Johannes Jakobsen Sidelmann

Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D

BACKGROUND Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. METHODS An 8-week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40,000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25-OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). RESULTS Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137-173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. CONCLUSIONS 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D-supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment.

Fibrin clot structure in patients with end-stage renal disease

Fibrin clots with reduced permeability, increased clot stiffness and reduced fibrinolysis susceptibility may predispose to cardiovascular disease (CVD). Little is known, however, about the structure of fibrin clots in patients with end-stage renal disease (ESRD). These patients suffer from a high risk of CVD in addition to their chronic low-grade inflammation. Using permeability, compaction and turbidity studies in 22 ESRD patients and 24 healthy controls, fibrin clots made from patient plasma were found to be less permeable (p < 0.001), less compactable (p < 0.001), and less susceptible to fibrinolysis (p < 0.001) than clots from controls. The maximum rate of turbidity increase was also higher for the patients than controls (p < 0.001), and scanning electron microscopy revealed higher clot density of fibrin fibers in clots from patients than clots from controls (p < 0.001). Patients had higher plasma concentrations of fibrinogen, C-reactive protein and interleukin 6 than controls. These plasma markers of inflammation correlated significantly with most of the fibrin structure characteristics observed in the patients. In contrast, plasma markers of azothemia showed no such correlations. The results suggest that in ESRD patients fibrin clots are significantly different from healthy controls, and that the fibrin structure characteristics in the patients are associated primarily with the inflammatory plasma milieu rather than with level of azothemia.

Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women

Objective: The purpose of this study was to examine key variables in the regulation of coagulation and fibrinolysis during intake of low-dose oral contraceptives containing newly developed progestogens. Study Design: Thirty-four healthy young women were allocated to 12 consecutive cycles of treatment with monophasic combinations of 20 μg ethinyl estradiol and 150 μg desogestrel ( n = 15) or 30 μg ethinyl estradiol and 75 μg gestodene ( n = 19). Nonparametric analysis of variance was used for statistical evaluation. Results: In both groups plasma levels of fibrinogen and Factor VIIc increased, and the capacity of coagulation inhibition was affected by increased protein C and decreased protein S levels. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and by reduced activity and concentration of plasminogen activator inhibitor. Thrombin-antithrombin III complexes and fibrin degradation products were unchanged, signifying no effect of hormonal intake on the degree of activation of the coagulation system or the efficacy of fibrinolysis. Conclusion: The overall dynamic balance between generation and resolution of fibrin was maintained during treatment with both hormonal compounds. Our findings suggest that the risk of thrombosis in normal women should not be increased.

A Study of the Conditions and Accuracy of the Thrombin Time Assay of Plasma Fibrinogen

The conditions, accuracy, precision and possible error of the thrombin time assay of plasma fibrinogen are determined. Comparison with an estimation of clottable protein by absorbance at 280 nm gave a correlation coefficient of 0.96 and the regression line y = 1.00 x + 0.56 (n = 34). Comparison with a radial immunodiffusion method yielded the correlation coefficient 0.97 and the regression line y = 1.18 x = 2.47 (n = 26). The presence of heparin in clinically applied concentrations produced a slight shortening of the clotting times. The resulting error in the estimated concentrations of fibrinogen was too small to affect the clinical usefulness of the determinations. The influence of fibrin(ogen) degradation products was significant only in excessive amounts in samples containing low levels of fibrinogen.

Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus

OBJECTIVE We evaluated established cardiovascular risk factors within lipoprotein metabolism, hemostasis, and endothelial function in women with insulin-dependent diabetes mellitus who were using oral contraceptives. STUDY DESIGN Twenty-five women with uncomplicated insulin-dependent diabetes mellitus, allocated to treatment with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene (treatment group, n = 12) or with nonhormonal contraception (control group, n = 13), were prospectively followed up for 12 months. Nonparametric methods were used for statistical evaluation. RESULTS No statistical differences in the biochemical risk markers were noted between the two groups at the start of the study. In the treatment group serum levels of low-density lipoprotein cholesterol decreased, whereas the concentrations of total cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides were unchanged. Within the coagulation system factor VII coagulant activity increased, while fibrinogen levels were unchanged. In the fibrinolytic system we found unchanged activities but decreased antigen concentrations of tissue plasminogen activator and plasminogen activator inhibitor. The concentration of von Willebrand factor increased, but no change in albumin excretion rates were found. In the control group no changes in any of the variables were observed. CONCLUSION Intake of modern oral contraceptives does not deteriorate the cardiovascular risk profile in women with insulin-dependent diabetes mellitus, but our study indicates a risk of disturbances of the endothelial integrity, which needs further investigation.

Energy availability and the female athlete triad in elite endurance athletes

The female athlete triad (Triad), links low energy availability (EA), with menstrual dysfunction (MD), and impaired bone health. The aims of this study were to examine associations between EA/MD and energy metabolism and the prevalence of Triad‐associated conditions in endurance athletes. Forty women [26.2 ± 5.5 years, body mass index (BMI) 20.6 ± 2.0 kg/m2, body fat 20.0 ± 3.0%], exercising 11.4 ± 4.5 h/week, were recruited from national teams and competitive clubs. Protocol included gynecological examination; assessment of bone health; indirect respiratory calorimetry; diet and exercise measured 7 days to assess EA; eating disorder (ED) examination; blood analysis. Subjects with low/reduced EA (< 45 kcal/kg FFM/day), had lower resting metabolic rate (RMR) compared with those with optimal EA [28.4 ± 2.0 kcal/kg fat‐free mass (FFM)/day vs 30.5 ± 2.2 kcal/kg FFM/day, P < 0.01], as did subjects with MD compared with eumenorrheic subjects (28.6 ± 2.4 kcal/kg FFM/day vs 30.2 ± 1.8 kcal/kg FFM/day, P < 0.05). 63% had low/reduced EA, 25% ED, 60% MD, 45% impaired bone health, and 23% had all three Triad conditions. 53% had low RMR, 25% hypercholesterolemia, and 38% hypoglycemia. Conclusively, athletes with low/reduced EA and/or MD had lowered RMR. Triad‐associated conditions were common in this group of athletes, despite a normal BMI range. The high prevalence of ED, MD, and impaired bone health emphasizes the importance of prevention, early detection, and treatment of energy deficiency.

