Assessment and clinical implications of functional vitamin B6 deficiency

Vitaminen zijn essentieel voor een gezond en lang leven. Tegenwoordig worden vitaminesupplementen dan ook veelvuldig gebruikt om het algemeen welbevingen te verbeteren en aandoeningen te verlichten of te voorkomen. Echter, bij veel groepen mensen, zoals patiënten met fibromyalgie en het chronisch vermoeidheidssyndroom, ontbreekt de wetenschappelijke basis hiervoor met als gevolg dat men mogelijk onnodig risico loopt op vitaminetoxiciteit, zoals onlangs met vitamine B6 is gebleken bij Sven Kramer. In dit proefschrift laten wij zien dat het tot nu toe uitgevoerde onderzoek naar een mogelijk verband tussen vitaminen en de ziekteactiviteit van fibromyalgie en het chronisch vermoeidheidssyndroom laag van kwaliteit is en dat er op basis van dit onderzoek geen duidelijk verband tussen vitaminen en ziekteactiviteit aanwijsbaar is. Hiermee hebben wij laten zien dat er vooralsnog geen goede wetenschappelijke basis bestaat voor het gebruik van vitaminesupplementen ter verlichting van de symptomen van fibromyalgie en het chronisch vermoeidheidssyndroom. Verder hebben wij aangetoond dat een vitamine B6 tekort relatief vaak voorkomt bij niertransplantatiepatiënten en dat dit tekort bepaalde intracellulaire processen op moleculair niveau lijkt te verstoren. Bovendien wijzen onze data erop dat vitamine B6 deficiënte niertransplantatiepatiënten en vrouwen uit de algemene bevolking een hogere kans hebben op voortijdige sterfte ten gevolge van cardiovasculaire aandoeningen, vergeleken met personen met een adequate vitamine B6 status. Wij concluderen dan ook dat niertransplantatiepatiënten en vrouwen mogelijk baat zouden kunnen hebben bij vitamine B6 supplementen. Voordat dit in de richtlijnen opgenomen kan worden, dienen interventiestudies met vitamine B6 supplementen echter eerst sluitend bewijs te leveren

Interpretation of Folate Results in Hemolytic Plasma Samples:A Practical Approach

Folate analysis in plasma is affected by hemolysis, which can lead to biased results. However, the degree of hemolysis that is considered acceptable is unclear. We explored the relationship between folate concentration and degree of hemolysis. Heparin plasma samples (N=77, hemolysis index ≤10 μmol/L) were spiked with increasing amounts of corresponding patient-specific hemolysate. Subsequently, the folate concentration and hemolysis index were measured using two Roche Cobas platforms, and their incremental relationship was investigated. The folate concentration ranged from 2.9 to 30.9 nmol/L with a median (interquartile range) of 11.4 (8.6-19.1) nmol/L. The linear relationship between the increments in folate concentration and hemolysis index was approximated by the function y=1.86x+1.56 (R(2)=0.996), where x represents the laboratory-specific critical difference in folate concentration, which can be calculated from the analytical variation of the employed folate assay(s), and y represents the hemolysis threshold. The hemolysis threshold did not significantly differ between the tertiles of plasma folate concentration (P=0.10). In conclusion, we have provided an evidence-based approach that can be used to reliably interpret folate concentrations in hemolytic samples, independent of the patient’s folate status

Associations of 24 h urinary excretions of alpha- and gamma-carboxyethyl hydroxychroman with plasma alpha- and gamma-tocopherol and dietary vitamin E intake in older adults:the Lifelines-MINUTHE Study

Background Urinary metabolites of vitamin E, i.e., alpha- and gamma-carboxyethyl hydroxychroman (alpha- and gamma-CEHC), have gained increasing attention and have been proposed as novel biomarkers of vitamin E intake and status. However, there are insufficient data on the relationship of plasma alpha-tocopherol and gamma-tocopherol and dietary vitamin E intake with 24 h urinary excretions of alpha- and gamma-CEHC. Objectives We aimed to (1) investigate the associations of urinary alpha- and gamma-CEHC/creatinine ratios and 24 h urinary excretions of alpha- and gamma-CEHC with plasma alpha- and gamma-tocopherol, respectively; (2) investigate the associations of urinary alpha- and gamma-CEHC/creatinine ratios and 24 h urinary excretions of alpha- and gamma-CEHC with dietary vitamin E intake, and we hypothesize that 24 h urinary excretions of alpha- and gamma-CEHC will better correlate with vitamin E intake than urinary alpha- and gamma-CEHC/creatinine ratios. Design 24 h Urine and plasma samples were collected from 1519 participants (60-75 years, male: 50%) included in the Lifelines-MINUTHE Study for the assessments of urinary alpha- and gamma-CEHC/creatinine ratios and 24 h urinary excretions of alpha- and gamma-CEHC, and plasma alpha- and gamma-tocopherol. Among those participants, dietary vitamin E intake data from 387 participants were available from an externally validated Flower-Food Frequency Questionnaire (FFQ). The associations of plasma alpha- and gamma-tocopherol, dietary vitamin E intake, with urinary alpha- and gamma-CEHC were assessed using multivariate linear regressions. Results 24 h Urinary excretion of alpha-CEHC (median (IQR): 0.9 (0.3-2.4) mu mol) was less than that of gamma-CEHC (median (IQR): 1.5 (0.5-3.5) mu mol). After adjustment for covariates, we found that 24 h urinary alpha-CEHC excretion and urinary alpha-CEHC/creatinine ratio were both positively associated with plasma alpha-tocopherol (std.beta: 0.06, p = 0.02; std.beta: 0.06, p = 0.01, respectively). Furthermore, the sum of 24 h urinary alpha- and gamma-CEHC excretions was positively associated with dietary vitamin E intake (std.beta: 0.08; p = 0.03), whereas there was no relation between urinary alpha- and gamma-CEHC/creatinine ratios and vitamin E intake. No association was observed neither between plasma alpha- and gamma-tocopherol and dietary vitamin E intake, nor between urinary gamma-CEHC and plasma gamma-tocopherol. Conclusion Our study confirmed our hypothesis that 24 h urinary alpha- and gamma-CEHC excretions would be a better marker for dietary vitamin E intake than urinary alpha- and gamma-CEHC/creatinine ratios. Considering that both 24 h urinary alpha- and gamma-CEHC excretions and alpha- and gamma-CEHC/creatinine ratios were also associated with plasma alpha-tocopherol status, we suggest that 24 h urinary alpha- and gamma-CEHC excretions could be used to assess overall vitamin E status

