Synergistic prognostic value of inflammatory and novel biomarkers for cardiovascular and renal outcomes in stage 3-4 chronic kidney disease

Background: Chronic Kidney Disease (CKD) progression is driven by intertwined pathways of inflammation, fibrosis, and disordered mineral metabolism. While cytokines like IL-6 and TNF-<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">α</span> are established inflammatory markers, their prognostic value may be enhanced by combining them with emerging partners, such as Galectin-3 (Gal3, a fibrosis/pro-inflammatory amplifier) and Fibroblast Growth Factor-23. We investigated the prognostic power of this novel panel, both individually and in combination, for renal and cardiovascular (CV) outcomes. Methods: A prospective, single-centre cohort study enrolled 218 patients with CKD stages 3 to 4. Baseline serum concentrations of TGF-<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">β</span>, IL-6, Gal-3, IL-1<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">β</span>, TNF-<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">α</span>, and FGF-23 were assessed. Participants were monitored for 36 months for a primary composite endpoint that included a decline in estimated glomerular filtration rate of at least 40 percent, progression to kidney failure requiring replacement therapy, or a major adverse cardiovascular event. Cox proportional-hazards models, Kaplan-Meier analysis, and receiver operating characteristic curves were utilized. In this prospective, single-centre cohort study, 218 patients with CKD stages 3-4 were enrolled. Baseline serum levels of IL-6, IL-1<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">β</span>, TNF-<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">α</span>, TGF-<span style="color: rgb(32, 33, 34); font-family: sans-serif; font-size: 16px; background-color: rgb(248, 249, 250);">β</span>, Gal-3, and FGF-23 were measured. Patients were followed for 36 months for a primary composite endpoint: &gt;40% decline in eGFR, progression to kidney failure requiring replacement therapy (KFRT), or a major adverse CV event (MACE). Cox proportional-hazards models, Kaplan-Meier analysis, and receiver operating characteristic (ROC) curves were employed. Results: Over the 36-month follow-up, 68 participants (31.2%) experienced the composite outcome. In time-to-event analyses, higher concentrations of all biomarkers except IL-1 b were significantly related to event occurrence in unadjusted models. However, after controlling for age, diabetes status, baseline eGFR, and albuminuria in multivariable Cox regression, only IL-6 (HR 1.82, 95% CI 1.30-2.55), Galectin-3 (HR 2.15, 95% CI 1.45-3.18), and FGF-23 (Hr 1.95, 95% CI 1.35-2.82) retained independent prognostic value. Building on these three markers, we constructed a Triple-Biomarker Risk Score (TBRS) using tertile-based categories of IL-6, Galectin-3, and FGF-23, which demonstrated a strong stepwise increase in risk across score strata. Individuals classified in the highest TBRS category had approximately a 9-fold greater hazard of reaching the composite endpoint than those in the lowest category (HR 9.10, 95% CI 3.82-21.68). Discrimination analyses showed that the TBRS achieved an AUC of 0.84, significantly outperforming eGFR as a standalone predictor (AUC 0.72, p&lt;0.01), underscoring the added value of this multi-marker approach for risk stratification. Conclusion: The combination of a classic inflammatory cytokine (IL-6), a fibrotic/pro-inflammatory lectin (Gal-3), and a phosphaturic hormone (FGF-23) provides a superior prognostic signature in moderate CKD. This panel reflects key pathological axes - inflammation, fibrosis, and mineral dysregulation - and significantly improves risk stratification for both renal and cardiovascular outcomes.