Integrative analysis of circ_DLGAP4, lncRNA KCNQ1OT1, and the miR-9/SOX7 interaction network in chronic kidney disease progression: a case-control study.

Timely recognition and monitoring of chronic kidney disease (CKD) is critical for improving patient outcomes. Non-coding RNAs (ncRNAs) are implicated in CKD pathophysiology. However, their clinical translation, particularly in patients on maintenance hemodialysis (MHD), and their association with erythropoiesis-stimulating agent (ESA) resistance remain under-investigated. This case-control study evaluated the signature of serum circ_DLGAP4, lncRNA KCNQ1OT1, and their targets miR-9/SOX7 in CKD across various stages, including MHD, and the clinical significance of their integration in diagnosis, staging, and ESA resistance. Overall, 180 individuals: 60 controls, 60 non-hemodialysis (non-HD) CKD G2-G4 patients, and 60 MHD patients with CKD G5, were enrolled. ncRNAs and SOX7 were measured using RT-qPCR and ELISA, respectively. Bioinformatics analysis revealed the interaction network of the investigated markers and their involvement in CKD pathophysiology. Serum circ_DLGAP4, KCNQ1OT1, and miR-9 were upregulated in CKD patients, with or without MHD, while SOX7 was downregulated in MHD patients compared to controls. circ_DLGAP4 and SOX7 were lower, and miR-9 was higher in MHD versus non-HD patients. circ_DLGAP4 and SOX7 were differentially expressed across CKD categories/stages. ROC analysis revealed diagnostic utility for circ_DLGAP4, KCNQ1OT1, and miR-9 and prognostic potential for circ_DLGAP4, miR-9, and SOX7. In multivariate analysis, KCNQ1OT1 was independently associated with CKD detection in non-HD patients. The circ_DLGAP4/SOX7 panel independently predicted CKD progression to MHD with high accuracy [Area under the curve (AUC) = 0.93, 95% confidence interval (CI) = 0.8823-0.9754]. We developed a simple nomogram for easier application in CKD progression prediction (AUC = 0.938, 95% CI = 0.8959-0.9808). circ_DLGAP4, miR-9, and SOX7 showed correlations with eGFR. miR-9 was associated with the ESA resistance index in MHD patients receiving epoetin alfa, independent of BMI. Conclusively, this study introduces serum KCNQ1OT1 as a potential candidate biomarker for CKD diagnosis, circ_DLGAP4/SOX7 as a novel panel useful for assessing CKD progression using a nomogram, and miR-9 as a potential candidate ESA resistance biomarker in MHD. Trial registration number: NCT07037953, date of registration: 10-6-2025.