Klotho, fibroblast growth factor-23, and the renin-angiotensin system - an analysis from the PEACE trial

Abstract

Aims: Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition.

Methods and results: A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; P_interaction < 0.01).

Conclusions: Low Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.

Keywords: Biomarker; Fibroblast growth factor-23; Heart failure; Klotho.

Figure 1.

6-year Kaplan-Meier event rates and observed risk for CV death or heart failure hospitalization by quartile of Klotho concentration in the placebo arm.

Figure 2.

6-year Kaplan-Meier event rates and adjusted risk of CV death or heart failure hospitalization in patients in the placebo arm stratified by Klotho and FGF-23 concentrations. As compared to Klotho Q4/FGF23 Q1–3 as the referent, the adjusted risk for CV death or heart failure hospitalization was HR_adj 1.08 (95% CI 0.31–3.83) for Klotho Q4/FGF23 Q4, HR_adj 2.03 (95% CI 0.88–4.66) for Klotho Q1–3/FGF23 Q1–3, and HR_adj 3.99 (95% CI 1.67–9.56) for Klotho Q1–3/FGF23 Q4. Adjustment covariates: age, sex, current smoker, HTN, T2DM, prior MI, prior revascularization, weight, SBP, LVEF, eGFR, cystatin-C, UACR, NT-proBNP, hsTnT, and hsCRP.

Figure 3.

Kaplan-Meier event rates for CV death or heart failure hospitalization by high risk or low risk status and randomized treatment. High risk status was defined as both Klotho concentration in Q1–3 and FGF-23 concentration in Q4. All other combinations were considered low risk.