Studies examining the relationship between total circulating 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D–binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D–deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.

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SummaryBackground and objectives Approximately one million Americans initiated chronic dialysis over the past decade; the first-year mortality rate reported by the U.S. Renal Data System was 19.6% in 2007. This estimate has historically excluded the first 90 days of chronic dialysis.Design, setting, participants, & measurements To characterize the mortality and hospitalization risks for patients starting chronic renal replacement therapy, we followed all patients initiating dialysis in 1733 facilities throughout the United States (n ϭ 303,289). Mortality and hospitalizations within the first 90 days were compared with outcomes after this period, and the results were analyzed. Standard time-series analyses were used to depict the weekly risk estimates for each outcome.Results Between 1997 and 2009, Ͼ300,000 patients initiated chronic dialysis and were followed for Ͼ35 million dialysis treatments; the highest risk for morbidity and mortality occurred in the first 2 weeks of treatment. The initial 2-week risk of death for a typical dialysis patient was 2.72-fold higher, and the risk of hospitalization was 1.95-fold higher when compared to a patient who survived the first year of chronic dialysis (week 53 after initiation). Similarly, over the first 90 days, the risk of mortality and hospitalization remained elevated. Thereafter, between days 91 and 365, these risks decreased considerably by more than half. Surviving these first weeks of dialysis was most associated with the type of vascular access. Initiating dialysis with a fistula was associated with a decreased early death risk by 61%, whereas peritoneal dialysis decreased the risk by 87%. ConclusionsThe first 2 weeks of chronic dialysis are associated with heightened mortality and hospitalization risks, which remain elevated over the ensuing 90 days.

Abstract-Patients with chronic kidney disease and end-stage renal disease are at 5-to 10-fold higher risk for developing cardiovascular disease (CVD) than age-matched controls. Clinically, CVD in this population manifests as coronary artery disease, arrhythmias, stroke, or congestive heart failure. Beyond the traditional risk factors (eg, diabetes mellitus and hypertension), uremia-specific factors that arise from accumulating toxins also contribute to the pathogenesis of CVD.In this review, we summarize the literature on the epidemiology of both traditional and uremia-related CVD and focus on postulated mechanisms of the latter. P. Jousset, MD, 1 describing common causes of death among patients with Bright disease C hronic kidney disease (CKD) is an increasingly urgent public health concern that is projected to grow worldwide at a rate of 8% annually, with the fastest growth expected in developing nations.2,3 It has long been known that patients with kidney failure are predisposed to cardiovascular disease (CVD) that manifests clinically in various forms, including coronary artery disease, atrial or ventricular arrhythmias, myocardial infarction, stroke, or congestive heart failure. Over the last 30 years, it has become clear that the risk of CVD increases early in the course of progressive kidney disease and that the epidemiology, pathophysiology, prevention, and treatment of CVD and CKD are closely related and interdependent. 4 In this review, we initially describe the epidemiology of CVD among people with CKD, noting the limitations of available research. We then discuss common risk factors for CVD (traditional and nontraditional) and key shared aspects of its pathophysiology with CKD. Next we describe emerging diagnostic tools and novel therapies that may help to delay or prevent end-stage renal disease (ESRD) and to curtail the escalating burden of cardiorenal disease. In the final section, we discuss the health services and health policy challenges that CKD and its inextricably linked CVD morbidities pose worldwide, particularly for low-and middle-income countries (LMICs). Phenotypes and Epidemiology of CVD in Patients With CKDPatients with CKD and some forms of CVD share a number of risk factors and underlying pathophysiological mechanisms that, by virtue of their similarities, offer opportunities to improve their management. The epidemiology of 4 of the commonest clinical phenotypes of CVD associated with CKD is discussed below. Coronary Artery DiseaseCoronary artery disease (CAD) is a leading cause of death among people with advanced CKD. Clinical syndromes compatible with CAD (including angina and myocardial infarction) are exceedingly common in patients with nondialysis-dependent CKD, and the incidence of myocardial

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Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by β-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and “stabilized” forms of β-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting β-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell–specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of β-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on β-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote β-catenin degradation.

Carbamylation describes a non-enzymatic, posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally rises. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins, and have been directly implicated in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation’s relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances.

Background Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high risk population. In non-autoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. Objective To determine whether early dysregulation of circulating angiogenic factors, can predict APO in high risk SLE and/or APL pregnancies. Study Design We used data and samples from the PROMISSE Study (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus), a multi-center prospective study that enrolled 492 pregnant women with SLE and/or APL between September 2003 and August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured monthly and subjects followed for APO, classified as severe (PE<34 weeks, fetal/neonatal death, indicated pre-term delivery <30 weeks) or moderate (PE≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). Results Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and sEng levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio=17.3 comparing highest and lowest quartiles, 95% CI: 3.5-84.8; positive predictive value (PPV)=61%; negative predictive value (NPV)=93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/ml) and sFlt1 in highest quartile (>1872 pg/ml; odds ratio=31.1; 95% CI: 8.0-121.9; PPV=58%; NPV=95%). Severe APO rate in this high risk subgroup was 94% (95%CI: 70%-99.8%), if lupus anticoagulant or history of high blood pressure is additionally present. In contrast, among patients with both sFlt1 <1872 pg/ml and PlGF >70.3 pg/ml, rate of severe APO was only 4.6% (95% CI: 2.1%-8.6%). Conclusions Circulating angiogenic factors measured during early gestation have a high negative predictive value in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of healthcare resources.