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 The purpose of this study is to evaluate serum bicarbonate as a risk factor for renal outcomes, cardiovascular events and mortality in patients with chronic kidney disease (CKD). Study Design Observational cohort study. Setting & Participants 3939 participants with CKD stages 2-4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 - December 2008. Predictor Serum bicarbonate. Outcomes Renal outcomes, defined as end-stage renal disease (either initiation of dialysis or kidney transplantation) or 50% reduction in eGFR; atherosclerotic events (myocardial infarction, stroke, peripheral arterial disease); congestive heart failure events; and death. Measurements Time to event. Results The mean eGFR was 44.8 ± 16.8 (SD) mL/min/1.73 m2, and the median serum bicarbonate was 24 (IQR, 22-26) mEq/L. During a median follow-up of 3.9 years, 374 participants died, 767 had a renal outcome, and 332 experienced an atherosclerotic event and 391 had a congestive heart failure event. In adjusted analyses, the risk of developing a renal endpoint was 3% lower per mEq/L increase in serum bicarbonate (HR, 0.97; 95% CI, 0.94-0.99; p=0.01). The association was stronger for participants with eGFR> 45ml/min/1.73m2 (HR, 0.91; 95%CI, 0.85-0.97; p=0.004). The risk of heart failure increased by 14% (HR, 1.14; 95%CI, 1.03-1.26; p=0.02) per mEq/L increase in serum bicarbonate over 24 mEq/L. Serum bicarbonate was not independently associated with atherosclerotic events (HR, 0.99; 95%CI, 0.95-1.03; p=0.6) and all-cause mortality (HR, 0.98; 95%CI, 0.95-1.02; p=0.3). Limitations Single measurement of sodium bicarbonate. Conclusions In a cohort of participants with CKD, low serum bicarbonate was an independent risk factor for kidney disease progression, particularly for participants with preserved kidney function. The risk of heart failure was higher at the upper extreme of serum bicarbonate. There was no association between serum bicarbonate and all-cause mortality or atherosclerotic events.

Background Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies. Study Design Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach. Setting & Participants Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black. Index Test CRIC GFR estimating equation Reference Test or Outcome Urinary 125I-iothalamate clearance testing (measured GFR) Other Measurements Laboratory measures including serum creatinine and cystatin C, and anthropometrics Results In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR. Limitations Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors. Conclusions The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants.

Hemoglobin levels vary substantially over time in hemodialysis patients, and this variability may portend poor outcomes. For a given patient, hemoglobin concentration over time can be described by absolute levels, rate of change, or by the difference between observed level and expected level based on the preceding trend (i.e., seemingly random variability). We investigated the independent associations of these different methods of describing hemoglobin over time with mortality in a retrospective cohort of 34,963 hemodialysis patients. Hemoglobin concentration over time was modeled with linear regression for each subject, and the model was then used to define the subject's absolute level of hemoglobin (intercept), temporal trend in hemoglobin (slope), and hemoglobin variability (residual standard deviation). Survival analyses indicated that each 1g/dl increase in the residual standard deviation was associated with a 33% increase in rate of death, even after adjusting for multiple covariates. Patient characteristics accounted for very little of the variation in our hemoglobin variability metric (R 2 ϭ 0.019). We conclude that greater hemoglobin variability is independently associated with higher mortality.

Studies of brain development suggest that the increase in risk taking observed during adolescence may be due to insufficient prefrontal executive function compared to a more rapidly developing subcortical motivation system. We examined executive function as assessed by working memory ability in a community sample of youth (n = 387, ages 10 to 12 at baseline) in three annual assessments to determine its relation to two forms of impulsivity (sensation seeking and acting without thinking) and a wide range of risk and externalizing behavior. Using structural equation modeling, we tested a model in which differential activation of the dorsal and ventral striatum produces imbalance in the function of these brain regions. For youth high in sensation seeking, both regions were predicted to develop with age. However, for youth high in the tendency to act without thinking, the ventral striatum was expected to dominate. The model predicted that working memory ability would exhibit (1) early weakness in youth high in acting without thinking but (2) growing strength in those high in sensation seeking. In addition, it predicted that (3) acting without thinking would be more strongly related to risk and externalizing behavior than sensation seeking. Finally, it predicted that (4) controlling for acting without thinking, sensation seeking would predict later increases in risky and externalizing behavior. All four of these predictions were confirmed. The results indicate that the rise in sensation seeking that occurs during adolescence is not accompanied by a deficit in executive function and therefore requires different intervention strategies from those for youth whose impulsivity is characterized by early signs of acting without thinking.