Redefining membranous nephropathy by autoantibody-specific subclassification

通过自身抗体特异性亚分类重新定义膜性肾病

• 批准号: 8422158
• 负责人: Laurence H Beck
• 金额: $ 34.9万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-22 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422158
• 关键词: Achievement; Adult; Adverse effects; Affect; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Autoantibodies; Autoimmune Diseases; Binding; Biological Assay; Biopsy; Blood; Blood Cells; Blood Circulation; Blood Clot; Blood coagulation; Characteristics; Clinical; Clinical Data; Data; Data Set; Deposition; Diagnosis; Dialysis procedure; Disease; Disease remission; End stage renal failure; Enrollment; Enzyme-Linked Immunosorbent Assay; Fc Receptor; Focal Segmental Glomerulosclerosis; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Health; Idiopathic Membranous Nephropathy; Immune; Immune System Diseases; Immunohistochemistry; Immunologic Monitoring; Immunosuppressive Agents; Individual; Infection; Intention; Kidney; Knowledge; Laboratories; Lead; Leukocytes; Life; Measures; Membranous Glomerulonephritis; Modality; Molecular; Molecular Profiling; Molecular Target; Monitor; Morbidity - disease rate; Nephrotic Syndrome; Organ; Outcome; Pathway interactions; Patients; Phospholipase A2; Population; Principal Investigator; Proteins; Proteinuria; Reliance; Renal function; Risk; Sampling; Serological; Serum; Slide; Staining method; Stains; Subgroup; Swelling; System; Testing; Time; Tissues; Transplantation; Weight Gain; arm; base; clinical phenotype; clinical remission; cohort; common treatment; design; disorder subtype; improved; novel; outcome forecast; peripheral blood; programs; public health relevance; receptor; response; time use

DESCRIPTION (provided by applicant): Idiopathic membranous nephropathy (IMN) is an autoimmune disease of the kidney and a common cause of the nephrotic syndrome in adults. In addition to the weight gain, swelling, and risk of blood clots that accompany this disease, a substantial fraction of patients will develop progressive loss of kidney function and require dialysis or transplantation. Treatment for IMN often requires toxic immunosuppressive agents, which themselves cause health problems and risk of serious infection. The questions of who, when, and how long to treat have been difficult to answer due to an incomplete understanding of which patients will undergo remission from this disease on their own and who will progress to end-stage kidney disease. The recent identification by our laboratory of circulating antibodies that target a kidney protein, the phospholipase A2 receptor (PLA2R), in the majority of patients with IMN has not only allowed a redefinition of IMN based on these autoantibodies, but has also provided a potential mechanism by which to monitor the immunologic activity of the disease and guide these often-difficult treatment decisions. This proposal outlines our plans to use samples and data sets from the 150 patients with IMN to be enrolled in NEPTUNE (Nephrotic Syndrome Study Network) to better characterize the newly-recognized subgroups of IMN. Aim 1 will classify each of the 150 IMN patients into two subgroups based on the presence of anti-PLA2R antibodies in the bloodstream or the presence of the PLA2R antigen within immune deposits of biopsy tissue already collected for this study. This will stratify the cohort into anti-PLA2R-associated or anti-PLA2R-negative disease. We will use the extensive NEPTUNE data sets of baseline demographic and clinical data, as well as the precise features seen in the biopsies of these patients, to find features that distinguish these two subtypes of IMN. A second portion of this aim will examine anti-PLA2R levels over time and use this information to follow immunological disease activity and thereby define 'immunological remission.' We will use the data from this aim to validate our hypothesis that immunological activity as reflected by the level of anti-PLA2R occurs prior to the clinical response, and may be a better measure of disease activity in general. Aims 2 and 3 will harness the powerful gene transcription data sets available from the NEPTUNE cohort of IMN patients. Aim 2 seeks to define anti-PLA2R-associated transcriptional networks in biopsy tissue in order to better understand molecular mechanisms of disease in IMN. Aim 3 is designed to identify gene expression profiles that can functionally define and predict immunological remission, using gene expression data sets collected from circulating blood cells as well as the baseline kidney biopsy tissue. In aggregate, this project wil generate data that (1) defines and fully characterizes anti-PLA2R-associated IMN, (2) establishes the definition of immunological remission and its relationship to clinical remission, and (3) defines descriptive and predictive gene pathways that will greatly impact our future understanding of membranous nephropathy.

描述（申请人提供）：特发性膜性肾病（IMN）是一种肾脏自身免疫性疾病，是成人肾病综合征的常见原因。除了伴随这种疾病的体重增加，肿胀和血栓风险外，相当一部分患者将发展为肾功能进行性丧失，需要透析或移植。IMN的治疗通常需要有毒的免疫抑制剂，这本身会导致健康问题和严重感染的风险。由于不完全了解哪些患者将自行缓解这种疾病以及谁将进展为终末期肾病，因此很难回答谁、何时以及治疗多长时间的问题。 我们的实验室最近鉴定了大多数IMN患者中靶向肾脏蛋白磷脂酶A2受体（PLA 2 R）的循环抗体，不仅允许基于这些自身抗体重新定义IMN，而且还提供了一种潜在的机制，通过该机制监测疾病的免疫活性并指导这些通常困难的治疗决策。该提案概述了我们计划使用来自NEPTUNE（肾病综合征研究网络）招募的150名IMN患者的样本和数据集，以更好地表征新认识的IMN亚组。 目的1将根据血流中抗PLA 2 R抗体的存在或本研究已经收集的活检组织免疫沉积物中PLA 2 R抗原的存在将150名IMN患者分为两个亚组。这将队列分层为抗PLA 2 R相关或抗PLA 2 R阴性疾病。我们将使用广泛的NEPTUNE基线人口统计学和临床数据数据集，以及这些患者活检中观察到的精确特征，以找到区分IMN这两种亚型的特征。该目标的第二部分将检查随时间推移的抗PLA 2 R水平，并使用该信息来跟踪免疫疾病活性，从而定义“免疫缓解”。“我们将利用这一目标的数据来验证我们的假设，即免疫活性反映在水平上， 抗-PLA 2 R的检测发生在临床反应之前，并且通常可以是疾病活动的更好测量。目标2和3将利用来自NEPTUNE IMN患者队列的强大基因转录数据集。目的2旨在确定活检组织中抗PLA 2 R相关的转录网络，以便更好地了解IMN疾病的分子机制。目的3是使用从循环血细胞以及基线肾活检组织收集的基因表达数据集，鉴定可以功能性地定义和预测免疫缓解的基因表达谱。总的来说，该项目将产生以下数据：（1）定义并充分表征抗PLA 2 R相关的IMN，（2）建立免疫缓解的定义及其与临床缓解的关系，（3）定义描述性和预测性基因通路，这将极大地影响我们对膜性肾病的未来理解。