Ameliorating Sickle Nephropathy and Pulmonary Hypertension

描述（由申请人提供）：镰状细胞性贫血（SCA）患者的肾脏受到几种不同方式的影响。患有SCA的儿童，甚至婴儿会出现尿浓缩缺陷（UCD）、肾小球滤过率（GFR）升高、近端肾小管功能异常和钾排泄能力受损。髓小管间质损伤也可见血尿（肉眼或镜下）。随着年龄的增长，肾小球病变开始发展，最初表现为微量蛋白尿，然后是大量蛋白尿，进展为肾功能衰竭和终末期肾病。早期肾脏和肾小球增大，GFR升高。随着时间的推移，局灶性和节段性肾小球硬化，GFR降低和终末期肾病发展。镰状肾病（SN）存在于40-50%的成年人中。我们有关于镰状细胞病的新型生物标志物的强有力的初步数据和动物数据，支持氯沙坦的介入试验，以改善镰状细胞病的UCD、蛋白尿和肺动脉高压。我们建议在SCA患者中进行关键的试点研究，以指导氯沙坦III期随机对照试验的设计；并组装场地、统计和数据管理中心（SDMC）、规范性文件、研究监测和数据管理计划，以确保有效执行三期多中心研究。在目标1中，我们将开展试点研究，研究SN的进展和氯沙坦减少/预防SN的可行性，以收集设计SN和ph的III期随机对照试验所需的关键数据。试点研究将有助于估计累积患者的可行性，确定精确的持续时间/剂量，以及在资助的头两年所需的样本量和反应率。在目标2中，我们将在资助的第三年设计氯沙坦治疗SN的多中心III期随机试验。在目标3中，我们将组装基础设施以进行执行良好的多中心试验。在资助的第三年，我们将根据符合条件的患者确定额外的临床地点，并聘请SDMC制定临床方案，同意和同意表格，操作手册，研究者手册，延长IND并准备提交IRB的文件，建立DSMB，数据管理和研究监测计划以及为研究人员提供培训材料。我们汇集了四个参与地点：两个成人和两个儿科地点进行试点研究：辛辛那提儿童医院医学中心、辛辛那提大学辛辛那提大学附属医院、全国儿童医院和俄亥俄州哥伦布市俄亥俄州立大学附属医院进行试点研究。这些场址也将参与第三阶段研究，同时根据从这项规划赠款中获得的试点数据，根据需要确定和招募其他场址。上述目标是该计划拨款的重点方法，旨在获得设计稳健的三期试验的关键数据，申请RO1资金，积累必要的基础设施，以执行设计良好的三期研究，并有效地将我们实验室的研究发现转化为临床，以影响镰状肾病的有效治疗方法。

DESCRIPTION (provided by applicant): The kidney is affected in several different ways in sickle cell anemia (SCA). Children, and even infants with SCA develop a urine concentrating defect (UCD), increased glomerular filtration rate (GFR), supranormal proximal tubular function and impaired ability to excrete potassium. Also seen is hematuria (gross or microscopic) from medullary tubulo-interstitial damage. With increasing age, glomerulopathy develops, manifest initially as micro-albuminuria, then macro- albuminuria, progressing to renal failure and end stage renal disease. Kidneys and glomeruli are enlarged and GFR increased in early stages. With time, focal and segmental glomerulosclerosis, reduced GFR and end stage renal disease develops. Sickle nephropathy (SN) is present in 40-50% of adults. We have strong preliminary data on novel biomarkers on SN and animal data that supports an interventional trial with losartan to ameliorate UCD, albuminuria and pulmonary hypertension in sickle cell disease. We propose to conduct critical pilot studies in patients with SCA to guide the design of a robust phase III randomized controlled trial of losartan; and to assemble the sites, Statistics and Data Management Center (SDMC), regulatory documents, study monitoring and data management plan to ensure effective execution of a phase III multi-center study. In aim 1, we will conduct pilot studies to study the progression of SN and the feasibility of reducing/preventing SN with losartan, in order to gather critical data necessary to design a phase III randomized control trial for SN and PH. The pilot studies will help estimate feasibility of accruing patients, determine a refined duration/dose and the sample size and response rate necessary in the first two years of funding. In aim 2, we will design a multi-center phase III randomized trial of losartan for SN in the third year of funding. In aim 3, we will assemble the infrastructure to carry out a well executed multi-center trial. in the third year of funding, we will identify additional clinical sites based on eligible patients, and engage a SDMC to develop the clinical protocol, consent and assent forms, manual of operations, investigators brochure, extend the IND and prepare documents for IRB submission, establish a DSMB, data management and study monitoring plan and training materials for the study staff. We have assembled four participating sites: two adult and two pediatric sites for the pilot studies: Cincinnati Childrens Hospital Medical Center, University Hospital at the University of Cincinnati in Cincinnati and Nationwide Childrens Hospital and the Ohio State University Hospital in Columbus, Ohio for the pilot studies. These sites will also participate in the phase III study, while additional sites are identified and recruited, as needed based on the pilot data obtained from this planning grant. The above aims are a focused approach in this planning grant to obtain data critical for the design of a robust phase III trial, apply for RO1 funding and amass the infrastructure necessary to execute a well-designed phase III study and effectively translate research discoveries made in our laboratory to the clinic to affect effective therapeutic approaches to sickle nephropathy.