The Klotho-FGF23-CPP axis and cardiovascular outcomes in diabetic patients with chronic limb threatening ischemia: a prospective study

Abstract Background: Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-FGF23-CPP axis is associated with endothelial injury and cardiovascular risk.The aim of this study was to analyze the relationship between Klotho-FGF23-CPP serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI.Methods: Baseline levels of Klotho, FGF23, and CPP, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER.Results: A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs 446.4 ± 171.7 pg/mL, p<0.01), whereas increased serum levels FGF23 (75.0 ± 11.8 pg/mL vs 53.2 ± 15.4 pg/mL, p<0.01) and CPP (461.8 ± 168.6 pg/mL vs 269.3 ± 184.3 pg/mL, p<0.01) were significantly associated with the development of MACE. ROC analysis confirmed the predictive power of the Klotho-FGF23-CPP axis. Furthermore, decreased Klotho serum levels were associated with the occurrence of MALE after LER (329.1 ± 136.8 pg/mL vs 495.4 ± 183.9 pg/mL, p<0.01).Conclusions: Klotho-FGF23-CPP axis imbalance is a potential biomarker for increased cardiovascular risk after LER in diabetic patients with PAD and CLTI.