Towards Measures of Lupus Nephritis Activity & Damage for Children

描述（由申请人提供）：虽然儿童期发病的系统性红斑狼疮（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，高达80%的儿童有肾脏受累，即狼疮肾炎（LN）。国际肾脏病与肾脏病理学会（ISN/RPS） LN分类是为了提高肾脏组织学对SLE成人患者的预测有效性而制定的。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”，但鉴于其侵入性和成本，评估LN的病程是不切实际的。事实上，在如何区分可接受抗炎治疗的LN活性与不可逆转的纤维化和硬化性肾损伤方面，科学知识存在一个重要的空白。该应用程序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损害测量。需要验证的中心假设是：1)目前的LN测量方法缺乏有效评估LN病程的敏感性和特异性；2)LN指标包括新型肾脏生物标志物（RBM），即中性粒细胞明胶酶相关的脂连蛋白、转铁蛋白、铜蓝蛋白、铝酸糖蛋白、趋化因子配体2、脂联素、肝磷脂、肝型脂肪酸结合蛋白和脂连蛋白样前列腺素- d合成酶；可以无创、准确地评估LN活动和损伤。我们将使用来自CARRA狼疮注册中心的154名患者的样本和纵向临床数据，并在肾活检时额外招募50名cSLE患者来检验中心假设，并通过追求以下具体目标来实现本应用的目标：目的#1a：评估当前cSLE LN活性测量的结构和区别有效性。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。目标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，这项研究将对当前的LN指数进行彻底的验证，确认其反映LN活动和损害的次优能力。我们期望开发更准确的LN指数，即C-RAI和C-LID，并进行初步验证程序。C-RAI和C-LID将提供便利

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.