Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study.

Rationale & Objective: Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Study Design: Prospective cohort study. Settings & Participants: A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Exposure: Baseline plasma FGF23. Outcomes: Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF] ≥ 50%), HF with reduced EF (HFrEF, EF < 50%) and HF with unknown EF (HFuEF). Analytical Approach: Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF. Results: During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events. Limitations: Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization. Conclusions: In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes. Plain-Language Summary: Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N = 3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.

Associations between endogenous sex hormones and FGF-23 among women and men in the Multi-Ethnic Study of Atherosclerosis.

Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30-46) vs 38 (31-47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.

Risk-Based Intensive Blood Pressure Lowering and Prevention of Heart Failure: A SPRINT Post Hoc Analysis.

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Change in ankle-brachial index and mortality among individuals with chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Patients with chronic kidney disease (CKD) have an increased risk of peripheral arterial disease (PAD). The ankle-brachial index (ABI), a noninvasive measure of PAD, is a predictor of adverse events among individuals with CKD. In general populations, changes in ABI have been associated with mortality, but this association is not well understood among patients with CKD. METHODS: We conducted a prospective study of 2920 participants in the Chronic Renal Insufficiency Cohort Study without lower extremity revascularization or amputation at baseline and with at least one follow-up ABI measurement (taken at annual visits) during the first 4 years of follow-up. The ABI was obtained by the standard protocol. RESULTS: In Cox proportional hazard regression analyses, we found a U-shaped association of average annual change in ABI with all-cause mortality. After adjusting for baseline ABI and other covariates, compared with participants with an average annual change in ABI of 0-<0.02, individuals with an average annual change in ABI <-0.04 or ≥0.04 had multivariable-adjusted hazard ratios (HRs) of 1.81 [95% confidence interval (CI) 1.34-2.44) and 1.42 (95% CI 1.12-1.82) for all-cause mortality, respectively. Compared with the cumulative average ABI of 1.0-<1.4, multivariable-adjusted HRs for those with a cumulative average ABI of <0.9, 0.9-<1.0 and ≥1.4 were 1.93 (95% CI 1.42-2.61), 1.20 (0.90-1.62) and 1.31 (0.94-1.82), respectively. CONCLUSIONS: This study indicates both larger decreases and increases in average annual changes in ABI (>0.04/year) were associated with higher mortality risk. Monitoring changes in ABI over time may facilitate risk stratification for mortality among individuals with CKD.

Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease.

Disordered iron and mineral homeostasis are interrelated complications of chronic kidney disease that may influence cardiovascular and kidney outcomes. In a prospective analysis of 3747 participants in the Chronic Renal Insufficiency Cohort Study, we investigated risks of mortality, heart failure, end-stage kidney disease (ESKD), and atherosclerotic cardiovascular disease according to iron status, and tested for mediation by C-terminal fibroblast growth factor 23 (FGF23), hemoglobin and parathyroid hormone. Study participants were agnostically categorized based on quartiles of transferrin saturation and ferritin as "Iron Replete" (27.1% of participants; referent group for all outcomes analyses), "Iron Deficiency" (11.1%), "Functional Iron Deficiency" (7.6%), "Mixed Iron Deficiency" (iron indices between the Iron Deficiency and Functional Iron Deficiency groups; 6.3%), "High Iron" (9.2%), or "Non-Classified" (the remaining 38.8% of participants). In multivariable-adjusted Cox models, Iron Deficiency independently associated with mortality (hazard ratio 1.28, 95% confidence interval 1.04-1.58) and heart failure (1.34, 1.05- 1.72). Mixed Iron Deficiency associated with mortality (1.61, 1.27-2.04) and ESKD (1.33, 1.02-1.73). High Iron associated with mortality (1.54, 1.24-1.91), heart failure (1.58, 1.21-2.05), and ESKD (1.41, 1.13-1.77). Functional Iron Deficiency did not significantly associate with any outcome, and no iron group significantly associated with atherosclerotic cardiovascular disease. Among the candidate mediators, FGF23 most significantly mediated the risks of mortality and heart failure conferred by Iron Deficiency. Thus, alterations in iron homeostasis associated with adverse cardiovascular and kidney outcomes in patients with chronic kidney disease.

