Abstract
Background The early identification of patients at high‑risk for end‑stage renal disease (ESRD) is essential for pro‑ viding optimal care and implementing targeted prevention strategies. While the Kidney Failure Risk Equation (KFRE) offers a more accurate prediction of ESRD risk compared to static eGFR‑based thresholds, it does not provide insights into the patient‑specific biological mechanisms that drive ESRD. This study focused on evaluating the effectiveness of KFRE in a UK‑based advanced chronic kidney disease (CKD) cohort and investigating whether the integration of a proteomic signature could enhance 5‑year ESRD prediction. Methods Using the Salford Kidney Study biobank, a UK‑based prospective cohort of over 3000 non‑dialysis CKD patients, 433 patients met our inclusion criteria: a minimum of four eGFR measurements over a two‑year period and a linear eGFR trajectory. Plasma samples were obtained and analysed for novel proteomic signals using SWATH‑ Mass‑Spectrometry. The 4‑variable UK‑calibrated KFRE was calculated for each patient based on their baseline clinical characteristics. Boruta machine learning algorithm was used for the selection of proteins most contributing to differ‑ entiation between patient groups. Logistic regression was employed for estimation of ESRD prediction by (1) prot‑ eomic features; (2) KFRE; and (3) proteomic features alongside KFRE. Results SWATH maps with 943 quantified proteins were generated and investigated in tandem with available clinical data to identify potential progression biomarkers. We identified a set of proteins (SPTA1, MYL6 and C6) that, when used alongside the 4‑variable UK‑KFRE, improved the prediction of 5‑year risk of ESRD (AUC = 0.75 vs AUC = 0.70). Functional enrichment analysis revealed Rho GTPases and regulation of the actin cytoskeleton pathways to be statistically significant, inferring their role in kidney function and the pathogenesis of renal disease. Conclusions Proteins SPTA1, MYL6 and C6, when used alongside the 4‑variable UK‑KFRE achieve an improved performance when predicting a 5‑year risk of ESRD. Specific pathways implicated in the pathogenesis of podocyte dysfunction were also identified, which could serve as potential therapeutic targets. The findings of our study carry