Context High levels of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), associate with mortality in patients with end-stage renal disease (ESRD), but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease (CKD). Objective Evaluate FGF23 as a risk factor for adverse outcomes in patients with CKD. Design, Setting and Participants A prospective study of 3,879 participants with CKD stages 2 – 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. Main Outcome Measures All-cause mortality and ESRD. Results At enrollment, mean estimated glomerular filtration rate (eGFR) was 42.8 ± 13.5 ml/min/1.73m2, and median FGF23 was 145 (interquartile range [IQR] 96 – 239) reference units/ml (RU/ml). During a median follow-up of 3.5 (IQR 2.5 – 4.4) years, 266 participants died (20.3/1000 person-years) and 410 reached ESRD (33.0/1000 person-years). Higher FGF23 levels independently associated with a greater risk of death in adjusted analyses of FGF23 on a continuous scale (hazard ratio [HR] per SD of lnFGF23, 1.5; 95%CI 1.3 – 1.7) or in quartiles (quartile 1, reference; quartile 2, HR 1.3; 95%CI 0.8 – 2.2; quartile 3, HR 2.0; 95%CI 1.2 – 3.3; quartile 4, HR 3.0; 95%CI 1.8 – 5.1). FGF23 was not independently associated with ESRD in adjusted analyses of the entire cohort, however, the effect was modified by eGFR (P for interaction = 0.005), which was the strongest predictor for ESRD. FGF23 independently associated with significantly greater risk of ESRD among participants with eGFR 30 – 44 (HR 1.3 per SD of lnFGF23; 95%CI 1.04 – 1.6) and ≥ 45 (HR 1.7; 95%CI 1.1 – 2.4), but not < 30 ml/min/1.73m2. Conclusion Elevated FGF23 is an independent risk factor for ESRD in patients with relatively preserved kidney function and for mortality across the spectrum of CKD.

BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44615 ml/min per 1.73 m 2 ). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR] . Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Background A low rate of blood pressure control has been reported among patients with chronic kidney disease (CKD). These data were derived from population-based samples with a low rate of CKD awareness. Study Design Cross-sectional Setting & Participants Data from the baseline visit of the Chronic Renal Insufficiency Cohort (CRIC) study (n=3612) were analyzed. Participants with an estimated glomerular filtration rate of 20 to 70 ml/min/1.73m2 were identified from physician offices and review of laboratory databases. Outcomes Prevalence and awareness of hypertension, treatment patterns, control rates and factors associated with hypertension control. Measurements Following a standardized protocol, blood pressure was measured three times by trained staff and hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg and/or self-reported antihypertensive medication use. Patients’ awareness and treatment of hypertension were defined using self-report and two levels of hypertension control were evaluated: systolic/diastolic blood pressure <140/90 mmHg and <130/80 mmHg. Results The prevalence of hypertension was 85.7%, and 98.9% of CRIC participants were aware of this diagnosis, 98.3% were treated with medications while 67.1% and 46.1% had their hypertension controlled to <140/90 mmHg and <130/80 mmHg, respectively. Of CRIC participants with hypertension, 15%, 25%, 26% and 32% were taking one, two, three and four or more antihypertensive medications, respectively. After multivariable adjustment, older patients, blacks, those with higher urinary albumin excretion were less likely while participants taking ACE-inhibitors and angiotensin receptor blockers were more likely to have controlled their hypertension to <140/90 mmHg and <130/80 mmHg. Limitations Data were derived from a single study visit. Conclusions Despite almost universal hypertension awareness and treatment in this cohort of patients with CKD, rates of hypertension control were sub-optimal.

Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories $60, 45-59, 30-44, and ,30 ml/ min per 1.73 m 2 , respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of ,30 ml/ min per 1.73 m 2 had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P,0.001) relative to subjects with eGFR$60 ml/min per 1.73 m 2 . This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m 2 also significantly associated with LVH and abnormal LV geometry compared with eGFR$60 ml/min per 1.73 m 2 . In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables.