Renal Molecular Imaging of Mesangial Cell Function with Tc-99m-Tilmanocept

父级拨款摘要 2017年，国际糖尿病联合会估计，全球糖尿病患病率将 从2015年的4.15亿增加到2040年的6.42亿。大约40%的糖尿病患者患上 糖尿病肾病(DN)。其中20%的人没有遵循典型的慢性病道路 肾脏疾病，这是蛋白尿和血肌酐几十年来缓慢增长的疾病，目前的标准是 OF--对慢性肾脏疾病(KD)的监测。因此，临床上对常规治疗的需求尚未得到满足。 慢性KD前十年的监测。 我们建议体外成像肾小球系膜细胞功能作为糖尿病肾病的生物标志物。我们的 推理基于以下几点。系膜细胞基质(MCM)扩张是糖尿病的组织学特征 肾病，患者肾小球滤过率降低或蛋白尿增加的先兆。 此外，糖尿病肾病的所有临床表现与MCM扩张高度相关。 目前尚不存在对系膜细胞敏感的影像、血清或尿液生物标志物 功能。目前的显像剂和生物标志物只对肾小球滤过、有效的肾脏血浆敏感 血流，或蛋白尿，当治疗干预无效时，在疾病晚期改变。 我们建议进行一期临床试验，即在肝脏和肾脏中蓄积的99m-替马诺普。 分子机制是与CD206结合，CD206位于细胞表面的固定巨噬细胞内 肝脏和肾脏内的系膜细胞。我们提供了由人类SPECT/CT和 大鼠肾皮质的microPET图像。此外，我们提出了通过TC-MCM扩展的敏感性的证据。 糖尿病肾病公认的疾病模型db/db小鼠的99m-tilmanocept动态显像。 我们提出了一项开放的研究，以研究两个剂量水平(2.0和20nmoL)的生物分布 TC-99M-替马诺普。我们将在每个剂量下研究5组(每组10名受试者)：1)进展期糖尿病肾病，2)早期糖尿病肾病，3) 糖尿病无肾脏疾病，4)高血压合并KD，5)HTN无KD。这项研究 将包括30分钟的动态肾脏SPECT/CT，以及定期的血液和尿液采样。 动态成像将得出血浆清除半衰期，以及肝和肾的蓄积率；SPECT/CT将 为心脏、肝脏、肾皮质、肾髓质提供SUV。我们还将计算膀胱蓄积量。 我们预计肾图和生物分布数据将反映以下病理：第1组，重症 MCM扩张；G2，轻度MCM扩张；G3&GS，无MCM扩张；G4，低MCM扩张。 这项研究是FDA批准99m-替曼考作为肾脏显像剂的必要的第一步 探员。这项研究还将提供糖尿病肾病患者对MCM扩大的影像敏感性的证据，以及 对HTN患者不敏感。如果将~(99m)Tc-替马诺普肾图作为“一线”，则需要进行此检查。 糖尿病患者的诊断测试。

Parent Grant Summary In 2017 the International Diabetes Federation estimated that the worldwide prevalence of diabetes would increase from 415 million in 2015 to 642 million in 2040. Approximately 40% of individuals with diabetes develop diabetic nephropathy (DN). Twenty percent of these individuals do not follow the typical path toward chronic kidney disease, which is a slow multi-decade increase in albuminuria and serum creatinine, the current standard- of-care for surveillance of chronic kidney disease (KD). Consequently, there is an unmet clinical need for routine surveillance during the first decade of chronic KD. We propose external imaging of mesangial cell function as a biomarker for diabetic nephropathy. Our reasoning is based on the following. Mesangial cell matrix (MCM) expansion is a histologic hallmark of diabetic nephropathy, which precedes the reduction of a patient's glomerular filtration rate or increase in albuminuria. Additionally, all the clinical manifestations of diabetic nephropathy are highly correlated with MCM expansion. There currently does not exist an imaging, serum, or urine biomarker that is sensitive to mesangial cell function. Current imaging agents and biomarkers are only sensitive to glomerular filtration, effective renal plasma flow, or albuminuria, which are altered late in the disease when therapeutic intervention is not effective. We propose a Phase 1 clinical trial of Tc-99m-tilmanocept, which accumulates in the liver and kidneys. The molecular mechanism is binding to CD206, which resides on the cell surface of fixed macrophages within the liver and mesangial cells within the kidney. We present preliminary data consisting of human SPECT/CT and rat microPET images of renal cortex. Additionally, we present evidence of sensitivity to MCM expansion via Tc- 99m-tilmanocept dynamic imaging of db/db mice, an accepted disease model of diabetic nephropathy. We propose an open-label study to investigate the biodistribution at two dose levels (2.0 & 20 nmol) of Tc-99m-tilmanocept. We will study 5 groups at each dose (10 subjects each): 1) Advance DN, 2) early DN, 3) diabetes with no kidney disease, 4) advanced hypertension (HTN) with KD, and 5) HTN without KD. The study will include a 30-min dynamic followed be a 30-min kidney SPECT/CT, and periodic blood and urine sampling. Dynamic imaging will yield plasma clearance half-lifes, and liver and kidney accumulation rates; SPECT/CT will yield SUVs for the heart, liver, renal cortex, renal medulla. We will also calculate urinary bladder accumulation. We expect the renograms and biodistribution data to reflect the following pathology: Group 1, severe MCM expansion; G2, mild MCM expansion; G3 & GS, no MCM expansion; and G4, low MCM expansion. This study is the necessary first step toward FDA-approval of Tc-99m-tilmancoept as a kidney imaging agent. The study will also provide evidence of imaging sensitivity to MCM expansion in DN patients, and insensitivity to patients with HTN. This senerio will be required if Tc-99m-tilmanocept renograms as "first-line" diagnostic test for diabetic patients.