Rituximab Treatment of Focal Segmental Glomerulosclerosis

摘要 局灶节段性肾小球硬化症（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。循环渗透系数（PF） 已经被怀疑是某些形式的FSGS发病机制的中心，但其 身份很难辨别。皮质类固醇是治疗 FSGS和其他免疫抑制药物，包括环孢霉素，环磷酰胺， 血浆置换、蛋白A免疫吸附和霉酚酸酯已被 尝试了不同的功效。这些药物的疗效表明， FSGS具有自身免疫成分。用利妥昔单抗治疗， 抗人CD 20抗原的鼠/人单克隆抗体 在B细胞上表达导致B细胞的快速可逆消除， 持续6至12个月。我们治疗了一名儿童肾移植患者， 开发了快速复发的FSGS，与利妥昔单抗移植后淋巴瘤。 治疗后，FSGS相关蛋白尿消退，患者 PTLD和FSGS在1年时仍处于缓解状态。我们的案件和几个类似的案件 最近在文献中报道的病例导致我们的新假设，至少一些 FSGS病例中，B细胞自身免疫成分是疾病的一部分 病理生理学 我们将在两个具体目标的背景下检验这一假设： 目标1.进行一项初步试验，以确定初步疗效、安全性和耐受性， 利妥昔单抗治疗类固醇耐药的FSGS。 目标2.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。 一个研究小组，由一名具有免疫学专业知识的移植外科医生组成， 利妥昔单抗，具有FSGS专业知识的成人和儿童肾病学家， 经验丰富的实验室人员和临床研究协调员。如果 成功的，这个试点试验将提供新的见解FSGS的病理生理学 并为在这种反应不良的疾病中进行大型临床试验奠定基础。

Abstract 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.