Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease.

Effects of Vitamin D2 Supplementation on Vitamin D3 Metabolism in Health and CKD.

BACKGROUND AND OBJECTIVES: Vitamin D supplements are prescribed to correct low circulating concentrations of 25-hydroxyvitamin D. In CKD, vitamin D metabolism is complicated by decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by CYP27B1 and possibly decreased conversion of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D by CYP24A1. The aim of this study was to determine the effects of vitamin D2 supplementation on vitamin D metabolism in health and CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a treatment-only intervention study of 25 individuals with CKD (eGFR<60 ml/min per 1.73 m2) and 44 individuals without CKD from three academic centers, all with screening 25-hydroxyvitamin D <30 ng/ml. Each participant was prescribed vitamin D2 (ergocalciferol) 50,000 IU orally twice weekly for 5 weeks. We tested whether changes in plasma concentrations of vitamin D metabolites and vitamin D metabolic ratios differed by CKD status. Plasma 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio were calculated as estimates of CYP27B1 and CYP24A1 function, respectively. RESULTS: With treatment, plasma 25-hydroxyvitamin D2 and total 25-hydroxyvitamin D concentrations increased similarly for participants with and without CKD. For participants without CKD, 1,25-dihydroxyvitamin D2 increased (2.8±1.3-32.9±1.4 pg/ml), whereas 1,25-dihydroxyvitamin D3 decreased (45.6±1.9-14.6±1.9 pg/ml), resulting in no significant change in total 1,25-dihydroxyvitamin D; 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio decreased (3.0±0.2-1.7±0.2 pg/ng), and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio increased (115.7±7.8-195.2±7.9 pg/ng). Individuals with CKD had lower baseline levels and smaller changes in magnitude for 1,25-dihydroxyvitamin D2 (2.1±1.6-24.4±1.6 pg/ml; P interaction =0.01), 1,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio (1.8±0.2-1.1±0.2 pg/ng; P interaction =0.05), and 24,25-dihydroxyvitamin D3-to-25-hydroxyvitamin D3 ratio (72.0±9.1-110.3±9.3 pg/ng; P interaction <0.001). Fibroblast growth factor-23 and parathyroid hormone were not significantly changed in either group. CONCLUSIONS: Vitamin D2 supplementation decreases conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 and induces vitamin D3 catabolism as evidenced by changes in D3 metabolites and vitamin D metabolic ratios. These effects occur without significant changes in fibroblast growth factor-23 or parathyroid hormone and are blunted in CKD. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_02_CJASNPodcast_17_09.mp3.

Fibroblast Growth Factor 23 and Risk of CKD Progression in Children.

BACKGROUND AND OBJECTIVES: Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1-16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. RESULTS: At enrollment, median age was 11 years [interquartile range (IQR), 8-15], GFR was 44 ml/min per 1.73 m2 (IQR, 33-57), and FGF23 was 132 RU/ml (IQR, 88-200). During a median follow-up of 5.5 years (IQR, 3.5-6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P=0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P=0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. CONCLUSIONS: High plasma FGF23 is an independent risk factor for CKD progression in children.

Correlates of left ventricular mass in chronic hemodialysis recipients.

We aimed to clarify the correlates of left ventricular mass and secondarily, left ventricular volume, in a cohort of prevalent hemodialysis recipients. Left ventricular hypertrophy is common and left ventricular mass is a widely-accepted surrogate for clinical outcomes in dialysis recipients, who are often subjected to chronic pressure and volume overload. However, the precise pathophysiologic mechanisms of left ventricular hypertrophy in this unique population have not been well understood. This was a cross-sectional study of patients receiving conventional thrice-weekly dialysis in Toronto, Canada. Left ventricular mass and volume were assessed with cardiac magnetic resonance and indexed to the patient's height to the power of 2.7. Fibroblast growth factor-23 concentration was measured using a C-terminal enzyme-linked immunosorbent assay. Patient demographics, comorbidities, dialysis-associated blood pressures and ultrafiltration volumes, biochemical and hematologic parameters, vascular access and medications were extracted from clinical records. Multivariable linear regression was used to identify independent correlates of left ventricular mass index (LVMI) and the left ventricular end diastolic volume index (LVEDVI). We enrolled 56 patients, of whom 23 (41.1 %) were women with mean age 54 ± 12 years. Mean LVMI was 31.1 ± 6.8 g/m(2.7). In multivariable analyses, systolic blood pressure and LVEDVI were the only factors significantly associated with LVMI. Post-dialysis weight, percent reduction in urea and the presence of a permanent form of vascular access were associated with LVEDVI. Fibroblast growth factor-23 was not associated with either LVMI or LVEDVI. Blood pressure and left ventricular dilatation are independent determinants of elevated left ventricular mass. Aggressive blood pressure reduction and avoidance of volume overload may confer LVM regression and improve clinical outcomes.

FGF23 or PTH: which comes first in CKD ?

In the past 40 years, disordered mineral metabolism has been among the most intensely studied areas of nephrology. A June 2010 PubMed search for 'secondary hyperparathyroidism and kidney disease' yielded 5866 references. Among these are papers documenting the development and application of numerous therapeutic agents-including calcitriol, vitamin D analogs, phosphate binders, and cinacalcet-that remain in widespread use in the day-to-day management of dialysis patients worldwide. However, almost 6000 papers later, fundamental pathophysiological concepts remain unclear, particularly regarding the early pathogenesis of disordered mineral metabolism.

Chronic kidney disease, hypovitaminosis D, and mortality in the United States.

Low serum 25-hydroxy vitamin D (25OHD) predicts a higher cardiovascular risk in the general population. Because patients with chronic kidney disease are more likely to have low serum 25OHD, we determined the relationship between hypovitaminosis D and death in this group. Analysis was done using a cohort composed of 3011 patients from the Third National Health and Nutrition Examination Survey who had chronic kidney disease but were not on dialysis and who had a mean follow-up of 9 years. In analyses adjusted for demographics, cardiovascular risk factors, serum phosphorus, albumin, hemoglobin, stage of chronic kidney disease, albuminuria, and socioeconomic status, individuals with serum 25OHD levels less than 15 ng/ml had an increased risk for all-cause mortality when compared to those with levels over 30 ng/ml. This significantly higher risk for death with low serum 25OHD was evident in 15 of the 23 subgroups. The higher risk for cardiovascular and non-cardiovascular mortality became statistically nonsignificant on multivariable adjustment. The trend for higher mortality in patients with 25OHD levels 15-30 ng/ml was not statistically significant. Our results indicate there is a graded relationship between serum 25OHD and the risk for death among subjects with chronic kidney disease who are not undergoing dialysis. Randomized, controlled trials are needed to conclusively determine whether vitamin D supplementation reduces mortality.