Chronobiology and Chronopharmacology to Prevent Sickle Cell Nephropathy

 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脏损伤是镰状细胞发病率和死亡率增加的危险因素 然而，尚未确定进展性疾病的早期标志，也未确定防止心血管不良结局发展的治疗方法。24小时血压监测所定义的昼夜血压在诊断继发性高血压方面比临床血压更准确，在其他疾病中，夜间血压异常与进展性肾脏疾病有关。 方法/目的：对40例夜间血压下降异常的青少年HbSS和SB0地中海贫血患者进行随机可行性试验。在这项为期六个月的可行性试验中，将分析氯沙坦的两种剂量策略(滴定以保持血压第95个百分位数与75个百分位数)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)中进行前瞻性队列研究，以评估高血压的发生率以及监测肾脏损伤和高血压的潜在生物标志物的作用。队列参与者将接受高血压和肾脏损伤标志物的年度评估(参与者的24小时血压监测=11岁；血液：尿酸；尿液：胱抑素-c、Kim-1、NGAL、B2M)。预期结果：在可行性试验完成后，将获得重要的背景信息，以设计一项决定性的多中心镰刀病高血压试验。在队列研究完成后，将确定儿童高血压的发病率，并将更好地了解监测血液和尿液生物标记物的作用。 由于肾功能衰竭患者的治疗是令人沮丧的，及早发现有风险的SCD患者并进行治疗试验以防止病情恶化是当务之急。

 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.