKID，是否有用的MADS与小儿CKD人群中的简历负担有关。