Dataset Information

Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.

ABSTRACT: Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.

SUBMITTER: Isakova T

PROVIDER: S-EPMC5791067 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.

Isakova Tamara T Cai Xuan X Lee Jungwha J Xie Dawei D Wang Xue X Mehta Rupal R Allen Norrina B NB Scialla Julia J JJ Pencina Michael J MJ Anderson Amanda H AH Talierco John J Chen Jing J Fischer Michael J MJ Steigerwalt Susan P SP Leonard Mary B MB Hsu Chi-Yuan CY de Boer Ian H IH Kusek John W JW Feldman Harold I HI Wolf Myles M

Journal of the American Society of Nephrology : JASN 20171122 2

Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. H ...[more]

PMID: 29167351

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Project description:Background and objectivesHigh plasma concentration of fibroblast growth factor 23 (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, & measurementsWe performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ?95th percentile), adjusted for demographics, body mass 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 LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was 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 associated with 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 adjusted odds ratio, 2.02 per doubling of FGF23; 95% confidence interval, 1.29 to 3.17; P<0.01). By contrast, in participants with eGFR<45 ml/min per 1.73 m2, FGF23 did not associate with LVH.ConclusionsPlasma FGF23 concentration ?170 RU/ml is an independent predictor of LVH in children with eGFR?45 ml/min per 1.73 m2.

Project description:Background and objectivesIn children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study.Design, setting, participants, & measurementsPlasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1-16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR.ResultsMedian GFR for the cohort was 45 ml/min per 1.73 m(2) (interquartile range=33-57; range=15-109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60-69 ml/min per 1.73 m(2) than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR<50 ml/min per 1.73 m(2).ConclusionIn children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

Project description:BackgroundFew studies have investigated the changes in weight that may occur over time among adults with the progression of chronic kidney disease (CKD). Whether such weight changes are independently associated with death after the onset of end-stage renal disease has also not been rigorously examined.Study designProspective cohort study.Setting & participantsWe studied 3,933 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a longitudinal cohort of patients with CKD. We also performed similar analyses among 1,067 participants of the African American Study of Kidney Disease and Hypertension (AASK).PredictorsEstimated glomerular filtration rate (eGFR) and weight change during CKD.OutcomeWeight and all-cause mortality after dialysis therapy initiation.ResultsDuring a median follow-up of 5.7 years in CRIC, weight change was not linear. Weight was stable until cystatin C-based eGFR (eGFRcys) decreased to <35mL/min/1.73m2; thereafter, weight declined at a mean rate of 1.45 kg (95% CI, 1.19-1.70) for every 10 mL/min/1.73m2 decline in eGFRcys. Among the 770 CRIC participants who began hemodialysis or peritoneal dialysis therapy during follow-up, a >5% annualized weight loss after eGFR decreased to <35mL/min/1.73m2 was associated with a 54% higher risk for death after dialysis therapy initiation (95% CI, 1.17-2.03) compared with those with more stable weight (annualized weight changes within 5% of baseline) in adjusted analysis. Similar findings were observed in the AASK.LimitationsInclusion of research participants only; inability to distinguish intentional versus unintentional weight loss.ConclusionsSignificant weight loss began relatively early during the course of CKD and was associated with a substantially higher risk for death after dialysis therapy initiation. Further studies are needed to determine whether interventions to optimize weight and nutritional status before the initiation of dialysis therapy will improve outcomes after end-stage renal disease.

Project description:The high risk of cardiovascular disease (CVD) and premature death in patients with CKD associates with a plethora of elevated circulating biomarkers that may reflect distinct signaling pathways or simply, are epiphenomena of CKD. We compared the predictive strength of 12 biomarkers analyzed concomitantly in patients with stage 5 CKD.From 1994 to 2014, 543 patients with stage 5 CKD (median age =56 years old; 63% men; 199 patients had CVD) took part in our study on malnutrition, inflammation, and CVD in incident dialysis patients. Circulating levels of albumin, ferritin, high-sensitivity C-reactive protein (hsCRP), IGF-1, IL-6, orosomucoid, troponin T (TnT), TNF, soluble intracellular adhesion molecule, soluble vascular cellular adhesion molecule 1 (sVCAM-1), and platelet and white blood cell (WBC) counts were analyzed as predictors of the presence of clinically overt CVD at baseline, protein-energy wasting (PEW), and subsequent all-cause mortality. During follow-up for a median of 28 months, there were 149 deaths, 81 of which were caused by CVD.Most biomarkers were elevated compared with reference values and--except for albumin, ferritin, and IGF-1-higher in patients with CVD. In receiver operating characteristic analysis, age, IL-6, TnT, hsCRP, and IGF-1 were classifiers of baseline CVD and predictors of all-cause mortality. In addition to age, diabetes mellitus, smoking (for CVD), and PEW, only IL-6, relative risk (RR) 1.10 and 95% confidence interval ([95% CI], 1.02 to 1.19), sVCAM-1 RR 1.09 (95% CI, 1.01 to 1.17), and serum albumin RR 0.89 (95% CI, 0.83 to 0.95) associated with baseline CVD, and only WBC, hazard ratio (HR) 1.94 (95% CI, 1.34 to 2.82), IL-6 HR 1.79 (95% CI, 1.20 to 2.67), and TNF HR 0.65 (95% CI, 0.44 to 0.97) predicted all-cause mortality.In addition to age and comorbidities, only IL-6, sVCAM-1, and albumin could-independently of other biomarkers-classify clinical CVD, and only IL-6, WBC, and TNF could-independently of other biomarkers-predict all-cause mortality risk. These data underscore the robustness of IL-6 as a classifier of clinically overt CVD and predictor of all-cause mortality in patients with stage 5 CKD.

Dataset Information

Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.

Publications

Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.

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