Chapters and Other Papers 1-6-2018 FGF 23 and Left Ventricular Hypertrophy in Children with CKD .

BackgroundandObjectivesHighplasmaconcentrationoffibroblast growth factor23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. Design, setting, participants, &measurementsWeperformed echocardiograms andmeasured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study.Weused linear and logistic regression to analyze the associationofplasmaFGF23with left ventricular mass index (LVMI) and LVH (LVMI$95th percentile), adjusted for demographics, bodymass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. ResultsMedian age was 12 years (interquartile range, 8–15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38–64). Overall prevalence of LVHwas 11%. After adjustment for demographics and bodymass index, the odds of having LVHwas higher by 2.53 (95% confidence interval, 1.28 to 4.97;P,0.01) in participants with FGF23 concentrations$170 RU/ml compared with those with FGF23,100 RU/ml, but this association was attenuated after full adjustment. Among participants with eGFR$45 ml/min per 1.73 m2, the prevalence of LVH was 5.4%, 11.2%, and 15.3% for those with FGF23 ,100 RU/ml, 100–169 RU/ml, and $170 RU/ml, respectively (Ptrend=0.01). When eGFR was $45 ml/min per 1.73 m2, higher FGF23 concentrations were independently associatedwith LVH (fully adjusted odds ratio, 3.08 in the highest versus lowest FGF23 category; 95% confidence interval, 1.02 to 9.24;P,0.05; fully adjustedodds ratio, 2.02perdoublingof FGF23; 95%confidence interval, 1.29 to 3.17; P,0.01). By contrast, in participants with eGFR,45ml/min per 1.73m2, FGF23 did not associate with LVH. Conclusions Plasma FGF23 concentration $170 RU/ml is an independent predictor of LVH in children with eGFR$45 ml/min per 1.73 m2. Clin J Am Soc Nephrol 13: 45–52, 2018. doi: https://doi.org/10.2215/CJN.02110217 Introduction Left ventricular hypertrophy (LVH) is the most common cardiovascular abnormality in children with CKD, with a reported prevalence of 17%–49% (1–3). LVH develops early and progresses throughout the course of CKD, and when untreated, poses an increased risk for cardiovascular disease morbidity and mortality (4). Understanding the factors contributing to the development of LVH in children and adolescents with CKD is essential to reducing future cardiovascular risk. Recent studies have identified fibroblast growth factor 23 (FGF23), a bone-derived circulating peptide, as a novel CKD-related risk factor in the development of LVH. Plasma concentrations of FGF23 increase early and progressively in both children (5) and adults (6) with advancing CKD. High FGF23 is associated with premature death (7,8), cardiovascular events (9), and LVH (10,11), with experimental data favoring a direct pathophysiologic role of FGF23 in promoting LVH via an FGF receptor 4 (FGFR4)–dependent pathway (12,13). However, few studies have assessed the role of FGF23 in the development of LVH in children with CKD, and the findings are inconsistent (14,15). In this study, we tested the hypothesis that high plasma concentrations of FGF23 are independently associated with a significantly higher prevalence of LVH in children and adolescents with predialysis CKD. We also assessed whether this relationship was modified by level of GFR. Materials and Methods The CKD in Children (CKiD) Study, a prospective observational cohort study, enrolled children aged 1–16 years with eGFR between 30 and 90 ml/min per 1.73 m2 at 54 pediatric nephrology centers across North America; the studydesign,methods, and exclusion criteria have been described (16). The study was approved by a Monitoring Board appointed by the National Institute of Diabetes and Digestive and Kidney Diseases, and by the institutional review boards of each participating center. Informed consent was obtained from each participant’s parent or guardian and from the participant, when age-appropriate. Division of Nephrology