Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 has been proposed as an early biomarker of disordered phosphorus metabolism in earlier stages of chronic kidney disease (CKD), but data from large, well-characterized CKD cohorts are lacking. We measured FGF23 in baseline samples from 3,879 participants in the Chronic Renal Insufficiency Cohort study, a nationally representative, diverse CKD cohort with mean (± sd) estimated glomerular filtration rate (eGFR) of 42.8 ± 13.5 ml/min/1.73m2. Serum phosphate (3.7 ± 0.7 mg/dl) and parathyroid hormone (PTH; median 54, interquartile range [IQR] 35 – 89 pg/ml) levels were in the normal range, but FGF23 (median 145, IQR 96 – 239 RU/ml) was markedly greater than in healthy populations and increased significantly with decreasing eGFR. FGF23 excess, defined as ≥ 100 RU/ml, was more common than secondary hyperparathyroidism (≥ 65 pg/ml) and hyperphosphatemia (≥ 4.6 mg/dl) in all strata of eGFR, and the eGFR threshold at which the slope of FGF23 increased (57.8; 95%CI: 55.4 – 60.8 ml/min/1.73m2) was higher than the corresponding threshold for PTH (46.9; 95%CI: 45.5 – 51.4 ml/min/1.73m2). Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increases in phosphate or PTH. These findings provide additional support for use of FGF23 as a sensitive early screening test to identify disordered phosphorus metabolism in CKD patients with normal serum phosphate levels.

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Context Long-term acute care hospitals have emerged as a novel approach for the care of patients recovering from severe acute illness, but the extent and growth of their activity at the national level is unknown. Objective To examine temporal trends in long-term acute care hospital utilization after an episode of critical illness among fee-for-service Medicare beneficiaries ≥ 65 years of age. Design, Setting and Patients Retrospective cohort study using the Medicare Provider Analysis and Review files from 1997 to 2006. We included all Medicare hospitalizations involving admission to an intensive care unit of an acute-care, non-federal hospital within the continental United States. Main outcome measures Overall long-term acute care utilization, associated costs, and survival following transfer. Results The number of long-term acute care hospitals in the United States increased at a mean rate of 8.8% per year, from 192 in 1997 to 408 in 2006. During that time, the annual number of long-term acute care admissions after critical illness increased from 13,732 to 40,353, with annual costs increasing from $484 million to $1.325 billion. The age-standardized population incidence of long-term acute care utilization after critical illness increased from 38.1/100,000 in 1997 to 99.7/100,000 in 2006, with greater use among male individuals and black individuals in all time periods. Over time, transferred patients had higher numbers of comorbidities (5.0 in 1997–2000 versus 5.8 in 2004–2006, p<0.001), and were more likely to receive mechanical ventilation at the long-term acute care hospital (16.4% in 1997–2000 versus 29.8% in 2004–2006, p<0.001). One-year mortality after long-term acute care hospital admission was high throughout the study period: 50.7% in 1997–2000 and 52.2% in 2004–2006. Conclusions Long-term acute care hospital utilization after critical illness is common and increasing. Survival among Medicare beneficiaries transferred to long-term acute care after critical illness is poor.

The pathogenic mechanisms of Alzheimer's disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.

Background/Aims: Low heart rate variability (HRV) is a risk factor for adverse outcomes in the general population. We aimed to determine the factors associated with HRV and evaluate the association between low HRV and clinical outcomes in patients with chronic kidney disease (CKD). Methods: A 10-second electrocardiogram was obtained at baseline in the Chronic Renal Insufficiency Cohort (CRIC) Study. HRV was measured by the standard deviation of all R-R intervals (SDNN) and the root mean square of successive differences between R-R intervals (RMSSD). Results: In 3,245 CRIC participants with available baseline SDNN and RMSSD, lower HRV was associated with older age, lack of exercise, heart failure, elevated phosphorus and hemoglobin A1c, and low estimated glomerular filtration rate. After a median follow-up of 4.2 years, in fully adjusted models, lower HRV was not associated with renal [SDNN: hazard rate, HR = 0.96 (95% confidence interval, CI 0.88-1.05); RMSSD: HR = 0.97 (95% CI 0.88-1.07)] or cardiovascular outcomes [SDNN: HR = 1.02 (95% CI 0.92-1.13); RMSSD: HR = 1.00 (95% CI 0.90-1.10)]. There was a nonlinear relationship between RMSSD and all-cause mortality with increased risk with both low and high RMSSD (p = 0.04). Conclusions: In a large cohort of patients with CKD, multiple risk factors for renal and cardiovascular diseases were associated with lower HRV. Lower HRV was not associated with increased risk for renal or cardiovascular outcomes, but both low and high RMSSD were associated with increased risk for all-cause mortality. In conclusion, HRV measured by RMSSD may be a novel and independent risk factor for mortality in CKD patients.