Ameliorating Sickle Nephropathy and Pulmonary Hypertension

描述（由申请人提供）：镰状细胞性贫血（SCA）以几种不同的方式影响肾脏。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）增加、近端肾小管功能超常和排钾能力受损。还可见到由肾小管间质损伤引起的血尿（肉眼或显微镜下）。随着年龄的增长，肾小球病发展，最初表现为微量白蛋白尿，然后是大量白蛋白尿，进展为肾衰竭和终末期肾病。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降低和终末期肾病的发展。镰状肾病（SN）存在于40-50%的成人中。我们有关于SN的新型生物标志物的强有力的初步数据和动物数据，支持氯沙坦改善镰状细胞病中的UCD，白蛋白尿和肺动脉高压的干预性试验。我们建议在SCA患者中进行关键性的初步研究，以指导设计一项可靠的氯沙坦III期随机对照试验;并将研究中心、统计和数据管理中心（SDMC）、法规文件、研究监查和数据管理计划集合起来，以确保III期多中心研究的有效执行。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，确定在前两年资助所需的精确持续时间/剂量以及样本量和应答率。在目标2中，我们将在资助的第三年设计一项氯沙坦治疗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，以进行良好的多中心试验。在资助的第三年，我们将根据合格患者确定其他临床研究中心，并聘请SDMC制定临床方案、知情同意书和同意书、操作手册、研究者手册，扩展IND并准备IRB提交文件，建立DSMB、数据管理和研究监查计划以及研究人员培训材料。我们已经召集了四个参与研究中心：两个成人和两个儿科研究中心进行试点研究：辛辛那提儿童医院医疗中心，辛辛那提大学辛辛那提大学医院和全国儿童医院以及俄亥俄州哥伦布市的俄亥俄州立大学医院进行试点研究。这些研究中心还将参加第三阶段研究，同时根据从该规划赠款中获得的试验数据，视需要确定和招募更多的研究中心。上述目标是该计划拨款的重点，以获得设计强大的III期试验的关键数据，申请RO 1资金并积累执行精心设计的III期研究所需的基础设施，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。 公共卫生相关性：镰状细胞性贫血患者的肾脏早在婴儿期就受到影响，并随着年龄的增长而逐渐受损，近40-50%的成年人患有肾损伤（镰状肾病），最终导致终末期肾病。目前，还没有建立预防或减少镰状肾病的治疗方法。有了这个R34拨款提案，我们计划研究镰状肾病的过程，并进行试点研究，以治疗或预防镰状肾病与氯沙坦，一种药物，已确定通过我们的基本调查镰状小鼠。初步研究将有助于设计一个强大的确定性临床试验，以测试氯沙坦在镰状肾病的治疗效益。

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. PUBLIC HEALTH RELEVANCE: The kidney is affected as early as infancy and is damaged progressively with increasing age in patients with sickle cell anemia, with nearly 40-50% of adults suffering from kidney damage (sickle nephropathy), that eventually results in end stage renal disease. Currently, there are no established therapies for preventing or reducing sickle nephropathy. With this R34 grant proposal, we plan to study the course of sickle nephropathy and perform pilot studies to treat or prevent sickle nephropathy with losartan, a drug that has been identified through our basic investigations in sickle mice. The pilot studies will help design a robust definitive clinical trial to test the therapeutic benefit of losartan in sickle nephropathy.