Wang Pei, Zhang Yan, Wang Yu, Brem Andrew S, Liu Zhangsuo, Gong Rujun
Blood Purification Center, Institute of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Divisions of Kidney Disease and Hypertension, Rhode Island Hospital, and.
Pediatrics. 2017 Jul;140(1). doi: 10.1542/peds.2016-2169.
There is increasing evidence supporting the use of corticotropin as an alternative treatment of refractory proteinuric glomerulopathies. The efficacy of short-acting corticotropin, however, remains unknown and was tested here in an adolescent with steroid-dependent nephrotic syndrome caused by minimal change disease. After developing Cushing syndrome and recently being afflicted with severe cellulitis, the patient was weaned off all immunosuppressants, including corticosteroids. This resulted in a relapse of generalized anasarca, associated with massive proteinuria and hypoalbuminemia. Subsequently, mono-therapy with short-acting animal-derived natural corticotropin was initiated and resulted in a rapid response, marked by substantial diuresis, reduction in body weight, and partial remission of proteinuria. Ten days later, the patient developed mild skin rash and subcutaneous nodules at injection sites. A relapse followed despite doubling the dose of corticotropin, consistent with delayed-onset resistance to treatment. Immunoblot-based antibody assay revealed de novo formation of antibodies in the patient's serum that were reactive to the natural corticotropin. In cultured melanoma cells known to express abundant melanocortin receptors, addition of the patient's serum strikingly mitigated dendritogenesis and cell signaling triggered by natural corticotropin, denoting neutralizing properties of the newly formed antibodies. Collectively, short-acting natural corticotropin seems effective in steroid-dependent nephrotic syndrome. De novo formation of neutralizing antibodies is likely responsible for acquired resistance to corticotropin therapy. The proof of concept protocols established in this study to examine the anticorticotropin neutralizing antibodies may aid in determining the cause of resistance to corticotropin therapy in future studies.
越来越多的证据支持使用促肾上腺皮质激素作为难治性蛋白尿性肾小球病的替代治疗方法。然而，短效促肾上腺皮质激素的疗效仍不明确，本文对一名由微小病变病引起的激素依赖型肾病综合征青少年患者进行了测试。在出现库欣综合征并近期罹患严重蜂窝织炎后，该患者停用了所有免疫抑制剂，包括皮质类固醇。这导致全身性水肿复发，伴有大量蛋白尿和低蛋白血症。随后，开始使用短效动物源性天然促肾上腺皮质激素进行单药治疗，结果迅速见效，表现为大量利尿、体重减轻和蛋白尿部分缓解。十天后，患者在注射部位出现轻度皮疹和皮下结节。尽管将促肾上腺皮质激素剂量加倍，仍出现复发，这与治疗延迟性抵抗一致。基于免疫印迹的抗体检测显示患者血清中出现了对天然促肾上腺皮质激素有反应的新形成抗体。在已知表达丰富促黑素受体的培养黑色素瘤细胞中，加入患者血清显著减轻了天然促肾上腺皮质激素触发的树突形成和细胞信号传导，表明新形成抗体具有中和特性。总体而言，短效天然促肾上腺皮质激素似乎对激素依赖型肾病综合征有效。中和抗体的新形成可能是促肾上腺皮质激素治疗获得性抵抗的原因。本研究中建立的用于检测抗促肾上腺皮质激素中和抗体的概念验证方案可能有助于在未来研究中确定促肾上腺皮质激素治疗抵抗的原因。
