Associations between calcium and vitamin D supplement use as well as their serum concentrations and subclinical cardiovascular disease phenotypes.

BACKGROUND: Supplementation of calcium (Ca) and vitamin D for the prevention of osteoporosis is frequently found in Western countries. Recent re-analyses of clinical trials observed a higher risk of myocardial infarction and stroke in subjects taking Ca (+vitamin D) supplements, although the underlying mechanisms are not clear. OBJECTIVE: Thus, we analyzed the associations between Ca and vitamin D supplementation as well as serum concentrations of Ca and 25-hydroxyvitamin D (25(OH)D) and subclinical cardiovascular disease (CVD) phenotypes, namely intima-media thickness, ankle-brachial-index (ABI), intermittent claudication, and atrial fibrillation (AF). DESIGN: Data of 1601 participants aged 50-81 years of the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Germany were analyzed. Logistic and linear regression models were used to estimate odds ratios (OR) (95% confidence intervals (CI)) and ß-estimates (p-values), respectively. RESULTS: Regular Ca supplementation showed a significant positive association with the presence of AF after multivariable adjustment (OR = 3.89; 95% CI 1.28-11.81). Higher serum 25(OH)D concentrations were independently associated with a lower prevalence of asymptomatic peripheral arterial disease as assessed by ABI measurements (ß = 0.007; p = 0.01). No other significant associations between supplementation or serum concentrations of Ca or vitamin D and CVD phenotypes were identified. CONCLUSIONS: Although based on few cases the finding of a significant higher prevalence of AF in Ca supplement users hints at one possible mechanism that may contribute to an increased risk of myocardial infarction and stroke. The observed association between serum 25(OH)D and ABI supports results from other studies.

Intravenous iron administration: new observations and time for the next steps.

In this issue of Kidney International, the Dialysis Outcomes and Practice Patterns Study reports that hemodialysis patients with monthly intravenous iron supplementation of 300-399 mg or ⩾400 mg had a 13 or 18% higher risk of dying, respectively, compared with those receiving 100-199 mg per month, with no obvious differences in cause-specific mortalities. This study supports that randomized controlled trials are urgently needed to identify optimized iron supplementation strategies for anemic dialysis patients.

Iron supplementation and mortality in incident dialysis patients: an observational study.

BACKGROUND: Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting. METHODS: In our observational single-center cohort study (INVOR study) we prospectively studied 235 incident dialysis patients. Time-dependent Cox proportional hazards models using all measured laboratory values for up to 7.6 years were applied to study the association between iron supplementation and all-cause mortality, cardiovascular and sepsis-related mortality. Furthermore, the time-dependent association of ferritin levels with mortality in patients with normal C-reactive protein (CRP) levels (<0.5 mg/dL) and elevated CRP levels (≧0.5 mg/dL) was evaluated by using non-linear P-splines to allow flexible modeling of the association. RESULTS: One hundred and ninety-one (81.3%) patients received intravenous iron, 13 (5.5%) patients oral iron, whereas 31 (13.2%) patients were never supplemented with iron throughout the observation period. Eighty-two (35%) patients died during a median follow-up of 34 months, 38 patients due to cardiovascular events and 21 patients from sepsis. Baseline CRP levels were not different between patients with and without iron supplementation. However, baseline serum ferritin levels were lower in patients receiving iron during follow up (median 93 vs 251 ng/mL, p<0.001). Iron supplementation was associated with a significantly reduced all-cause mortality [HR (95%CI): 0.22 (0.08-0.58); p = 0.002] and a reduced cardiovascular and sepsis-related mortality [HR (95%CI): 0.31 (0.09-1.04); p = 0.06]. Increasing ferritin concentrations in patients with normal CRP were associated with a decreasing mortality, whereas in patients with elevated CRP values ferritin levels>800 ng/mL were linked with increased mortality. CONCLUSIONS: Iron supplementation is associated with reduced all-cause mortality in incident dialysis patients. While serum ferritin levels up to 800 ng/mL appear to be safe, higher ferritin levels are associated with increased mortality in the setting of concomitant inflammation.

Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: common SNPs, rare haplotypes, no causative mutation.

