Improving Scientific Rigor of Renal Clinical Endpoints for Sickle Cell Anemia

项目摘要 镰状细胞性贫血（SCA）患者的肾脏疾病发病率和死亡率高， 疾病为了改善SCA患者的临床结局，我们必须确保采用科学严谨的方法 to monitoring监控disease疾病progression进展.在儿童SCA中，肾小球滤过率升高（超滤） 慢性肾脏病（CKD）的发病机制高达70%的SCA成人将发展为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 在开始透析的第一年内死亡。证据清楚，我们必须准确识别SCA患者 存在ESRD和早期死亡的风险，以便临床医生可以在ESRD发展之前进行干预。 监测SCA肾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，因为它需要注射滤过标记物 （碘海醇）并在至少6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），在非SCA患者中采用一种新的、具有时效性的mGFR方法， 测量三小时内的血液清除率估计肾小球滤过率（eGFR）方程提供了一个 使用单次血液样品测量（半胱氨酸蛋白酶抑制剂）监测患者肾功能的替代方法 和/或肌酸酐）。eGFR已在非SCA患者中得到验证，具有较高的准确度和精密度。然而，在这方面， 我们的初步数据和其他人的工作清楚地表明eGFR方程在SCA中是无效的。的 eGFR和mGFR之间的差异高7倍，标准差高3倍， SCA研究与非SCA验证研究的比较。通过纳入SCA相关变量（血红蛋白 和网织红细胞计数）与标准GFR变量相比，初步数据显示， 新SCA特异性eGFR方程的精确度为25%。 这一建议解决了由于监测中的系统性偏差而导致的未来SCA研究的关键障碍 SCA患者的肾脏疾病进展。使用金标准碘海醇mGFR，本提案将使用 生物学上合理的SCA相关变量，以在儿童中开发新的SCA特异性eGFR方程， 成年人，并比较这些方程与标准eGFR方程的精密度和准确度（目的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 测量新的和标准eGFR方程与mGFR之间的一致性（1年）（目的2）。最后， 由于mGFR（碘海醇）在临床上监测SCA患者的时间效率不高，我们将检验VFI的相关性 在3小时内进行的mGFR与在6小时内进行的碘海醇mGFR相比（目标3）。如果成功，我们的工作将 改善SCA中使用GFR终点的临床研究的系统偏倚。这将改善我们的临床 有能力识别有慢性肾病风险的SCA患者，这些患者可能从其他前瞻性治疗中受益。我们 用于eGFR的改进方法可适用于CKD常见的其它血液学病症。

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.