Vitamin K-Transport in urämisch veränderten Lipoproteinen
Schreibing, Felix; Floege, Jürgen (Thesis advisor); Jankowski, Joachim (Thesis advisor)
Dissertation / PhD Thesis
Patients receiving hemodialysis suffer from an increased cardiovascular risk compared to the general population. One of the most important causes of this increased cardiovascular risk is an accelerated process of vascular calcification in hemodialysis patients.The pathogenesis of an accelerated vascular calcification in the setting of chronic kidney disease and especially in the setting of hemodialysis therapy is not entirely understood. By now it is known that matrix gla-protein (MGP), a Gla-protein which is synthesized by the vascular endothelium and which is activated by vitamin K, is one of the most important inhibitors of vascular calcification.In the past it has been shown that patients on hemodialysis suffer from a subclinical vitamin K-deficiency. The aim of our study was to examine the lipoprotein-transport of three different isotypes of vitamin K (vitamin K1, MK-4 and MK-7) and to compare the patterns of vitamin K-transport between healthy subjects and hemodialysis patients to prove our hypothesis that in hemodialysis patients vitamin K-transport in lipoproteins is impaired. A disorder in vitamin K-transport in lipoproteins within the framework of uremia might lead to an impaired activation of MGP and by that contribute to an accelerated vascular calcification.For this, 7 healthy subjects and 10 hemodialysis patients took a vitamin K-preparation (Vitamin K-Komplex) for breakfast together with a croissant and a glass of orange juice after an initial blood withdrawal (0h). After one (1h), three (3h) and six (6h) hours another blood sample was taken. The different lipoprotein-fractions (triglyceride-rich lipoprotein fraction (TGRLP), LDL and HDL) were separated by ultracentrifugation of the serum and subsequently vitamin K-concentrations were determined by UV-detection after another purification by high performance liquid chromatography (HPLC).Our study could show that the MK-4 concentration in LDL and HDL of hemodialysis patients had significantly increased compared to the baseline-concentration, 3 and 6 hours after vitamin K-intake, while the concentration of MK-4 in the lipoproteins of the healthy subjects remained largely constant. Concerning the transport of MK-7 in lipoproteins, we could show that in our healthy subjects the HDL percentage of the total transport of MK-7 increased after vitamin K intake and after slightly more than one hour made up the bulk of the MK-7 transport. This increase failed to appear in the hemodialysis group; accordingly, LDL made up the bulk of MK-7 transport in the hemodialysis patients. Moreover, we could observe that in the healthy population the concentration of MK-7 in HDL increased after vitamin K-intake, while this increase could not be observed in HDL of hemodialysis patients.Concluding, our study showed that in the serum of hemodialysis patients there appears to be a disorder in the HDL-transport of MK-7. This finding is of great relevance as especially the menaquinones (vitamin K2), which include MK-7, are important for the activation of MGP and accordingly for the prevention of vascular calcification. A transport disorder in lipoprotein-transport of vitamin K in hemodialysis patients could make a large contribution to the understanding of the pathomechanisms of accelerated vascular calcification in the arteries of hemodialysis patients. As well, this finding brings up the question for a vitamin K-substitution. Before therapeutic conclusions can be drawn, in a next step our phenomenological observations have to be supported by explanations on a mechanical level.