Rituximab Treatment of Focal Segmental Glomerulosclerosis

描述（由申请方提供）：局灶节段性肾小球硬化（FSGS）的治疗主要是经验性的，通常不充分，导致濒死，通常进展为肾衰竭和透析。FSGS经常在移植后迅速复发。循环渗透因子（PF）被怀疑是某些形式FSGS发病机制的核心，但其身份一直难以辨别。皮质类固醇是FSGS的一线治疗，但其他免疫抑制药物，包括环孢素，环磷酰胺，血浆置换，蛋白A免疫吸收，和霉酚酸酯已被尝试与可变的疗效。这些药物的疗效表明，FSGS的一些情况下有自身免疫性成分。利妥昔单抗（一种针对B细胞上表达的人CD 20抗原的嵌合小鼠/人单克隆抗体）治疗可导致B细胞快速可逆消除，这种消除持续6至12个月。我们已经治疗了一个儿童肾移植患者，谁开发了快速复发的FSGS，与利妥昔单抗移植后淋巴瘤。在这种治疗后，FSGS相关的蛋白尿消退，患者在1年时PTLD和FSGS均保持缓解。我们的情况下，最近在文献中报道的几个类似的情况下，导致我们的新的假设，至少有一些情况下FSGS有一个B细胞自身免疫性成分的一部分，疾病的病理生理。我们将在两个具体目标的背景下测试这一假设：目标1。开展一项初步试验，以确定利妥昔单抗治疗类固醇耐药FSGS的初步疗效、安全性和耐受性。目标二。比较选择的药代动力学/药效学试验，以区分对利妥昔单抗治疗有反应的受试者和对利妥昔单抗治疗无反应的受试者。已经成立了一个研究小组，由具有免疫学和利妥昔单抗专业知识的移植外科医生、具有FSGS专业知识的成人和儿童肾病学家组成，并由经验丰富的实验室人员和临床研究协调员提供支持。如果成功，这项试点试验将为FSGS的病理生理学提供新的见解，并为这种反应不良疾病的大型临床试验奠定基础。公共卫生相关性：FSGS是肾脏疾病的常见原因，占儿童特发性肾病综合征病例的10-20%和成人病例的35%，通常对当前治疗难治，最终导致肾衰竭。一种可以永久缓解和逆转器官损伤的治疗方法将通过减少这些费用对社会做出重大贡献。这项研究旨在测试抗B细胞药物利妥昔单抗作为治疗的能力。

DESCRIPTION (Provided by applicant): Treatment of focal segmental glomerulosclerosis (FSGS) is primarily empiric, often inadequate, results in moribity that typically progresses to renal failure and dialysis. FSGS frequently recurres rapidly post transplant. A circulating Permeability Factor (PF) has been suspected as central to the pathogenesis of some forms of FSGS but its identity has been difficult to discern. Corticosteroids are the first line of treatment for FSGS but other immunosuppressive drugs including cyclosporine, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and mycophenolate mofetil have been tried with variable efficacy. The efficacy of these drugs suggests that some cases of FSGS have an autoimmune component. Treatment with rituximab, a chimeric mouse/human monoclonal antibody directed against the human CD20 antigen expressed on B-cells results in rapid reversible elimination of B-cells, a depletion that lasts for 6 to 12 months. We have treated a pediatric renal transplant patient, who had developed a rapid recurrence of FSGS, with rituximab for a post transplant lymphoma. Following this treatment, the FSGS-associated proteinuria resolved and the patient remains in remission for both PTLD and FSGS at one year. Our case and several similar cases recently reported in the literature leads to our novel hypothesis that at least some cases of FSGS have a B-cell autoimmune component as part of the disease pathophysiology. We will test this hypothesis within the context of two specific aims: Aim 1. Conduct a pilot trial to determine the preliminary efficacy, safety and tolerability of rituximab in the treatment of steroid resistant FSGS. Aim 2. Compare pharmacokinetic/pharmacodynamic assays selected to distinguish subjects who respond from those who fail to respond to rituximab treatment. A research team, composed of a transplant surgeon with expertise in immunology and rituximab, adult and pediatric nephrologists with expertise in FSGS, supported by experienced laboratory personnel and clinical study coordinators, has been formed. If successful, this pilot trial would provide new insights into the pathophysiology of FSGS and form the basis for a large clinical trial in this poorly responsive disease. PUBLIC HEALTH RELEVANCE: FSGS, a common cause of kidney disease accounting for 10-20% of cases of idiopathic nephrotic syndrome in children and 35% of cases in adults, is typically refractory to current therapy and results eventually in kidney failure. A treatment that could induce permanent remission and reverseorgan damage would make a major contribution to society by reduction of these expenses. This study proposes to test the ability of the anti-B-cell drug rituximab as a treatment.