Factor VII-activating protease in patients with acute deep venous thrombosis

Factor VII-activating protease (FSAP) is involved in haemostasis and inflammation. FSAP cleaves single chain urokinase-type plasminogen activator (scu-PA). The 1601GA genotype of the 1601G/A polymorphism in the FSAP gene leads to the expression of a FSAP variant with reduced ability to activate scu-PA, without affecting the ability to activate coagulation Factor VII (FVII). Previous studies have investigated the association of the 1601GA genotype with incidence and progression of carotid stenosis and deep venous thrombosis (DVT). The present study is the first to evaluate the potential association between the FSAP phenotype and DVT. We studied the association between the 1601G/A polymorphism, FSAP activity, FSAP antigen, Factor VIIa (FVIIa), prothrombin fragment 1+2 (F1+2), and C-reactive protein (CRP) in plasmas of 170 patients suspected for DVT. FSAP genotypes were equally distributed in patients with (n=64) and without DVT (n=106), (P=0.94). The 1601GA genotype was associated with significant reduction of FSAP activity (P<0.001) and FSAP antigen levels (P=0.04). Patients with DVT showed significantly higher FSAP activity (P=0.008), FSAP antigen (P=0.003), and F1+2 levels (P<0.001) than patients without DVT. The association between the FSAP measures and DVT disappeared when adjusted for CRP levels. F1+2 correlated positively to FSAP antigen (P=0.01), while FVIIa-levels were comparable in patients with and without DVT. We conclude that even though FSAP measures are significantly increased in patients with acute DVT, alterations in the scu-PA activating properties of FSAP are presumably not markedly involved in the development of acute DVT, and that the association between FSAP and DVT disappears after adjustment for CRP.

Plasma concentrations of extracellular matrix protein fibulin-1 are related to cardiovascular risk markers in chronic kidney disease and diabetes

BackgroundFibulin-1 is one of a few extracellular matrix proteins present in blood in high concentrations. We aimed to define the relationship between plasma fibulin-1 levels and risk markers of cardiovascular disease.MethodsPlasma fibulin-1 was determined in subjects with chronic kidney disease (n = 32; median age 62.5, inter-quartile range 51 – 73 years) and 60 age-matched control subjects. Among kidney disease patients serological biomarkers related to cardiovascular disease (fibrinogen, interleukin 6, C-reactive protein) were measured. Arterial applanation tonometry was used to determine central hemodynamic and arterial stiffness indices.ResultsWe observed a positive correlation of fibulin-1 levels with age (r = 0.38; p = 0.033), glycated hemoglobin (r = 0.80; p = 0.003), creatinine (r = 0.35; p = 0.045), and fibrinogen (r = 0.39; p = 0.027). Glomerular filtration rate and fibulin-1 were inversely correlated (r = −0.57; p = 0.022). There was a positive correlation between fibulin-1 and central pulse pressure (r = 0.44; p = 0.011) and central augmentation pressure (r = 0.55; p = 0.001). In a multivariable regression model, diabetes, creatinine, fibrinogen and central augmentation pressure were independent predictors of plasma fibulin-1.ConclusionIncreased plasma fibulin-1 levels were associated with diabetes and impaired kidney function. Furthermore, fibulin-1 levels were associated with hemodynamic cardiovascular risk markers. Fibulin-1 is a candidate in the pathogenesis of cardiovascular disease observed in chronic kidney disease and diabetes.

Hormone replacement therapy and hypercoagulability. Results from the Prospective Collaborative Danish Climacteric Study

Objective To assess the influence of a variety of HRT regimens on the haemostatic balance using markers of fibrin turnover and inhibitors of coagulation.

Multivariate analysis of the relation between diet and warfarin dose

PurposeThe vitamin K antagonist (VKA) warfarin is effective for the prevention of thromboembolisms. Maintenance doses differ greatly among patients and are known to be primarily determined by genetic polymorphisms. The relative impact of dietary vitamin K intake is still a matter of debate. We hypothesize that a multivariate model is more suitable for exploring the relation between dietary intake of vitamin K and warfarin dose than conventional uni- or bivariate analyses.MethodsIn a cross-sectional study, we interviewed 244 patients in the maintenance phase of warfarin therapy and detected polymorphisms in the VKORC1 and CYP2C9 genes. Dietary vitamin K intake was estimated from food frequency questionnaires.ResultsA univariate correlation analysis and the regression coefficient from the multivariate model showed a small but significant negative relation between vitamin K intake and warfarin dose. A loading plot of the partial least squares regression model illustrated this counter-intuitive observation, which might be explained by the latent structure between variables. The variation in warfarin dose could be divided into two significant latent variables, the so-called components. In component one, pharmacogenetics explained 52% of dose variation. Component two described health-related behavior (diet, physical activity and body weight) and explained 8% of dose variation. Here, vitamin K intake positively correlated with warfarin dose.DiscussionThis study highlights the importance of choosing a statistical method that reflects the complexity of data for interpretation of results from observational studies. The multivariate model appears to be well suited to describe the complex relationship between vitamin K intake and VKA dose.