IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy.
Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Piazza OMS 1, 24128, Bergamo, Italy.
Nat Rev Nephrol. 2017 Sep;13(9):563-579. doi: 10.1038/nrneph.2017.92. Epub 2017 Jul 3.
In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLAR) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition. The anti-CD20 monoclonal antibody rituximab is safe and achieves remission of proteinuria in approximately two-thirds of patients with membranous nephropathy. In those with PLAR-related disease, remission can be predicted by anti-PLAR antibody depletion and relapse by antibody re-emergence into the circulation. Thus, integrated evaluation of serology and proteinuria could guide identification of affected patients and treatment with individually tailored protocols. Nonspecific and toxic immunosuppressive regimens will fall out of use. B-cell modulation by rituximab and second-generation anti-CD20 antibodies (or plasma cell-targeted therapy in anti-CD20 resistant forms of disease) will lead to a novel therapeutic paradigm for patients with membranous nephropathy.
在膜性肾病患者中，烷化剂（环磷酰胺或苯丁酸氮芥）单独或联合类固醇治疗比保守治疗或单独使用类固醇更有效地缓解肾病综合征，但会引起骨髓毒性、感染和癌症。钙调磷酸酶抑制剂可改善蛋白尿，但具有肾毒性。大多数患者在停药后复发，并可能成为治疗依赖性，这增加了肾毒性的风险。针对足细胞 M 型磷脂酶 A2 受体（PLAR）和血小板反应蛋白 1 型结构域包含蛋白 7A（THSD7A）抗原的致肾炎自身抗体的发现，为专门针对 B 细胞谱系的干预措施提供了明确的病理生理学依据，以防止抗体产生和上皮下沉积。抗 CD20 单克隆抗体利妥昔单抗安全，并使大约三分之二的膜性肾病患者的蛋白尿缓解。在与 PLAR 相关的疾病中，抗 PLAR 抗体耗竭可预测缓解，抗体重新出现在循环中可预测复发。因此，血清学和蛋白尿的综合评估可以指导确定受影响的患者，并制定个体化的治疗方案。非特异性和有毒的免疫抑制方案将不再使用。利妥昔单抗和第二代抗 CD20 抗体（或针对抗 CD20 耐药形式疾病的浆细胞靶向治疗）对 B 细胞的调节将为膜性肾病患者带来新的治疗范例。