Urinary Excretion of 6-Sulfatoxymelatonin, the Main Metabolite of Melatonin, and Mortality in Stable Outpatient Renal Transplant Recipients

Melatonin is a multifaceted hormone which rises upon the onset of darkness. Pineal synthesis of melatonin is known to be disturbed in patients with end-stage renal disease, but it is not known if its production is restored to normal after successful renal transplantation. We hypothesized that urinary excretion of 6-sulfatoxymelatonin, the major metabolite of melatonin, is lower in renal transplant recipients (RTRs) compared to healthy controls and that this is associated with excess mortality. Urinary 6-sulfatoxymelatonin was measured via LC-MS/MS in 701 stable outpatient RTRs and 285 healthy controls. Median urinary 6-sulfatoxymelatonin in RTR was 13.2 nmol/24 h, which was 47% lower than in healthy controls. Urinary 6-sufatoxymelatonin appeared undetectable in the majority of 36 RTRs with diabetic nephropathy as primary renal disease. Therefore, this subgroup was excluded from further analyses. Of the remaining 665 RTRs, during 5.4 years of follow-up, 110 RTRs died, of whom 38 died due to a cardiovascular cause. In Cox-regression analyses, urinary 6-sulfatoxymelatonin was significantly associated with all-cause mortality (0.60 (0.44–0.81), p = 0.001) and cardiovascular mortality (0.49 (0.29–0.84), p = 0.009), independent of conventional risk factors and kidney function parameters. Based on these results, evaluation and management of melatonin metabolism could be considered for improvement of long-term outcomes in RTRs

High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients

l-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and l-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] mu M vs. 2.78 [2.89-3.35] mu M (P <0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA

Urinary sulfate excretion and risk of late graft failure in renal transplant recipients - a prospective cohort study

Hydrogen sulfide (H2S), produced from metabolism of dietary sulfur-containing amino acids, is allegedly a renoprotective compound. Twenty-four-hour urinary sulfate excretion (USE) may reflect H2S bioavailability. We aimed to investigate the association of USE with graft failure in a large prospective cohort of renal transplant recipients (RTR). We included 704 stable RTR, recruited at least 1 year after transplantation. We applied log-rank testing and Cox regression analyses to study association of USE, measured from baseline 24 h urine samples, with graft failure. Median age was 55 [45–63] years (57% male, eGFR was 45 ± 19 ml/min/1.73 m2). Median USE was 17.1 [13.1–21.1] mmol/24 h. Over median follow-up of 5.3 [4.5–6.0] years, 84 RTR experienced graft failure. RTR in the lowest sex-specific tertile of USE experienced a higher rate of graft failure during follow-up than RTR in the middle and highest sex-specific tertiles (18%, 13%, and 5%, respectively, log-rank P < 0.001). In Cox regression analyses, USE was inversely associated with graft failure [HR per 10 mmol/24 h: 0.37 (0.24–0.55), P < 0.001]. The association remained independent of adjustment for potential confounders, including age, sex, eGFR, proteinuria, time between transplantation and baseline, BMI, smoking, and high sensitivity C-reactive protein [HR per 10 mmol/24 h: 0.51 (0.31–0.82), P = 0.01]. In conclusion, this study demonstrates a significant inverse association of USE with graft failure in RTR, suggesting high H2S bioavailability as a novel, potentially modifiable factor for prevention of graft failure in RTR

TRAILER project overview: tagging, recognition and acknowledgment of informal learning experiences

The evolution of new technology and its increasing use, have for some years been making the existence of informal learning more and more transparent, especially among young and older adults in both Higher Education and workplace contexts. However, the nature of formal and non-formal, coursebased, approaches to learning has made it hard to accommodate these informal processes satisfactorily, and although technology bring us near to the solution, it has not yet achieved. TRAILER project aims to address this problem by developing a tool for the management of competences and skills acquired through informal learning experiences, both from the perspective of the user and the institution or company. This paper describes the research and development main lines of this project.Peer ReviewedPostprint (published version