Chronobiology and Chronopharmacology to Prevent Sickle Cell Nephropathy

预防镰状细胞肾病的时间生物学和时间药理学

• 批准号: 9039658
• 负责人: Jeffrey D Lebensburger
• 金额: $ 19.11万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039658
• 关键词: Adherence; Adolescent; Age; Ambulatory Blood Pressure Monitoring; Antihypertensive Agents; Area; Biological Markers; Blood; Blood Pressure; Blood Pressure Monitors; Cardiovascular system; Childhood; Chronic Kidney Failure; Chronobiology; Circadian Rhythms; Clinic; Clinical Trials; Cohort Studies; Communities; Consent; Cystatins; Data; Development; Dialysis procedure; Disease; Dose; Eligibility Determination; Enrollment; Evaluation; Goals; Health; Height; High Prevalence; Hour; Hypertension; Incidence; Injury; Kidney; Kidney Diseases; Kidney Failure; LCN2 gene; Laboratories; Lead; Link; Losartan; Mentors; Mentorship; Methodology; Microalbuminuria; Monitor; Morbidity - disease rate; Multicenter Trials; National Heart, Lung, and Blood Institute; Oral; Organ; Outcome; Participant; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Prevalence; Procedures; Progressive Disease; Randomized; Rare Diseases; Research; Risk; Risk Factors; Role; Safety; Secondary Hypertension; Sickle Cell; Sickle Cell Anemia; Site; Sleep; Stroke; Testing; Thalassemia; Therapeutic Trials; Time; Titrations; Training; Transfusion; Uric Acid; Urine; cohort; design; disorder risk; hydroxyurea; insight; mortality; open label; potential biomarker; prevent; prospective; sickling; therapy development; treatment strategy; trial design; young adult

 DESCRIPTION (provided by applicant): Significance of proposed research: Untreated hypertension and renal injury are risk factors for increased morbidity and mortality in sickle cell disease, yet early markers of progressive disease have not been identified and therapies to prevent the development of adverse cardiovascular outcomes have not been defined. Circadian blood pressure, as defined by 24 hour blood pressure monitoring, is more accurate than clinic blood pressure in defining secondary hypertension and abnormal nocturnal blood pressured dipping has been linked to progressive renal disease in other diseases. Methodology/Aims: A randomized feasibility trial of losartan will be conducted among 40 adolescent HbSS and SB0 thalassemia patients (11-19 years) with abnormal nocturnal blood pressure dipping. During this six month feasibility trial, two dosing strategies of losartan (titraed to keep BP <95th percentile vs. <75th percentile) will be analyzed for safety and effect on restoring normal circadian blood pressure. A prospective cohort study among HbSS and SB0 thalassemia patients (6-19 years) will also be conducted to evaluate the incidence of hypertension and role of monitoring potential biomarkers of kidney injury and hypertension. Cohort participants will undergo annual evaluations of hypertension and markers of kidney injury (24 hour blood pressure monitoring for participants = 11yrs; Blood: uric acid; Urine: Cystatin-c, Kim-1, NGAL, B2M). Expected Results: At the completion of the feasibility trial, vital background information will be obtained to design a definitive multicenter trial of hypertension in sickle cel disease. At the completion of the cohort study, the incidence of pediatric hypertension will be identified and the role for monitoring blood and urine biomarkers will be better understood. As therapy for patients with renal failure is dismal, it is imperative that SCD patients at risk ar identified early and that therapeutic trials are conducted that prevent progression.

 描述（由申请人提供）：拟议研究的意义：未经治疗的高血压和肾损伤是镰状细胞病发病率和死亡率增加的危险因素 疾病，但尚未确定进行性疾病的早期标志物，并且尚未确定预防不良心血管结局发生的治疗方法。通过 24 小时血压监测定义的昼夜血压在定义继发性高血压方面比诊所血压更准确，并且夜间血压异常下降与其他疾病中的进行性肾病有关。 方法/目标：将在 40 名夜间血压异常下降的青少年 HbSS 和 SB0 地中海贫血患者（11-19 岁）中进行氯沙坦的随机可行性试验。在为期六个月的可行性试验中，将分析氯沙坦的两种给药策略（滴定以保持血压<95%和<75%）的安全性和恢复正常昼夜血压的效果。还将在 HbSS 和 SB0 地中海贫血患者（6-19 岁）中进行一项前瞻性队列研究，以评估高血压的发病率以及监测肾损伤和高血压的潜在生物标志物的作用。队列参与者将接受年度高血压和肾损伤标志物评估（参与者 24 小时血压监测 = 11 年；血液：尿酸；尿液：胱抑素-c、Kim-1、NGAL、B2M）。预期结果：可行性试验完成后，将获得重要的背景信息，以设计镰状细胞病高血压的明确多中心试验。队列研究完成后，将确定儿童高血压的发病率，并更好地了解监测血液和尿液生物标志物的作用。 由于肾衰竭患者的治疗效果不佳，因此必须尽早识别处于危险中的 SCD 患者，并进行治疗试验以防止进展。