Reduction of Oxidative Stress in Chronic Kidney Disease Does Not Increase Circulating alpha-Klotho Concentrations

The CKD-associated decline in soluble α-Klotho levels is considered detrimental. Some in vitro and in vivo animal studies have shown that anti-oxidant therapy can upregulate the expression of α-Klotho in the kidney. We examined the effect of anti-oxidant therapy on α-Klotho concentrations in a clinical cohort with mild tot moderate chronic kidney disease (CKD). We performed a post-hoc analysis of a prospective randomized trial involving 62 patients with mild to moderate CKD (the ATIC study), all using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for 12 months. On top of that, the intervention group received anti-oxidative therapy consisting of the combination of pravastatin (40 mg/d) and vitamin E (α-tocopherol acetate, 300 mg/d) while the placebo was not treated with anti-oxidants. α-Klotho concentrations were measured at baseline and after 12 months of anti-oxidant therapy. Data were analysed using T-tests and Generalized Estimating Equations, adjusting for potential confounders such as vitamin D, parathyroid hormone, fibroblast-growth-factor 23 (FGF23) and eGFR. The cohort existed of 62 patients with an eGFR (MDRD) of 35 ± 14 ml/min/1.72 m2, 34 were male and mean age was 53.0 ± 12.5 years old. Anti-oxidative therapy did successfully reduce oxLDL and LDL concentrations (P <0.001). α-Klotho concentrations did not change in patients receiving either anti-oxidative therapy (476.9 ± 124.3 to 492.7 ± 126.3 pg/mL, P = 0.23) nor in those receiving placebo 483.2 ± 142.5 to 489.6 ± 120.3 pg/mL, P = 0.62). Changes in α-Klotho concentrations were not different between both groups (p = 0.62). No evidence was found that anti-oxidative therapy affected α-Klotho concentrations in patients with mild-moderate CKD

Magnesium intake and vascular structure and function:the Hoorn Study

PURPOSE: Circulating and dietary magnesium have been shown to be inversely associated with the prevalence of cardiovascular disease (CVD) and mortality in both high and low-risk populations. We aimed to examine the association between dietary magnesium intake and several measures of vascular structure and function in a prospective cohort. METHODS: We included 789 participants who participated in the vascular screening sub-cohort of the Hoorn Study, a population-based, prospective cohort study. Baseline dietary magnesium intake was estimated with a validated food frequency questionnaire and categorised in energy-adjusted magnesium intake tertiles. Several measurements of vascular structure and function were performed at baseline and most measurements were repeated after 8 years of follow-up (n = 432). Multivariable linear and logistic regression was performed to study the cross-sectional and longitudinal associations of magnesium intake and intima-media thickness (IMT), augmentation index (Aix), pulse wave velocity (PWV), flow-mediated dilatation (FMD), and peripheral arterial disease (PAD). RESULTS: Mean absolute magnesium intake was 328 ± 83 mg/day and prior CVD and DM2 was present in 55 and 41% of the participants, respectively. Multivariable regression analyses did not demonstrate associations between magnesium intake and any of the vascular outcomes. Participants in the highest compared to the lowest magnesium intake tertile demonstrated in fully adjusted cross-sectional analyses a PWV of −0.21 m/s (95% confidence interval −1.95, 1.52), a FMD of −0.03% (−0.89, 0.83) and in longitudinal analyses an IMT of 0.01 mm (−0.03, 0.06), an Aix of 0.70% (−1.69, 3.07) and an odds ratio of 0.84 (0.23, 3.11) for PAD CONCLUSION: We did not find associations between dietary magnesium intake and multiple markers of vascular structure and function, in either cross-sectional or longitudinal analyses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00394-021-02667-0

Comparison of two methods for the assessment of intra-erythrocyte magnesium and its determinants:Results from the LifeLines cohort study

BACKGROUND: Direct methods for the assessment of intra-erythrocyte magnesium (dIEM) require extensive sample preparation, making them labor intensive. An alternative, less labor intensive method is indirect calculation of intra-erythrocyte magnesium (iIEM). We compared dIEM and iIEM and studied determinants of dIEM and iIEM, plasma magnesium and 24-h urinary magnesium excretion in a large population-based cohort study. METHODS: dIEM and iIEM were measured using a validated inductively coupled plasma mass spectrometry (ICP-MS) method in 1669 individuals from the second screening from the LifeLines Cohort Study. We used linear regression analyses to study the determinants of IEM, plasma magnesium and 24-h urinary magnesium excretion. RESULTS: Mean dIEM and iIEM were 0.20 ± 0.04 mmol/1012 cells and 0.25 ± 0.04 mmol/1012 cells, respectively. We found a strong correlation between dIEM and iIEM (r = 0.75). Passing-Bablok regression analyses showed an intercept of 0.015 (95% CI: 0.005; 0.023) and a slope of 1.157 (95% CI: 1.109; 1.210). In linear regression analyses, plasma levels of total- and LDL -cholesterol, and triglycerides were positively associated dIEM, iIEM, and plasma magnesium, while glucose and HbA1c were inversely associated with plasma magnesium. CONCLUSIONS: We observed a strong correlation between dIEM and iIEM, suggesting that iIEM is a reliable alternative for the labor intensive dIEM method

