促肾上腺皮质激素诱导缓解后肾病综合征复发：促肾上腺皮质激素抗体的意义。

Relapse of Nephrotic Syndrome after Adrenocorticotropic Hormone-Induced Remission: Implications of Adrenocorticotropic Hormone Antibodies.

机构信息

Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, USA.

Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, USA,

出版信息

Am J Nephrol. 2020;51(5):390-394. doi: 10.1159/000506854. Epub 2020 Mar 18.

DOI:10.1159/000506854

PMID:32187600

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7521046/

Abstract

BACKGROUND

Prolonged use of corticosteroids continues to be the mainstay in the management of most proteinuric glomerulopathies, but is limited by extensive side effects. Alternative medications such as adrenocorticotropic hormone (ACTH) have been recently used to treat refractory glomerulopathies and have shown superior outcomes when compared with steroids. However, the clinical responsiveness to ACTH therapy varies considerably with a number of patients exhibiting de novo or acquired resistance. The underlying mechanism remains unknown.

METHODS

A patient with steroid-dependent focal segmental glomerulosclerosis (FSGS) developed severe steroid side effects impacting quality of life and was converted to repository porcine ACTH therapy. Immediate response in the form of remission of nephrotic syndrome was noted followed by relapse in 10 weeks. Suspecting the role of some ACTH-antagonizing factors, the patient's serum was examined.

RESULTS

Immunoblot-based antibody assay revealed high titers of de novo IgG antibodies in the patient's serum that were reactive to the porcine corticotropin with negligible cross-reactivity to human corticotropin. In vitro, in cultured B16 melanoma cells that express abundant melanocortin receptors, addition of the patient's serum substantially abrogated the porcine corticotropin triggered signaling activity of the melanocortinergic pathway, marked by phosphorylation of glycogen synthase kinase 3β, thus suggesting a mitigating effect on the biological functionality of porcine corticotropin.

CONCLUSION

ACTH is a useful alternative therapeutic modality for refractory proteinuric glomerulopathies like FSGS. However, as quintessential therapeutic biologics, natural ACTH, regardless of purity and origin, is inevitably antigenic and may cause the formation of neutralizing antibodies in some sensitive patients, followed by resistance to ACTH therapy. It is imperative to develop ACTH analogues with less immunogenicity for improving its responsiveness in patients with glomerular diseases.

摘要

背景

在大多数蛋白尿性肾小球疾病的治疗中，长期使用皮质类固醇仍然是主要方法，但它的副作用广泛。最近，促肾上腺皮质激素（ACTH）等替代药物已被用于治疗难治性肾小球疾病，与类固醇相比，其疗效更好。然而，ACTH 治疗的临床反应差异很大，许多患者表现出新发或获得性耐药。其潜在机制尚不清楚。

方法

一位依赖激素的局灶节段性肾小球硬化症（FSGS）患者出现严重的激素副作用，影响生活质量，随后转换为储存猪促肾上腺皮质激素治疗。立即出现肾病综合征缓解，10 周后复发。由于怀疑存在一些 ACTH 拮抗因子，检测了患者的血清。

结果

基于免疫印迹的抗体检测显示，患者血清中存在针对猪促肾上腺皮质激素的新产生的 IgG 抗体，其效价很高，但对人促肾上腺皮质激素的交叉反应性可忽略不计。在体外，在表达丰富黑素皮质素受体的 B16 黑色素瘤细胞中，加入患者的血清可显著阻断猪促肾上腺皮质激素触发的黑素皮质素能途径的信号转导活性，其标志是糖原合酶激酶 3β的磷酸化，这表明对猪促肾上腺皮质激素的生物学功能具有缓解作用。

结论

ACTH 是治疗 FSGS 等难治性蛋白尿性肾小球疾病的一种有用的替代治疗方法。然而，作为典型的治疗性生物制剂，天然 ACTH 无论纯度和来源如何，都不可避免地具有抗原性，可能会在一些敏感患者中引起中和抗体的形成，随后对 ACTH 治疗产生耐药性。开发免疫原性较低的 ACTH 类似物对于提高其在肾小球疾病患者中的反应性至关重要。