Fibroblast Growth Factor 23 and Incident Cardiovascular Disease and Mortality in Middle-Aged Adults.

Background Higher circulating fibroblast growth factor 23 (FGF23) associates with greater risk of cardiovascular disease (CVD) and mortality in older adults. The association of FGF23 with cardiovascular outcomes in younger populations has been incompletely explored. Methods and Results We measured C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) in 3151 middle-aged adults (mean age, 45±4) who participated in the year 20 examination of the CARDIA (Coronary Artery Risk Development in Young Adults) study. We used separate Cox proportional hazards models to examine the associations of cFGF23 and iFGF23 with incident CVD and mortality, adjusting models sequentially for sociodemographic, clinical, and laboratory factors. A total of 157 incident CVD events and 135 deaths occurred over a median 7.6 years of follow-up (interquartile range, 4.1-9.9). In fully adjusted models, there were no statistically significant associations of FGF23 with incident CVD events (hazard ratio per doubling of cFGF23: 1.14, 95%CI 0.97,1.34; iFGF23: 0.76, 95%CI 0.57,1.02) or all-cause mortality (hazard ratio per doubling of cFGF23, 1.17; 95% CI, 1.00-1.38; iFGF23, 0.86; 95% CI, 0.64-1.17). In analyses stratified by CVD subtypes, higher cFGF23 was associated with greater risk of heart failure hospitalization (hazard ratio per doubling of cFGF23, 1.52; 95% CI, 1.18-1.96) but not coronary heart disease or stroke, whereas iFGF23 was not associated with CVD subtypes in any model. Conclusions In middle-aged adults with few comorbidities, higher cFGF23 and iFGF23 were not independently associated with greater risk of CVD events or death. Higher cFGF23 was independently associated with greater risk of heart failure hospitalization.

Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. STUDY DESIGN: A multicenter, prospective, cohort study. SETTING & PARTICIPANTS: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). OUTCOMES: Incident heart failure, myocardial infarction, and stroke events. ANALYTICAL APPROACH: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. RESULTS: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. LIMITATIONS: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. CONCLUSIONS: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

Association of tubular solute clearances with the glomerular filtration rate and complications of chronic kidney disease: the Chronic Renal Insufficiency Cohort study.

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. The degree to which secretory solute clearance corresponds with the glomerular filtration rate (GFR) and potential metabolic implications of net secretory clearance are largely unknown. METHODS: We evaluated 1240 participants with chronic kidney disease (CKD) from the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used targeted mass-spectrometry to quantify candidate secretory solutes in paired 24-h urine and plasma samples. CRIC study personnel measured GFR using 125I-iothalamate clearance (iGFR). We used correlation and linear regression to determine cross-sectional associations of secretory clearances with iGFR and common metabolic complications of CKD. RESULTS: Correlations between iGFR and secretory solute clearances ranged from ρ = +0.30 for hippurate to ρ = +0.58 for kynurenic acid. Lower net clearances of most secretory solutes were associated with higher serum concentrations of parathyroid hormone (PTH), triglycerides and uric acid. Each 50% lower kynurenic acid clearance was associated with a 21% higher serum PTH concentration [95% confidence interval (CI) 15-26%] and a 10% higher serum triglyceride concentration (95% CI 5-16%) after adjustment for iGFR, albuminuria and other potential confounders. Secretory solute clearances were not associated with statistically or clinically meaningful differences in serum calcium, phosphate, hemoglobin or bicarbonate concentrations. CONCLUSIONS: Tubular secretory clearances are modestly correlated with measured GFR among adult patients with CKD. Lower net secretory clearances are associated with selected metabolic complications independent of GFR and albuminuria, suggesting potential clinical and biological relevance.

Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study.

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.

Serum Calcification Propensity and Clinical Events in CKD.

BACKGROUND AND OBJECTIVES: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T50 with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality. RESULTS: The mean T50 was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T50 was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T50, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T50, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T50, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T50, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T50 was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality. CONCLUSIONS: Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.