Noninvasive Biomarker Detection of Early Kidney Disease in Patients with Insulin Resistance

项目摘要 当今世界上有超过4.2亿人患有2型糖尿病（T2 DM），约165 200万人同时患有慢性肾病（CKD）。慢性肾脏病的患病率在那些患有慢性肾脏病的人中高达5倍。 T2 DM-事实上，>50%的T2 DM患者在其一生中会发展为CKD。存在共病CKD， 糖尿病使平均预期寿命缩短约16年，并导致每年约2500亿美元的医疗保健费用。 年死亡率、损害生命的合并症（如心血管疾病）的表现以及总体 随着T2 DM中CKD严重程度的进展，医疗保健支出都大大增加。存在显著 在糖尿病病程早期识别CKD的临床需求未得到满足。早期诊断的影响（和主动 CKD管理的实施）在胰岛素抵抗的开始阶段已经被公认为 许多国际社会，然而，没有早期诊断测试存在。糖尿病前期， 2型糖尿病目前影响着大约8800万美国成年人，近90%的人不知道自己的病情， 这表明其中许多患者的病情进展顺利。虽然治疗干预是已知的， 对每一位前驱糖尿病患者进行积极的医学治疗是不切实际的，因为大多数患者的急性糖尿病风险较低， 发展为T2 DM或肾病。最近的研究结果表明，迄今未分类的病理生理 这一过程导致糖尿病前期快速进展为T2 DM，以及晚期CKD的早期发展。 然而，目前还没有机制来预测或分层这种“高风险”亚群， 糖尿病前期（将受益于早期实施有针对性的药物治疗）。AMDX PROGNOSTX将 生产一种新的ELISA检测，表明存在一个正在进行的，亚临床病理过程 加速T2 DM相关合并症和不可逆CKD的快速发展， 早在糖尿病前期就有胰岛素抵抗。我们的测试是基于使用一种新的生物标志物 这反映了CKD进展的病理生理学中的关键事件， T2 DM人群。初步结果表明，这种生物标志物水平升高的患者， 已经患有或迅速发展为CKD，并且具有特别高的死亡率。在第一阶段提案中，我们 将进一步开发和测试我们的原型单克隆抗体为基础的测定纵向人类样本，以评估其 区分两个群体的能力：i）在治疗后容易发展为CKD和T2 DM的糖尿病前期患者， 他们的诊断开始，和ii）从未发展任何形式的CKD和/或T2 DM的前驱糖尿病患者。 这项测试的结果将为医生提供一个新的视角，重新定义糖尿病领域， CKD管理，并通过促进早期医疗， 治疗，将减缓，并可能防止，进展到晚期CKD。我们请求第一阶段的支持， 测试我们的项目的可行性，并优化测试，这将有助于医生在识别这些高风险患者， CKD的早期阶段。最终，我们打算获得FDA批准和CMS覆盖/报销。

PROJECT SUMMARY There are over 420 million people living with type 2 diabetes mellitus (T2DM) in the world today and about 165 million also have chronic kidney disease (CKD). The prevalence of CKD is up to 5-fold higher in those with T2DM – in fact, >50% of all T2DM patients will develop CKD in their lifetime. The presence of comorbid CKD in diabetes shortens average life expectancy by ~16-years, and results in ~$250 billion/yr in healthcare costs. Annual mortality rates, manifestation of life-impairing comorbidities like cardiovascular disease, and overall healthcare spending are all greatly increased as CKD severity progresses in T2DM. There is a significant unmet clinical need to identify CKD early in the course of diabetes. Impact of early diagnosis (and proactive implementation of CKD management) in the beginning stages of insulin resistance has been recognized by multiple international societies, yet, no early diagnostic test exists. Prediabetes, the precursor condition to T2DM, currently affects an estimated 88 million U.S. adults, and nearly 90% are unaware of their condition, suggesting that many of these patients are uninhibitedly progressing. While therapeutic intervention is known, proactive medical treatment for every prediabetic patient is impractical since most are low-risk for acutely developing T2DM or kidney disease. Recent findings suggest that a hitherto unclassified pathophysiological process results in rapid progression of prediabetes to T2DM, as well as early development of late-stage CKD. Yet, there is currently no mechanism in place to predict or stratify this “high-risk” subpopulation within prediabetes (that would benefit from early implementation of targeted medical therapy). AMDX PROGNOSTX will produce a new ELISA test that indicates the presence of an ongoing, subclinical pathological process that accelerates T2DM-associated comorbidities and rapid development of irreversible CKD in those with insulin resistance as early as the prediabetic stage. Our test is based on the use of a novel biomarker that reflects critical events in the pathophysiology of CKD progression within this specific prediabetic/early T2DM population. Preliminary results demonstrate that patients with elevated levels of this biomarker either already have, or rapidly develop CKD, and have a particularly high mortality rate. In this Phase I proposal, we will further develop and test our prototype mAb-based assay on longitudinal human samples to evaluate its ability to discern between two populations: i) prediabetic patients who readily developed CKD and T2DM after the onset of their diagnosis, and ii) prediabetic patients who never develop any form of CKD and/or T2DM. Results of this test will offer physicians a new dimension of insight that will redefine the field of diabetes and CKD management and offer advancements in the clinical decision-making process by prompting early medical treatment that will slow, and possibly prevent, progression to late-stage CKD. We request Phase I support to test feasibility of our project and optimize a test that will aid physicians in identifying these high-risk patients in the earliest stages of CKD. Ultimately, we intend to obtain FDA-approval and CMS coverage/reimbursement.