Plasma complement proteins as biomarkers and therapeutic targets in chronic kidney disease: a Mendelian randomization analysis

Chronic Kidney Disease (CKD) is a progressive condition leading to End-Stage Kidney Disease (ESKD). With limited treatment options, identifying biomarkers related to CKD onset and progression is essential. The complement system, an immune network, has shown potential involvement in CKD pathogenesiss. This study investigates the causal role of diverse plasma complement proteins in CKD and its clinical types to discover new biomarkers and therapeutic targets. Using two-sample Mendelian randomization (MR), we examined the causal relationships between 28 plasma complement proteins and CKD outcomes. Plasma complement levels were sourced from a genome-wide association studies involving 35,559 Icelandic individuals, CKD outcome sourced from the FinnGen R11 and kidney function indicators sourced from CKDgen. Protein-protein interactions and GO enrichment analyses were used to identify related biological pathways. MR analysis identified causal relationships between 19 specific plasma complement proteins and CKD, 6 of which remained significant after false discovery rate correction. In addition, CR1 and CFD were not only found to be risk factors for CKD, but were also determined to be positively correlated with membranous nephropathy and diabetic nephropathy, respectively. CD55, C6, CR2, CFHR2, CFD were also correlated with renal function indicators, highlighting the role of complement proteins in CKD. This study supports plasma complement proteins as potential biomarkers and therapeutic targets for CKD. The identified causal associations highlight the relevance of complement activation in CKD progression, suggesting future potential for clinical applications in early diagnosis, risk stratification, and therapeutic intervention.

慢性肾脏病（Chronic Kidney Disease, CKD）是一类可进展至终末期肾脏病（End-Stage Kidney Disease, ESKD）的进行性疾病。当前临床治疗选择有限，故而识别与CKD发病及进展相关的生物标志物极为关键。补体系统作为一类免疫网络，已被证实可能参与CKD的致病过程。本研究旨在探究多种血浆补体蛋白在CKD及其临床亚型中的因果作用，以期发掘全新的生物标志物与治疗靶点。本研究采用双样本孟德尔随机化（two-sample Mendelian randomization, MR）方法，对28种血浆补体蛋白与CKD转归之间的因果关联展开分析。血浆补体水平数据来源于一项纳入35559名冰岛个体的全基因组关联研究，CKD转归数据取自FinnGen R11数据库，肾功能指标数据则来自CKDgen联盟。研究人员通过蛋白-蛋白相互作用分析与基因本体（Gene Ontology, GO）富集分析，对相关生物学通路进行了系统鉴定。孟德尔随机化分析结果显示，共有19种特定血浆补体蛋白与CKD存在因果关联，其中6种在经过假发现率（false discovery rate, FDR）校正后仍具有统计学显著性。此外，补体受体1（CR1）与补体因子D（CFD）不仅被确定为CKD的危险因素，还分别与膜性肾病及糖尿病肾病呈正相关。CD55、C6、CR2、CFHR2、CFD亦与肾功能指标存在显著关联，进一步凸显了补体蛋白在CKD发生发展中的重要作用。本研究证实血浆补体蛋白可作为CKD潜在的生物标志物与治疗靶点。本次鉴定出的因果关联突显了补体激活在CKD进展中的核心相关性，为其在早期诊断、风险分层及治疗干预中的临床应用指明了未来研究方向。