Focal segmental glomerulosclerosis (FSGS) causes renal fibrosis and may lead to kidney failure. FSGS and its common complication, proteinuria, are challenging to treat. Corticosteroids are ineffective in many patients with FSGS, and alternative treatments often yield suboptimal responses. Repository corticotropin injection (RCI; Acthar® Gel), a naturally sourced complex mixture of purified adrenocorticotropic hormone analogs and other pituitary peptides, may have beneficial effects on idiopathic FSGS via melanocortin receptor activation. Two studies in a preclinical (female Sprague-Dawley rats) puromycin aminonucleoside FSGS model assessed the effect of RCI on renal function and morphology: an 8-week comparison of a single RCI dose with methylprednisolone (N = 27), and a 12-week chronic RCI dose range study (N = 34). Primary outcomes were proteinuria and renal pathology improvements for measures of renal fibrosis, tubular damage, glomerular injury, and total kidney injury score. Impact of RCI treatment was also determined by assessing urinary biomarkers for renal injury, podocyte expression of podoplanin (a biomarker for injury), podocyte effacement by electron microscopy, and histological staining for fibrosis biomarkers. Compared with saline treatment, RCI 30 IU/kg significantly reduced proteinuria, with a 38% reduction in peak mean urine protein levels on day 28 in the 8-week model, and RCI 10 IU/kg, 30 IU/kg, and 60 IU/kg reduced peak mean urine protein in the 12-week model by 18, 47, and 44%, respectively. RCI also showed significant dose-dependent improvements in fibrosis, interstitial inflammation, tubular injury, and glomerular changes. Total kidney injury score (calculated from histopathological evaluations) demonstrated statistically significant improvements with RCI 30 IU/kg in the 8-week study and RCI 60 IU/kg in the 12-week study. RCI treatment improved levels of urinary biomarkers of kidney injury (KIM-1 and OPN), expression of podoplanin, and podocyte morphology. RCI also reduced levels of desmin and fibrosis-associated collagen deposition staining. Methylprednisolone did not improve renal function or pathology in this model. These results provide evidence supporting the improvement of FSGS with RCI, which was superior to corticosteroid treatment in this experimental model. To the authors’ knowledge, this is the first evidence that a drug for the treatment of FSGS supports podocyte recovery after repeated injury.

中文翻译：

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在局灶节段性肾小球硬化啮齿动物模型中，储存促肾上腺皮质激素注射液与皮质类固醇用于防止肾损伤。

局灶节段性肾小球硬化 (FSGS) 会导致肾纤维化并可能导致肾功能衰竭。FSGS 及其常见并发症蛋白尿的治疗具有挑战性。皮质类固醇对许多 FSGS 患者无效，替代治疗通常会产生次优反应。Repository corticotropin injection (RCI; Acthar® Gel) 是一种天然来源的纯化促肾上腺皮质激素类似物和其他垂体肽的复杂混合物，可能通过黑皮质素受体激活对特发性 FSGS 产生有益影响。在临床前（雌性 Sprague-Dawley 大鼠）嘌呤霉素氨基核苷 FSGS 模型中进行的两项研究评估了 RCI 对肾功能和形态学的影响：8 周比较单一 RCI 剂量与甲基强的松龙（N = 27）和 12 周慢性 RCI 剂量范围研究（N = 34）。主要结果是蛋白尿和肾脏病理学改善，用于衡量肾纤维化、肾小管损伤、肾小球损伤和总肾损伤评分。RCI 治疗的影响还通过评估肾损伤的尿生物标志物、足细胞足细胞表达的足细胞表达（损伤的生物标志物）、电子显微镜下足细胞消失以及纤维化生物标志物的组织学染色来确定。与生理盐水治疗相比，RCI 30 IU/kg 显着降低蛋白尿，8 周模型中第 28 天的峰值平均尿蛋白水平降低 38%，RCI 10 IU/kg、30 IU/kg 和 60 IU /kg 使 12 周模型中的峰值平均尿蛋白分别降低 18%、47% 和 44%。RCI 在纤维化、间质炎症、肾小管损伤和肾小球变化方面也显示出显着的剂量依赖性改善。总肾损伤评分（根据组织病理学评估计算）表明，8 周研究中 RCI 30 IU/kg 和 12 周研究中 RCI 60 IU/kg 有统计学显着改善。RCI 治疗改善了尿肾损伤生物标志物（KIM-1 和 OPN）、足蛋白表达和足细胞形态的水平。RCI 还降低了结蛋白和纤维化相关胶原沉积染色的水平。在该模型中，甲基强的松龙没有改善肾功能或病理。这些结果提供了支持用 RCI 改善 FSGS 的证据，这在该实验模型中优于皮质类固醇治疗。据作者所知，这是第一个证明用于治疗 FSGS 的药物支持重复损伤后足细胞恢复的证据。