Rituximab Treatment of Focal Segmental Glomerulosclerosis

摘要 局灶节段性肾小球硬化(FSGS)的治疗主要是经验性的，通常 不足，导致死亡，通常进展为肾功能衰竭和透析。 FSGS通常在移植后迅速复发。循环渗透系数(Pf) 一直被怀疑是某些形式的FSGS发病机制的核心，但其 身份一直很难辨别。皮质类固醇是治疗癌症的一线药物 FSGS，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 尝试了不同的效果。这些药物的疗效表明，一些病例 FSGS具有自身免疫成分。用嵌合体利妥昔单抗治疗 针对人CD20抗原的鼠/人单抗 在B细胞上的表达导致B细胞的快速可逆消除，这种耗竭 持续6至12个月。我们治疗了一位儿童肾移植患者，他有 用利妥昔单抗治疗移植后淋巴瘤，FSGS迅速复发。 在此治疗后，FSGS相关蛋白尿消失，患者 PTLD和FSGS在一年内仍处于缓解状态。我们的案例和几个类似的案例 最近文献中报道的案例导致了我们的新假设，即至少有一些 FSGS病例有B细胞自身免疫成分作为疾病的一部分 病理生理学。 我们将在两个具体目标的背景下测试这一假设： 目标1.进行试点试验，以确定其初步疗效、安全性和耐受性 利妥昔单抗治疗激素耐药的FSGS 目的2.比较所选的药代动力学/药效学方法 那些对利妥昔单抗治疗无效的受试者。 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和 利妥昔单抗、成人和儿童肾病学家，在FSGS方面有专门知识，由 已经形成了经验丰富的实验室人员和临床研究协调员。如果 这项试点试验的成功将为FSGS的病理生理学提供新的见解 并为对这种反应迟缓的疾病进行大规模临床试验奠定了基础。

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.