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: 8792215
• 负责人: Laurence H Beck
• 金额: $ 34.92万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792215
• 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 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; 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; 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（由申请人提供）：特发性膜性肾病（IMN）是肾脏的自身免疫性疾病，是成人肾病综合征的常见原因。除了体重增加，肿胀和这种疾病伴随血凝块的风险外，大部分患者还将逐渐逐渐丧失肾脏功能，需要透析或移植。 IMN的治疗通常需要有毒免疫抑制剂，这本身会引起健康问题和严重感染的风险。由于不完全了解哪些患者会自行从这种疾病中缓解，以及谁将发展为终末期肾脏疾病，因此谁，何时以及治疗多长时间难以回答的问题很难回答。 我们的大多数IMN患者的靶向肾脏蛋白磷脂酶A2受体（PLA2R）的循环抗体实验室的最新鉴定不仅允许基于这些自身抗体的IMN重新定义，而且还可以通过哪些人来监测这些疾病的潜在机制，并且经常指导这些疾病的可能性。该提案概述了我们使用150名IMN患者的样品和数据集的计划，以便加入Neptune（肾病综合征研究网络），以更好地表征IMN新认识的亚组。 AIM 1将根据血液中的抗PLA2R抗体的存在或PLA2R抗原存在于本研究中已收集的活检组织中的免疫沉积中，将150名IMN患者中的每一个分为两个亚组。这将使队列分为抗Pla2R相关或抗Pla2R阴性疾病。我们将使用基线人口统计学和临床​​数据的广泛的海王星数据集以及这些患者活检中看到的精确特征，以找到区分IMN这两个亚型的特征。此目标的第二部分将随着时间的流逝检查抗Pla2r水平，并使用此信息遵循免疫疾病活动，从而定义“免疫缓解”。我们将使用此目的中的数据来验证我们的假设，即免疫活动反映了水平 抗Pla2R的抗临床反应之前发生，通常可以更好地衡量疾病活性。目标2和3将利用IMN患者的海王星队列可用的强大基因转录数据集。 AIM 2试图在活检组织中定义与PLA2R相关的转录网络，以便更好地了解IMN中疾病的分子机制。 AIM 3旨在使用从循环血细胞和基线肾脏活检组织中收集的基因表达数据集，以确定可以在功能上定义和预测免疫学缓解的基因表达谱。总体而言，该项目将生成（1）定义并充分表征抗Pla2R相关的IMN的数据，（2）确定免疫学缓解及其与临床缓解的关系的定义，（3）定义描述性和预测性基因途径，这将极大地影响我们对我们对象征肾病的未来理解。