BACKGROUND: Iron-refractory iron deficiency anaemia (IRIDA) is a rare disorder which was linked to mutations in two genes (SLC11A2 and TMPRSS6). Common polymorphisms within these genes were associated with serum iron levels. We identified a family of Serbian origin with asymptomatic non-consanguineous parents with three of four children presenting with IRIDA not responding to oral but to intravenous iron supplementation. After excluding all known causes responsible for iron deficiency anaemia we searched for mutations in SLC11A2 and TMPRSS6 that could explain the severe anaemia in these children. METHODOLOGY/RESULTS: We sequenced the exons and exon-intron boundaries of SLC11A2 and TMPRSS6 in all six family members. Thereby, we found seven known and fairly common SNPs, but no new mutation. We then genotyped these seven SNPs in the population-based SAPHIR study (n = 1,726) and performed genetic association analysis on iron and ferritin levels. Only two SNPs, which were top-hits from recent GWAS on iron and ferritin, exhibited an effect on iron and ferritin levels in SAPHIR. Six SAPHIR participants carrying the same TMPRSS6 genotypes and haplotype-pairs as one anaemic son showed lower ferritin and iron levels than the average. One individual exhibiting the joint SLC11A2/TMPRSS6 profile of the anaemic son had iron and ferritin levels lying below the 5(th) percentile of the population's iron and ferritin level distribution. We then checked the genotype constellations in the Nijmegen Biomedical Study (n = 1,832), but the profile of the anaemic son did not occur in this population. CONCLUSIONS: We cannot exclude a gene-gene interaction between SLC11A2 and TMPRSS6, but we can also not confirm it. As in this case candidate gene sequencing did not reveal causative rare mutations, the samples will be subjected to whole exome sequencing.

Interaction of time-varying albumin and phosphorus on mortality in incident dialysis patients.

BACKGROUND AND OBJECTIVES: Hypoalbuminemia and hyperphosphatemia have been shown to be strong predictors of mortality in dialysis patients that might not be independent from each other. We prospectively investigated the relationship and interaction between serum albumin and phosphorus with all-cause mortality in an inception cohort of incident dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We followed 235 incident dialysis patients in a prospective single-center cohort study (INVOR study) applying a time-dependent Cox proportional hazards model using all measured laboratory values (2887 albumin and 10306 phosphorus values). RESULTS: Eighty-two patients (35%) died during a median follow-up of 35.1 months. Albumin was inversely associated with mortality (hazard ratio [95% confidence interval]: 0.23 [0.14 to 0.36]; P < 0.001), whereas higher phosphorus concentrations showed a trend to an increasing risk for mortality (hazard ratio 1.57 [95% confidence interval 0.97 to 2.54]; P = 0.07). Importantly, we observed a significant interaction between albumin and phosphorus (P = 0.01). The lowest risk was found with concurrent low phosphorus and high albumin values, whereas risk was increased with either concurrent low phosphorus and low albumin values or high phosphorus and high albumin values. CONCLUSIONS: In incident dialysis patients the associations of serum phosphorus and albumin concentrations with mortality are modified by each other over time. Phosphorus-lowering interventions that concomitantly can cause a fall in serum albumin level may be harmful and warrant additional studies. If confirmed, epidemiologic studies and therapeutic guidelines aiming for target values should consider this interplay.

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population.

BACKGROUND: A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. METHODS: The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. RESULTS: Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62-2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17-1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19-2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04-1.37) and high calcium (HR = 1.74, 95% CI 1.30-2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01-1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13-1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. CONCLUSION: Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting.

BACKGROUND: Metabolomics is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in a biological fluid. However, no single analytic technique covers the entire spectrum of the human metabolome. Here we present results from a multiplatform study, in which we investigate what kind of results can presently be obtained in the field of diabetes research when combining metabolomics data collected on a complementary set of analytical platforms in the framework of an epidemiological study. METHODOLOGY/PRINCIPAL FINDINGS: 40 individuals with self-reported diabetes and 60 controls (male, over 54 years) were randomly selected from the participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) study, representing an extensively phenotyped sample of the general German population. Concentrations of over 420 unique small molecules were determined in overnight-fasting blood using three different techniques, covering nuclear magnetic resonance and tandem mass spectrometry. Known biomarkers of diabetes could be replicated by this multiple metabolomic platform approach, including sugar metabolites (1,5-anhydroglucoitol), ketone bodies (3-hydroxybutyrate), and branched chain amino acids. In some cases, diabetes-related medication can be detected (pioglitazone, salicylic acid). CONCLUSIONS/SIGNIFICANCE: Our study depicts the promising potential of metabolomics in diabetes research by identification of a series of known and also novel, deregulated metabolites that associate with diabetes. Key observations include perturbations of metabolic pathways linked to kidney dysfunction (3-indoxyl sulfate), lipid metabolism (glycerophospholipids, free fatty acids), and interaction with the gut microflora (bile acids). Our study suggests that metabolic markers hold the potential to detect diabetes-related complications already under sub-clinical conditions in the general population.

A genome scan for loci influencing anti-atherogenic serum bilirubin levels.

Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34-37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25-26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34-37, 9q21, 10q25-26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.