On reminder effects, drop-outs and dominance: evidence from an online experiment on charitable giving

We present the results of an experiment that (a) shows the usefulness of screening out drop-outs and (b) tests whether different methods of payment and reminder intervals affect charitable giving. Following a lab session, participants could make online donations to charity for a total duration of three months. Our procedure justifying the exclusion of drop-outs consists in requiring participants to collect payments in person flexibly and as known in advance and as highlighted to them later. Our interpretation is that participants who failed to collect their positive payments under these circumstances are likely not to satisfy dominance. If we restrict the sample to subjects who did not drop out, but not otherwise, reminders significantly increase the overall amount of charitable giving. We also find that weekly reminders are no more effective than monthly reminders in increasing charitable giving, and that, in our three months duration experiment, standing orders do not increase giving relative to one-off donations

The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats

Background: Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function. Methods: Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis. Results: Hemorrhagic shock significantly decreased renal perfusion (240 +/- 138 to 51 +/- 40, p 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 +/- 3 vs 8 +/- 3 perfused vessels, p < 0.05). Conclusion: Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy

Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: A multi-center randomized clinical trial

Introduction: Because of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI).Methods: In this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied.Results: Of the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P &#60; 0.001). Filter survival times were superior for citrate (median 46 versus 32 hour

Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: An analysis of the MASTERPLAN cohort

Contains fulltext : 107913.pdf (postprint version ) (Open Access)BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a risk factor for cardiovascular disease and mortality throughout all stages of chronic kidney disease (CKD), independent from established risk factors and markers of mineral homeostasis. The relation of FGF23 with other renal and non-renal cardiovascular risk factors is not well established. METHODS: Using stored samples, plasma FGF23 was determined in 604 patients with moderate to severe kidney disease that participated in the MASTERPLAN study (ISRCTN73187232). The association of FGF23 with demographic and clinical parameters was evaluated using multivariable regression models. RESULTS: Mean age in the study population was 60 years and eGFR was 37 (+/- 14) ml/min/1.73 m(2). Median proteinuria was 0.3 g/24 hours [IQR 0.1-0.9]. FGF23 level was 116 RU/ml [67-203] median and IQR. Using multivariable analysis the natural logarithm of FGF23 was positively associated with history of cardiovascular disease (B = 0.224 RU/ml; p = 0.002), presence of diabetes (B = 0.159 RU/ml; p = 0.035), smoking (B = 0.313 RU/ml; p < 0.001), phosphate level (B = 0.297 per mmol/l; p = 0.0024), lnPTH (B = 0.244 per pmol/l; p < 0.001) and proteinuria (B = 0.064 per gram/24 hrs; p = 0.002) and negatively associated with eGFR (B = -0.022 per ml/min/1.73 m(2); p < 0.001). CONCLUSIONS: Our study demonstrates that in patients with CKD, FGF23 is related to proteinuria and smoking. We confirm the relation between FGF23 and other cardiovascular risk factors

Predictors for patient knowledge and reported behaviour regarding driving under the influence of medicines: a multi-country survey

<p>Abstract</p> <p>Background</p> <p>Reports on the state of knowledge about medicines and driving showed an increased concern about the role that the use of medicines might play in car crashes. Much of patient knowledge regarding medicines comes from communications with healthcare professionals. This study, part of the DRUID (Driving Under the Influence of Drugs, alcohol and medicines) project, was carried out in four European countries and attempts to define predictors for knowledge of patients who use driving-impairing medicines. The influence of socio-demographic variables on patient knowledge was investigated as well as the influence of socio-demographic factors, knowledge and attitudes on patients' reported behaviour regarding driving under the influence of medicines.</p> <p>Methods</p> <p>Pharmacists handed out questionnaires to patients who met the inclusion criteria: 1) prevalent user of benzodiazepines, antidepressants or first generation antihistamines for systemic use; 2) age between 18 and 75 years old and 3) actual driver of a motorised vehicle. Factors affecting knowledge and reported behaviour towards driving-impairing medicines were analysed by means of multiple linear regression analysis and multiple logistic regression analysis, respectively.</p> <p>Results</p> <p>A total of 633 questionnaires (out of 3.607 that were distributed to patients) were analysed. Patient knowledge regarding driving under the influence of medicines is better in younger and higher educated patients. Information provided to or accessed by patients does not influence knowledge. Patients who experienced side effects and who have a negative attitude towards driving under the influence of impairing medicines are more prone to change their driving frequency behaviour than those who use their motorised vehicles on a daily basis or those who use anti-allergic medicines.</p> <p>Conclusions</p> <p>Changes in driving behaviour can be predicted by negative attitudes towards driving under the influence of medicines but not by patients' knowledge regarding driving under the influence of medicines. Future research should not only focus on information campaigns for patients but also for healthcare providers as this might contribute to improve communications with patients regarding the risks of driving under the influence of medicines.</p