Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell–targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease.

We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence.

In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies.

Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.

肾小球滤过屏障的失效，主要是由于裂隙隔膜结构的丧失，是微小病变肾病综合征的基础。病因不明。B 细胞靶向治疗在某些患者中的疗效，以及已知的抗肾上腺素抗体在啮齿动物模型中的蛋白尿作用，促使我们假设肾上腺素自身抗体可能存在于微小病变患者中。

我们评估了来自参加肾病综合征研究网络 (NEPTUNE) 队列和我们自己机构的微小病变患者的血清，通过间接 ELISA 和免疫沉淀来自人肾小球提取物或重组纯化的全长肾上腺素的循环肾上腺素自身抗体人 nephrin 的胞外结构域。我们还通过免疫荧光评估了来自我们机构的肾活检，以确定与肾素共定位的足细胞相关点状 IgG。

在两个独立的患者队列中，我们发现在活动性疾病期间循环的 nephrin 自身抗体在微小病变患者的治疗反应期间显着减少或不存在。我们将这些自身抗体的存在与来自我们机构的肾活检组织中的足细胞相关点状 IgG 相关联。我们还确定了一名患有类固醇依赖性儿童期微小病变并进展为终末期肾病的患者；她在移植后出现大量蛋白尿复发，这与高移植前循环 nephrin 自身抗体有关。

我们在一部分患有微小病变的成人和儿童中发现肾上腺素自身抗体与已发表的动物研究相一致，并进一步支持自身免疫病因学。我们提出了一种新的 nephrin 自身抗体微小病变的分子分类，作为对这些患者进行精准治疗的框架。