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.