IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy.
IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
J Am Soc Nephrol. 2018 Jan;29(1):283-294. doi: 10.1681/ASN.2017030258. Epub 2017 Oct 13.
Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1-3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.
膜增生性 GN（MPGN）最近被重新分类为替代途径补体介导的 C3 肾小球病（C3G）和免疫复合物介导的膜增生性 GN（IC-MPGN）。然而，IC-MPGN 中也存在遗传和获得性替代途径异常。在这里，我们探讨了具有特定病理生理机制特征的不同疾病实体的存在。我们对来自 173 例 C3G/IC-MPGN 患者的组织学、遗传学和临床数据以及血清/血浆补体参数数据进行了无监督层次聚类，这是一种数据驱动的统计方法。这种方法将患者分为四个聚类，表明存在四种不同的发病机制模式。具体来说，该分析将液相对补体激活的患者（聚类 1-3）与固相补体激活的患者（聚类 4）分开，前者血清 C3 水平较低，且遗传和获得性替代途径异常的患病率较高，后者血清 C3 水平正常或轻度改变，发病较晚，肾脏预后较差。在液相对补体激活的患者中，聚类 1 和 2 的患者替代途径大量激活，包括末端途径的激活，且内皮下沉积物的患病率最高，但聚类 2 的患者经典途径也有额外的激活，且发病时肾病综合征的患病率最高。聚类 3 的患者 C3 转化酶的激活普遍，且电子致密的内皮下沉积物较多。此外，我们提供了一种简单的算法，可将 C3G/IC-MPGN 患者分配到特定的聚类中。这些不同的聚类可能有助于阐明疾病的病因，改善终末期肾病的风险评估，并为个性化治疗铺平道路。
