Towards Measures of Lupus Nephritis Activity & Damage for Children

描述（由申请人提供）：虽然儿童期发作的系统性红斑狼疮（cSLE）与成人SLE的疾病表现相似，但儿童往往有更严重的多器官受累，其中高达80%的患者有肾脏受累，即狼疮性肾炎（LN）。国际肾脏病学会和肾脏病理学会（ISN/RPS）LN分类旨在提高肾脏组织学的预测有效性，重点关注成人SLE患者。ISN/RPS分类报告了LN严重程度、炎症活性和不可逆LN损伤的组织学特征。尽管肾活检仍然是诊断LN的“金标准”，但考虑到其侵入性和成本，肾活检评估LN的病程是不切实际的。事实上，在如何区分LN活性的科学知识中存在着一个重要的差距，这是从不可逆的纤维化和硬化性肾损伤，不适合于肾移植治疗。本申请的目的是为临床医生和研究人员提供准确有效的LN活性和cSLE损伤测量。待测试的中心假设是1）当前LN测量的灵敏度和特异性不足以有效评估LN的过程，以及2）LN指数，其包括新的肾生物标志物（RBM），即中性粒细胞明胶酶相关脂质运载蛋白、转铁蛋白、血浆铜蓝蛋白、α 1-酸性糖蛋白、趋化因子配体2、脂联素、铁调素、肝型脂肪酸结合蛋白，和脂质运载蛋白样胰蛋白酶-D合成酶，可以无创和准确地评估LN活性和损害与cSLE。我们将使用来自参与CARRA狼疮登记研究的154例患者的库存样本和纵向临床数据，并在肾活检时招募50例额外的cSLE患者，以检验中心假设，并通过追求以下特定目标来实现本申请的目标：目标#1a：评估cSLE中LN活性的当前测量的结构和判别有效性。目的#1b：开发并初步验证儿童肾活动指数（C-RAI），以无创监测LN活动。目的#2：开发并初步验证儿童狼疮肾炎损伤指数（C-LID）。我们的期望是，这项研究将提供一个彻底的验证目前LN指数，确认他们的次优能力，以反映LN的活动和损害。我们期望开发更准确的LN指标，即C-RAI和C-LID，并进行初步验证程序。C-RAI和C-LID将促进 相关性（参见说明）：终末期肾病（ESRD）是LN的后遗症，由于临床工具不足以监测其病程，因此诊断太迟且管理不当。我们的研究将对美国公共卫生产生重大影响，因为LN是ESRD的第三大常见原因，其治疗费用每年为2.4亿美元。高质量的临床指标将提高临床医生诊断LN活动和预测其病程的准确性，使他们能够迅速实施适当的治疗方案。这可能有助于减少肾损伤，减少ESRD的频率，并降低肾脏替代治疗的成本。

DESCRIPTION (provided by applicant): Although childhood-onset Systemic Lupus Erythematosus (cSLE) has similar disease manifestations as SLE in adults, children often have more severe multi-organ involvement, and up to 80% of them have kidney involvement, i.e. lupus nephritis (LN). The International Societies for Nephrology & Renal Pathology (ISN/RPS) Classification of LN was developed to improve predictive validity of kidney histology with focus on adults with SLE. The ISN/RPS Classification reports on histological features of LN severity, inflammatory activity and irreversible LN -damage. Despite remaining the "gold standard" for diagnosing LN, kidney biopsies are impractical to assess the course of LN given their invasiveness and cost. Indeed, there is an important gap in the scientific knowledge of how to discriminate LN activity that is amenable to antiinflammatory therapy from irreversible fibrotic and sclerotic kidney damage that is not. The objective of this application is to make accurate validated measures of LN activity and damage for cSLE available to clinicians and researchers. The central hypotheses to be tested are 1) that current LN measures have insufficient sensitivity and specificity to effectively assess the course of LN and that 2) LN indices which include novel renal biomarkers (RBM), i.e. neutrophil gelatinase associated lipocalin, transferrin, ceruloplasmin, al-acid glycoprotein, chemokine ligand 2, adiponectin, hepcidin, liver-type fatty acid binding protein, and lipocalin-like prostaglandin-D synthetase, can noninvasively and accurately assess LN activity and damage with cSLE. We will use banked samples, longitudinal clinical data from 154 patients participating in the CARRA Lupus Registry and enroll 50 additional cSLE patients at the time of kidney biopsy to test the central hypotheses and achieve the objectives of this application by pursuing the following specific aims: Aim #1a: To assess the construct and discriminant validity of current measures of LN activity in cSLE. Aim #1b: To develop and initially validate for Children a Renal Activity Index (C-RAI) to non-invasively monitor LN activity. Aim #2: To develop and initially validate for Children a Lupus Nephritis Index for Damage (C-LID). Our expectations are that this study will provide a thorough validation of current LN indices, confirming their suboptimal ability to reflect the LN activity & damage. We anticipate developing more accurate LN indices, i.e. the C-RAI and the C-LID, and carry out initial validation procedures. The C-RAI and C-LID will facilitate RELEVANCE (See instructions): End-stage renal disease (ESRD) is the sequelae of LN that is diagnosed too late and managed inadequately due to insufficient clinical tools to monitor Its course. Our research is poised to have a maior impact on the U.S. public health, because LN constitutes the 3rd most common cause of ESRD and its therapy costs $240 million annually. High-quality clinical indices will increase the accuracy by which clinicians can diagnose LN activity and predict its course, enabling them to implement appropriate therapeutic regimens eady. This will likely help reduce kidney damage, diminish the frequency of ESRD, and lower the cost of renal replacement therapy.