Improving Scientific Rigor of Renal Clinical Endpoints for Sickle Cell Anemia

提高镰状细胞性贫血肾脏临床终点的科学严谨性

• 批准号: 10029190
• 负责人: Jeffrey D Lebensburger
• 金额: $ 75.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10029190
• 关键词: Address; Adult; African American; Albuminuria; Biological; Blood; Blood specimen; Caring; Cessation of life; Child; Childhood; Chronic Kidney Failure; Clinic; Clinical; Clinical Research; Clinical Trials; Consumption; Cost Measures; Creatinine; Cystatins; Data; Development; Dialysis procedure; Disease; Disease Progression; End stage renal failure; Ensure; Equation; Exhibits; Filtration; Future; Glomerular Filtration Rate; Goals; Gold; Hematological Disease; Hemoglobin; High Prevalence; Hour; Individual; Injections; Iohexol; Kidney; Kidney Diseases; Kinetics; Life; Logistics; Measurement; Measures; Methods; Monitor; Morbidity - disease rate; Outcome; Participant; Patients; Pediatric cohort; Renal function; Reproducibility; Research; Reticulocyte count; Risk; Sampling; Sickle Cell Anemia; Systematic Bias; Testing; Therapeutic Clinical Trial; Therapeutic Trials; Time; Training; United States National Institutes of Health; Validation; Work; clinical care; clinically relevant; cohort; design; experience; fluorescence imaging; high risk; high standard; improved; mortality; multidisciplinary; novel; novel strategies; novel therapeutics; post gamma-globulins; prevent; prospective; sex; standard measure; validation studies

Project Summary Patients living with sickle cell anemia (SCA) are at high risk for morbidity and mortality associated with renal disease. To improve the clinical outcomes for SCA patients, we must ensure a scientifically rigorous approach to monitoring disease progression. In pediatric SCA, an elevated glomerular filtration rate (hyperfiltration) precedes the development of chronic kidney disease (CKD). Up to 70% of SCA adults will develop CKD and among patients that progress to end-stage renal disease (ESRD) and require dialysis, one quarter of patients die within the first year of starting dialysis. The evidence is clear that we must accurately identify SCA patients at risk for ESRD and early death so that clinicians can intervene prior to the development of ESRD. The gold standard method for monitoring SCA kidney disease progression, measured glomerular filtration rate (mGFR) is too time consuming for annual clinical care monitoring as it requires injection of a filtration marker (iohexol) and measuring blood clearance of this marker over at least six hours. Our research team validated a novel, time-efficient mGFR approach in non-SCA patients by injecting visible fluorescent imaging (VFI) and measuring blood clearance over three hours. Estimated glomerular filtration rate (eGFR) equations provide an alternative approach to monitoring a patient's kidney function using a single blood sample measurement (cystatin and/or creatinine). eGFR has been validated in non-SCA patients with high accuracy and precision. However, our preliminary data and work of others clearly demonstrate that the eGFR equations are not valid in SCA. The difference between eGFR and mGFR is seven times higher and the standard deviation is three times higher in SCA studies as compared to the non-SCA validation studies. By including SCA-relevant variables (hemoglobin and reticulocyte count) to the standard GFR variables, the preliminary data shows an improvement in the precision of novel SCA-specific eGFR equations by 25%. This proposal addresses the critical barriers for future SCA research due to the systematic bias in monitoring renal disease progression in SCA patients. Using the gold standard iohexol mGFR, this proposal will use biologically plausible SCA-relevant variables to develop novel SCA-specific eGFR equations in children and adults and compare the precision and accuracy of these equations against standard eGFR equations (aim 1). To validate these equations for use in annual clinical monitoring and design of future clinical trials, we will measure the concordance (one year) between the novel and standard eGFR equations to mGFR (aim 2). Finally, as mGFR (iohexol) is not time-efficient for monitoring SCA patients in clinic, we will test the correlation of VFI mGFR performed over 3 hours to iohexol mGFR performed over 6 hours (aim 3). If successful, our work will improve the systematic bias of clinical research using GFR endpoints in SCA. This will improve our clinical capacity to identify SCA patients at risk for CKD who may benefit from additional prospective therapies. Our improved methods for eGFR may be applicable to other hematological disorders where CKD is common.

项目概要 镰状细胞性贫血 (SCA) 患者与肾病相关的发病和死亡风险较高 疾病。为了改善 SCA 患者的临床结果，我们必须确保采用科学严谨的方法 监测疾病进展。在儿童 SCA 中，肾小球滤过率升高（超滤） 先于慢性肾脏病（CKD）的发展。高达 70% 的 SCA 成年人会发展为 CKD， 在进展为终末期肾病 (ESRD) 并需要透析的患者中，四分之一的患者 在开始透析后的第一年内死亡。证据明确表明我们必须准确识别 SCA 患者 处于终末期肾病 (ESRD) 和过早死亡的风险中，以便临床医生可以在发生终末期肾病 (ESRD) 之前进行干预。 监测 SCA 肾脏疾病进展的金标准方法，测量肾小球滤过率 (mGFR) 对于年度临床护理监测来说太耗时，因为它需要注射过滤标记物 （碘海醇）并在至少六个小时内测量该标记物的血液清除率。我们的研究团队验证了 通过注射可见荧光成像 (VFI) 和 测量三个小时内的血液清除率。估计肾小球滤过率 (eGFR) 方程提供了 使用单一血液样本测量来监测患者肾功能的替代方法（胱抑素 和/或肌酐）。 eGFR 已在非 SCA 患者中得到验证，具有较高的准确度和精确度。然而， 我们的初步数据和其他人的工作清楚地表明 eGFR 方程在 SCA 中无效。这 eGFR 和 mGFR 之间的差异高出七倍，标准差高出三倍 SCA 研究与非 SCA 验证研究的比较。通过包含 SCA 相关变量（血红蛋白 和网织红细胞计数）到标准 GFR 变量，初步数据显示， 新颖的 SCA 特定 eGFR 方程的精度提高了 25%。 该提案解决了由于监测中的系统偏差而导致未来 SCA 研究的关键障碍 SCA 患者的肾脏疾病进展。使用黄金标准碘海醇 mGFR，本提案将使用 生物学上合理的 SCA 相关变量，用于开发儿童和儿童中新的 SCA 特异性 eGFR 方程 并将这些方程与标准 eGFR 方程的精度和准确度进行比较（目标 1）。 为了验证这些方程用于年度临床监测和未来临床试验的设计，我们将 测量新颖和标准 eGFR 方程与 mGFR 之间的一致性（一年）（目标 2）。最后， 由于mGFR（碘海醇）在临床监测SCA患者时效率不高，我们将测试VFI的相关性 mGFR 执行时间超过 3 小时，碘海醇 mGFR 执行时间超过 6 小时（目标 3）。如果成功的话，我们的工作将 使用 SCA 中的 GFR 终点改善临床研究的系统偏倚。这将改善我们的临床 识别有 CKD 风险的 SCA 患者的能力，这些患者可能会受益于额外的前瞻性治疗。我们的 eGFR 的改进方法可能适用于 CKD 常见的其他血液疾病。