Rupal Mehta

Association of Fibroblast Growth Factor 23 With Atrial Fibrillation in Chronic Kidney Disease, From the Chronic Renal Insufficiency Cohort Study

IMPORTANCE Levels of fibroblast growth factor 23 (FGF23) are elevated in chronic kidney disease (CKD) and strongly associated with left ventricular hypertrophy, heart failure, and death. Whether FGF23 is an independent risk factor for atrial fibrillation in CKD is unknown. OBJECTIVE To investigate the association of FGF23 with atrial fibrillation in CKD. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 3876 individuals with mild to severe CKD who enrolled in the Chronic Renal Insufficiency Cohort Study between June 19, 2003, and September 3, 2008, and were followed up through March 31, 2013. EXPOSURES Baseline plasma FGF23 levels. MAIN OUTCOMES AND MEASURES Prevalent and incident atrial fibrillation. RESULTS The study cohort comprised 3876 participants. Their mean (SD) age was 57.7 (11.0) years, and 44.8% (1736 of 3876) were female. Elevated FGF23 levels were independently associated with increased odds of prevalent atrial fibrillation (n = 660) after adjustment for cardiovascular and CKD-specific factors (odds ratio of highest vs lowest FGF23 quartile, 2.30; 95% CI, 1.69-3.13; P < .001 for linear trend across quartiles). During a median follow-up of 7.6 years (interquartile range, 6.3-8.6 years), 247 of the 3216 participants who were at risk developed incident atrial fibrillation (11.9 events per 1000 person-years). In fully adjusted models, elevated FGF23 was independently associated with increased risk of incident atrial fibrillation after adjustment for demographic, cardiovascular, and CKD-specific factors, and other markers of mineral metabolism (hazard ratio of highest vs lowest FGF23 quartile, 1.59; 95% CI, 1.00-2.53; P = .02 for linear trend across quartiles). The results were unchanged when further adjusted for ejection fraction, but individual adjustments for left ventricular mass index, left atrial area, and interim heart failure events partially attenuated the association of elevated FGF23 with incident atrial fibrillation. CONCLUSIONS AND RELEVANCE Elevated FGF23 is independently associated with prevalent and incident atrial fibrillation in patients with mild to severe CKD. The effect may be partially mediated through a diastolic dysfunction pathway that includes left ventricular hypertrophy, atrial enlargement, and heart failure events.

Is Nocturnal Blood Pressure Reduction the Secret to Reducing the Rate of Progression of Hypertensive Chronic Kidney Disease

Hypertension is a significant risk factor for cardiovascular and renal disease. Lowering blood pressure (BP) has been shown to reduce the incidence of cardiovascular disease, but randomized trials have not demonstrated a benefit of lowering BP for the progression of renal disease except in secondary analyses in patients with significant proteinuria. Recently, there has been increasing interest in measuring BP outside of the clinic, using both home and ambulatory blood pressure monitoring (ABPM). ABPM has the advantage of measuring BP throughout both the day and night. Elevated nighttime BP and a lack of decline in BP from day to night (nondipping) are more potent risk factors for cardiovascular and renal outcomes than elevated daytime or clinic BP. Studies have shown that it is possible to lower nighttime BP and restore normal dipping with the administration of antihypertensive medications in the evening, known as chronotherapy. Evening administration of antihypertensives not only lowers nighttime BP but also is associated with decreased urinary protein excretion, decreased cardiovascular events, and decreased all-cause mortality. Reducing nighttime BP may slow the progression of chronic kidney disease and may be the key to linking the treatment of hypertension with improved renal outcomes.

Longitudinal FGF23 Trajectories and Mortality in Patients with CKD

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.

Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study

BACKGROUND AND OBJECTIVES Anemia is an early complication of CKD that is associated with increased morbidity and mortality. Prior data show associations between abnormal mineral metabolism markers and decreased erythropoiesis. However, few studies have investigated elevated fibroblast growth factor 23 as a risk factor for the development of anemia in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a prospective cohort study of 3869 individuals with mild to severe CKD enrolled in the Chronic Renal Insufficiency Cohort Study between 2003 and 2008 and followed through 2013. We hypothesized that elevated baseline fibroblast growth factor 23 levels are associated with prevalent anemia, decline in hemoglobin over time, and development of incident anemia, defined as serum hemoglobin level <13 g/dl in men, serum hemoglobin level <12 g/dl in women, or use of erythropoietin stimulating agents. RESULTS In the 1872 of 3869 individuals who had prevalent anemia at baseline, mean age was 58 (11) years old, and mean eGFR was 39 (13) ml/min per 1.73 m2. Higher levels of fibroblast growth factor 23 were significantly associated with prevalent anemia (odds ratio per 1-SD increase in natural log-transformed fibroblast growth factor 23, 1.39; 95% confidence interval, 1.26 to 1.52), decline in hemoglobin over 4 years, and risk of incident anemia (hazard ratio per 1-SD increase in natural log-transformed fibroblast growth factor 23, 1.13; 95% confidence interval, 1.04 to 1.24; quartile 4 versus quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.19 to 2.11) independent of demographic characteristics, cardiovascular disease risk factors, CKD-specific factors, and other mineral metabolism markers. The results of our prospective analyses remained unchanged after additional adjustment for time-varying eGFR. CONCLUSIONS Elevated fibroblast growth factor 23 is associated with prevalent anemia, change in hemoglobin over time, and development of anemia. Future studies are needed to elucidate the mechanisms for these associations.

