Ameliorating Sickle Nephropathy and Pulmonary Hypertension

改善镰状肾病和肺动脉高压

• 批准号: 8514056
• 负责人: Punam Malik
• 金额: $ 19.43万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514056
• 关键词: Adult; Affect; Age; Age-Years; Albuminuria; Antibodies; Applications Grants; Biological Markers; Blood; Blood Tests; Cardiac Catheterization Procedures; Child; Childhood; Chronic Kidney Failure; Clinic; Clinic Visits; Clinical Protocols; Clinical Trials; Consent; Cross-Sectional Studies; Data; Defect; Development; Dose; End stage renal failure; Ensure; Environment; Focal Segmental Glomerulosclerosis; Funding; Generations; Glomerular Filtration Rate; Grant; Hematuria; Hospitals; Human; Hypoxia; Infant; Injury; Institutional Review Boards; Investigation; Kidney; Kidney Diseases; Kidney Failure; Kidney Glomerulus; Laboratories; Losartan; Lung; Manuals; Measures; Medical center; Microscopic; Molecular; Molecular Analysis; Monitor; Mus; Myocardial; Nephrons; Observational Study; Ohio; Pamphlets; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Physiologic intraventricular pressure; Pilot Projects; Potassium; Pulmonary Hypertension; Randomized Controlled Trials; Receptor, Angiotensin, Type 1; Recruitment Activity; Rectum; Research; Research Infrastructure; Research Personnel; Sample Size; Secondary to; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Site; Staging; Testing; Therapeutic; Time; Training; Translating; Tubular formation; Universities; University Hospitals; Urine; Ventricular; Walking; animal data; base; clinical research site; data management; design; infancy; interstitial; longitudinal analysis; next generation; novel; older patient; operation; phase 3 study; pressure; prevent; randomized trial; response; screening; sickling; statistics

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.

描述（由申请人提供）：肾脏细胞贫血（SCA）以几种不同的方式影响肾脏。儿童，甚至患有SCA的婴儿会出现尿液浓缩缺陷（UCD），肾小球滤过率（GFR）的增加，超近端管状功能和排泄钾的能力受损。还可以看到髓中部微调造成的血尿（总或显微镜）。随着年龄的增长，肾小球病的发展，最初表现为微珠蛋白尿，然后是大蛋白尿症，发展为肾功能衰竭和末期肾脏疾病。肾脏和肾小球肿大，GFR在早期阶段增加。随着时间的流逝，局灶性和节段性肾小球硬化，GFR减少和末期肾脏疾病会发展。镰状肾病（SN）存在于40-50％的成年人中。我们对SN和动物数据的新型生物标志物具有强大的初步数据，该数据支持与Losartan进行介入的试验，以改善镰状细胞病中的UCD，蛋白尿和肺动脉高压。我们建议对SCA患者进行重要的试点研究，以指导Losartan稳健的III期随机对照试验的设计；并组装站点，统计和数据管理中心（SDMC），监管文件，研究监控和数据管理计划，以确保有效执行III期多中心研究。在AIM 1中，我们将进行试点研究，以研究SN的进展以及减少劳萨坦SN的可行性，以收集为SN和pH设计III期随机控制试验所需的关键数据。试点研究将有助于估计应计的患者的可行性，确定资金前两年所需的精致持续时间/剂量以及样本量和应答率。在AIM 2中，我们将在第三年的资金中设计一个多中心的III期随机试验。在AIM 3中，我们将组装基础架构，以进行良好执行的多中心试验。在资助的第三年，我们将根据合格患者确定其他临床部位，并参与SDMC开发临床方案，同意和同意形式，操作手册，研究人员手册，扩展IND并为IRB提交的文档，建立DSMB，DSMB，数据管理，数据管理和研究员工的研究计划和培训材料。我们聚集了四个参与的地点：两个成人和两个儿科现场进行试点研究：辛辛那提儿童医院医学中心，辛辛那提大学辛辛那提大学大学医院和全国儿童医院以及俄亥俄州哥伦布俄亥俄州俄亥俄州俄亥俄州俄亥俄州立大学医院。这些站点还将参与III期研究，同时根据需要根据该计划赠款获得的试点数据来确定和招募其他站点。以上目的是该计划赠款中的一种重点方法，以获取对强大的III期试验设计至关重要的数据，申请RO1资金并积累了执行精心设计的III期研究所需的基础设施，并有效地将实验室中的研究发现转化为临床上的研究发现，以影响有效的治疗方法，以对镰状肾上腺细胞影响有效的治疗方法。

项目成果

Angiotensin receptor signaling in sickle cell anemia has a reno-protective effect on urine concentrating ability but results in sickle glomerulopathy.

• DOI: 10.1002/ajh.25118
• 发表时间: 2018-07
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Roy S;Rai P;Eiymo Mwa Mpollo MS;Chang KH;Rizvi T;Shanmukhappa SK;VandenHeuvel K;Aronow B;Inagami T;Cancelas JA;Malik P
• 通讯作者: Malik P

Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial.

氯沙坦治疗镰状细胞性贫血肾病：一项 2 期、多中心试验。

• DOI: 10.1002/ajh.24810
• 发表时间: 2017
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Quinn,CharlesT;Saraf,SantoshL;Gordeuk,VictorR;Fitzhugh,CourtneyD;Creary,SusanE;Bodas,Prasad;George,Alex;Raj,AshokB;Nero,AleciaC;Terrell,CatherineE;McCord,Lisa;Lane,Adam;Ackerman,HansC;Yang,Yu;Niss,Omar;Taylor,Michae
• 通讯作者: Taylor,Michae