FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease

Abstract

<b><i>Introduction:</i></b> High plasma fibroblast growth factor 23 (FGF-23) predicts cardiovascular events in chronic kidney disease (CKD) patients. Experimental evidence suggests FGF receptor 4 (FGFR4) activation by FGF-23, and deficiency of the soluble form of its co-receptor Klotho promotes left-ventricular hypertrophy (LVH). To evaluate the clinical relevance of these findings, a Mendelian randomization study analyzed the association of genetic variants of FGFR4 and Klotho with echocardiographic parameters and cardiac events in CKD patients. <b><i>Methods:</i></b> The prospective Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation study recruited CKD G2–G4 patients, of whom 519 consented to SNP genotyping (FGFR4: rs351855; Klotho: rs9536314). Echocardiographic examinations at baseline and 5 years later assessed prevalence of LVH by measurement of left-ventricular mass index (LVMI). Patients were followed for 5.1 ± 2.1 years for the primary endpoints of cardiac decompensation and atherosclerotic cardiovascular disease (ASCVD). <b><i>Results:</i></b> Carriers of the different alleles did neither differ in baseline LVMI (rs351855: <i>p</i> = 0.861; rs9536314: <i>p</i> = 0.379) nor in LVMI changes between baseline and follow-up (rs351855: <i>p</i> = 0.181; rs9536314: <i>p</i> = 0.995). Hundred and four patients suffered cardiac decompensation, and 144 patients had ASCVD. Time to cardiac decompensation (rs351855: <i>p</i> = 0.316; rs9536314: <i>p</i> = 0.765) and ASCVD (<i>p</i> = 0.508 and <i>p</i> = 0.800, respectively) did not differ between carriers of different alleles. <b><i>Discussion/Conclusion:</i></b> rs351855 and rs9536314 were not associated with LVMI or cardiac events. These findings do not provide evidence for a relevant clinical role of either FGFR4 stimulation or soluble form of Klotho deficiency in LVH development.