Phosphate, fibroblast growth factor 23 and retinopathy in chronic kidney disease: the Chronic Renal Insufficiency Cohort Study

BACKGROUND Elevated circulating concentrations of phosphate and fibroblast growth factor 23 (FGF23) contribute to the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Retinopathy is a common manifestation of microvascular disease in CKD, but its associations with phosphate and FGF23 have not been studied. We tested the hypothesis that higher serum phosphate is associated with more severe retinopathy in individuals with CKD, independent of FGF23 and known risk factors for retinopathy. METHODS We tested the associations of serum phosphate and plasma FGF23 with retinopathy in a cross-sectional analysis of 1800 participants in the Chronic Renal Insufficiency Cohort Study who underwent fundus photography. Retinopathy severity was graded according to the Early Treatment of Diabetic Retinopathy Severity score, and retinal venous and arterial diameters were measured. RESULTS Mean estimated glomerular filtration rate (eGFR) was 46.5 ± 15.4 mL/min/1.73 m(2), mean serum phosphate was 3.7 ± 0.6 mg/dl and median plasma C-terminal FGF23 was 133 RU/mL (interquartile range 87.2, 217.8 RU/mL). In multivariable ordinal logistic regression models, higher serum phosphate was associated with greater retinopathy severity independent of hypertension, diabetes, CKD severity and FGF23 [adjusted odds ratio of being in one higher category of retinopathy severity: 1.19 per 1 standard deviation increase; 95% confidence interval (CI) 1.05, 1.36; P = 0.007]. Presence of diabetes or hypertension did not modify the results. Higher serum phosphate was also independently associated with greater retinal venous diameter (multivariable-adjusted 1.70 µm increase per 1 standard deviation increase in phosphate; 95% CI 0.46, 2.93; P = 0.007). FGF23 levels were not independently associated with retinopathy severity or retinal venous diameter, and neither FGF23 nor phosphate was associated with retinal arterial diameter. CONCLUSIONS Among individuals with moderate-to-severe CKD, higher serum phosphate but not FGF23 was independently associated with more severe retinopathy and microvascular retinal venous dilatation.

FGF23 (Fibroblast Growth Factor-23) and Incident Hypertension in Young and Middle-Aged AdultsNovelty and Significance: The CARDIA Study

Blacks have the highest prevalence of hypertension in the United States. Higher levels of FGF23 (fibroblast growth factor-23) have been associated with worse cardiovascular outcomes. Whether FGF23 is associated with rising blood pressure (BP) and racial differences in incident hypertension is unclear. We studied 1758 adults (45.0±3.7 years; 57.8% female; 36.9% black) without hypertension or cardiovascular disease who participated in the year 20 (2005–2006) follow-up examination of the CARDIA study (Coronary Artery Risk Development in Young Adults). We investigated the associations of baseline (year 20) cFGF23 (C-terminal FGF23) levels with longitudinal BP patterns and incident hypertension (defined as being on antihypertensive medication, systolic BP ≥130 or diastolic BP ≥80 mm Hg) during 2 follow-up visits (years 25 and 30). During follow-up, 35.2% of participants developed hypertension. In multivariable linear mixed models, there were greater increases in systolic BP from year 20 to 25 and year 25 to 30 in the highest FGF23 quartile relative to the lowest quartile (+2.1 mm Hg, P=0.0057 and +2.2 mm Hg, P=0.0108, respectively for each time period), whereas there were greater increases in diastolic BP from year 20 to 25 in the highest quartile relative to the lowest (+1.6 mm Hg; P=0.0024). In multivariable modified Poisson regression analyses, the highest FGF23 quartile was associated with a 45% greater risk of developing hypertension during follow-up compared with the lowest quartile (relative risk, 1.45 [1.18–1.77]). Results did not vary by race (Pinteraction=0.1523). Higher FGF23 levels are independently associated with rising BP over time and an increased risk of incident hypertension but not racial differences in hypertension.

