Peter Marckmann

Background: Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), are prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated whether vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients. Methods: In a 2-year, double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomized to vitamin K [menaquinone-7 (MK-7), 360 µg daily] or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aortic calcification (AAC) were used to assess arterial calcification. Results: Thirty-seven participants completed Year 1, and 21 completed Year 2. At Year 2, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo {mean dp-ucMGP difference: −1380 pmol/L [95% confidence interval (CI) −2029 to −730]}. There was no significant effect of vitamin K supplementation on cfPWV [mean difference at Year 2: 1.2 m/s (95% CI −0.1 to 2.4)]. CAC Agatston score increased significantly in vitamin K supplemented participants, but was not significantly different from placebo [mean difference at Year 2: 664 (95% CI −554 to 1881)]. AAC scores increased in both groups, significantly so within the placebo group at Year 1, but with no significant between-group differences. Conclusions: Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients.

INTRODUCTION AND AIMS: Patients in maintenance dialysis (MD) are at highly increased risk of cardiac death. Arterial calcification - as assessed from coronary arterial calcification (CAC) or abdominal aortic calcification (AAC) - is an established risk marker of cardiac death. Pulse wave velocity (PWV) increases with arterial calcification and is a risk marker of cardiac death. The present study aimed to compare CAC scores of MD patients with scores of healthy subjects and patients with ischemic heart disease (IHD), and to examine the correlations between CAC, AAC, and PWV in MD patients.

Fibulin-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. Plasma 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. We 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. Increased 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.

Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. 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). 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. 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.

Hypovitaminosis D is highly prevalent in adult kidney-transplanted patients. The knowledge of vitamin D status in kidney-transplanted children and adolescents is sparse. The present study investigated the vitamin D status of a cohort of kidney-transplanted children and adolescents, and the association between vitamin D status and plasma concentrations of PTH, ionized calcium, and phosphate. The study included 35 patients with a functioning graft. Their mean age was 12.0 yr, and the mean graft age was 2.8 yr. Forty percent of the patients were vitamin D insufficient (P-25-hydroxyvitamin D 40-75 nm), and 14% were deficient (P-25-hydroxyvitamin D < 40 nm). S-25-hydroxyvitamin D was inversely associated with PTH (p = 0.02) and positively associated with S-1,25-dihydroxyvitamin D (p = 0.02). There was no significant association between S-1,25-dihydroxyvitamin D and PTH. In conclusion, we found hypovitaminosis D in 54% of the study population despite the fact that samples were collected in spring and summer months. Hypovitaminosis D was associated with adverse effects on PTH and 1,25-dihydroxyvitamin D. Our data suggest that it is warranted to monitor vitamin D status of kidney-transplanted children and adolescents and indicate that correction of hypovitaminosis D might have favorable effects on calcium-phosphate metabolism.