Development and validation of a composite risk score incorporating the FGF23–Klotho axis for prediction of CKD progression and cardiovascular remodelling: a cross-sectional study

Abstract Fibroblast Growth Factor [FGF23] and α-Klotho, key regulators of phosphate balance, become progressively dysregulated in Chronic Kidney Disease [CKD]. This study aimed to create a composite risk score integrating these biomarkers with renal and cardiovascular markers. One hundred sixty hospitalised patients with CKD stages G2-G5 (40 per stage) participated in the study. FGF23–Klotho CKD–CV composite score (FKCS) derived from: FGF23–Klotho axis sub-score of log FGF23 plus soluble α-Klotho plus FGF23: Klotho (0–8 points), CKD progression sub-score of eGFR plus creatinine plus bicarbonate plus haemoglobin (0–8 points) and cardiovascular remodelling sub-score of composite index Carotid Intima Media Thickness [CIMT] plus Ankle Brachial Pressure Index [ABPI] plus Left Ventricular Hypertrophy [LVH] plus Aortic Valve[AV] sclerosis (0–6 points). Total score varies from a score of 0–24 categorised as low (0–8), moderate (9–16), and high (17–24). Bootstrap resampling used for internal validation. Median composite scores increased significantly across CKD stages: G2:5.0, G3:10.0, G4:14.5, G5:16.0 (Kruskal-Wallis p < 0.001). Log-FGF23 and FGF23:Klotho ratio increased significantly with advancing stage (both p < 0.001), but klotho did not ( p = 0.907), reflecting early, ubiquitous nature of Klotho depletion. CIMT showed strongest correlation with the composite score ( r = 0.648, p < 0.001) and eGFR ( r = − 0.824, p < 0.001). The FGF23:Klotho ratio correlated significantly with CIMT ( r = 0.329, p < 0.001) and composite Cardio Vascular [CV] index ( r = 0.209, p = 0.009). Area Under Curve [AUC] for discriminating advanced CKD (G4 + G5) was 0.921, as compared with eGFR alone (0.988). High cardiovascular remodelling burden AUC was 0.858. Risk tier distribution, strongly stage-stratified: G2 patients(82.5% )- Low-risk, G5 patients(45.0%) - High-risk. FKCS is an internally validated composite score that captures CKD-related endocrine and cardiovascular burden, offering risk stratification beyond eGFR, but requires prospective validation and therapeutic assessment.