Incidence and Progression of Chronic Kidney Disease in Black and White Individuals with Type 2 Diabetes

BACKGROUND AND OBJECTIVES Type 2 diabetes and associated CKD disproportionately affect blacks. It is uncertain if racial disparities in type 2 diabetes-associated CKD are driven by biologic factors that influence propensity to CKD or by differences in type 2 diabetes care. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a post hoc analysis of 1937 black and 6372 white participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to examine associations of black race with change in eGFR and risks of developing microalbuminuria, macroalbuminuria, incident CKD (eGFR<60 ml/min per 1.73m2, ≥25% decrease from baseline eGFR, and eGFR slope <-1.6 ml/min per 1.73 m2 per year), and kidney failure or serum creatinine >3.3 mg/dl. RESULTS During a median follow-up that ranged between 4.4 and 4.7 years, 278 black participants (58 per 1000 person-years) and 981 white participants (55 per 1000 person-years) developed microalbuminuria, 122 black participants (16 per 1000 person-years) and 374 white participants (14 per 1000 person-years) developed macroalbuminuria, 111 black participants (21 per 1000 person-years) and 499 white participants (28 per 1000 person-years) developed incident CKD, and 59 black participants (seven per 1000 person-years) and 178 white participants (six per 1000 person-years) developed kidney failure or serum creatinine >3.3 mg/dl. Compared with white participants, black participants had lower risks of incident CKD (hazard ratio, 0.73; 95% confidence intervals, 0.57 to 0.92). There were no significant differences by race in eGFR decline or in risks of microalbuminuria, macroalbuminuria, and kidney failure or of serum creatinine >3.3 mg/dl. CONCLUSIONS Black participants enrolled in a randomized controlled trial had lower rates of incident CKD compared with white participants. Rates of eGFR decline, microalbuminuria, macroalbuminuria, and kidney failure did not vary by race.

Continued Search for Therapies to Favorably Modify Phosphate and FGF23 Levels in CKD

Over the last two decades, scientific developments have enhanced our understanding of the pathogenesis of cardiovascular disease in patients with CKD, and specific nontraditional risk factors have emerged. Elevated serum phosphate has been implicated in the development of vascular and valvular

Associations of Fenofibrate Therapy with Incidence and Progression of Chronic Kidney Disease in Patients with Type 2 Diabetes

Introduction Abnormalities in lipid metabolism may contribute to the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR), but it may have protective effects on microvascular complications of diabetes. We hypothesized that randomization to fenofibrate versus placebo would be associated with beneficial long-term effects on kidney outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. Methods We conducted a post hoc analysis in the ACCORD Lipid Trial to examine the association of randomization to fenofibrate versus placebo with change in eGFR and with time-to-development of microalbuminuria, macroalbuminuria, CKD, and kidney failure. Results We analyzed 2636 participants in the fenofibrate arm and 2632 in the placebo arm. During a median follow-up of 4 years, treatment with fenofibrate was associated with lower rate of eGFR decline (−0.28 ml/min per 1.73 m2 per year in the fenofibrate group vs. −1.25 ml/min per 1.73 m2 per year in the placebo group, P < 0.01) and with lower incidence of microalbuminuria (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.43–0.72, P < 0.001) and macroalbuminuria (HR 0.72, 95% CI 0.57–0.91, P < 0.001). There was no difference in incidence of CKD (HR 0.92, 95% CI 0.74–1.15, P = 0.46) and/or kidney failure (HR 0.95, 95% CI 0.68–1.33, P = 0.76). Conclusion Compared with placebo, randomization to fenofibrate was associated with lower rates of incident albuminuria and a slower eGFR decline, but no difference in incidence of CKD or kidney failure in ACCORD participants.

Sleep disordered breathing and fibroblast growth factor 23 in the Hispanic Community Health Study/Study of Latinos

Preclinical data suggest that hypoxia stimulates fibroblast growth factor 23 (FGF23) transcription and cleavage in osteocytes, resulting in elevated circulating c-terminal (cFGF23) levels but normal intact FGF23 (iFGF23) levels. We conducted a case-control study within the Hispanic Community Health Study/Study of Latinos to investigate whether sleep disordered breathing, as a model of hypoxemia, is independently associated with elevated cFGF23 levels in the general population and with elevated cFGF23 and iFGF23 levels in patients with chronic kidney disease (CKD), in whom FGF23 cleavage may be impaired. Cases (n = 602) had severe sleep disordered breathing defined as an apnea/hypopnea index (AHI) of ≥30. Controls without severe sleep disordered breathing (n = 602) were matched for sex and CKD stage. The median AHI in the cases was 45.8 (IQR 35.5-62.5) compared to 2.6 (IQR 0.6-8.2) in the controls. Cases had higher cFGF23 levels than controls (66.2 RU/mL, IQR 52.8-98.4 vs. 61.2 RU/mL, IQR 49.5-80.1, p value <0.001). There were no differences in iFGF23 levels between cases and controls. In adjusted linear regression and multinomial regression analyses, body mass index attenuated the relationship between severe sleep disordered breathing and cFGF23 levels. No significant relationships were seen in analyses of severe sleep disordered breathing and iFGF23 levels or in analyses of iFGF23 and cFGF23 stratified by CKD status. Additional studies using other models of intermittent and chronic hypoxia are needed to confirm whether hypoxia stimulates FGF23 transcription in humans and to determine the impact on iFGF23 levels in CKD.