Treating vascular dysfunction in chronic kidney disease : intervention with vitamin D

Abstract: Background: Chronic kidney disease (CKD) is common, affecting 10-15% of the population worldwide. It is currently recognised by both cardiologists and nephrologists as a strong risk factor for cardiovascular events and death. During the last decades it has been shown that CKD leads to a state of activated renin angiotensin-aldosterone system and sympathetic nervous system, to endothelial dysfunction, chronic vascular inflammation, mineral bone disorder, and in late stages also to an acidotic and uremic cell milieu. Together these disturbances create an advanced and rapidly progressing vascular disease, leading to vascular stiffening and calcification. CKD patients have chronically low levels of activated vitamin D, a vitamin now regarded as a hormone involved in a wide range of processes in the body. It affects immune cells, leading to a shift towards anti-inflammatory responses, and inhibits the production of oxidants. Vitamin D upregulates the expression of eNOS, a crucial enzyme in endothelial function, and downregulates the expression of renin. Accordingly vitamin D deficiency might affect several of the processes involved in the progressive vascular disease seen in CKD. The aim of this PhD project was to investigate the effects of intervention with vitamin D on measures and markers of vascular function, inflammation, and upstream epigenetic regulation in patients with CKD. Methods and results: We performed a randomised placebo-controlled double blind trial (RCT) including 36 participants, with non-diabetic CKD stage 3-4. Patients were randomised to intervention for 12 weeks with 1 or 2 μg of paricalcitol, an active vitamin D analogue, or placebo. In paper I, we investigated physiological measures of macro- and microvascular function as well as muscle sympathetic nerve activity. We found that treatment with 2 μg of paricalcitol attenuated a decline in endothelial function measured by flow mediated vasodilation and iontophoresis by acetylcholine, and that both treated groups showed ameliorated measures of microcirculation, compared to placebo. In paper II, a milliplex assay was performed to assess cytokine expression before and after intervention. We found that treatment with both 1 and 2 μg of paricalcitol suppressed levels of PDGF and VEGF, cytokines known to be implicated in vascular function and atherosclerosis. We also examined microRNAs, by PCR-techniques, and detected a downregulation of microRNAs 432, 495 and 576, shown to be involved in atherosclerosis, platelet function and inflammation. In paper III, concentrations of microparticles (MPs), and their expression of the vascular activation and atherosclerotic markers ICAM-1 and VCAM-1 were determined by antibody labelling and flow cytometry. We showed that treatment with paricalcitol induced a decline in the expression of ICAM-1 on MPs compared to placebo. The results from the combined investigation of cell specific MP profiles showed that treatment with 2 μg of paricalcitol resulted in sustained levels of endothelial, platelet and leukocyte MPs, in contrast to the other two groups where levels declined. Paper IV used meta-analysis techniques to assess the overall effect-size post treatment in flow mediated vasodilation (FMD) after intervention with any vitamin D compound. Inclusion criteria were any stage of chronic kidney disease, and with no restrictions regarding underlying diseases. Four articles fulfilled the criteria, comprising 305 participants. The overall effect size was in favour of treatment with vitamin D. The results were strongest for the study with the youngest population, for treatment with 2 μg of paricalcitol and treatment with cholecalciferol. Conclusions: In our examined population, vitamin D has positive effects on endothelial macro- and microcirculatory functions, suppress levels of atherosclerotic and inflammatory markers and maintain the production of microparticles, potentially due to a more normally functioning endothelium. Important questions that remain are whether these findings may translate to effects on hard endpoints, in which patient groups, and the optimal timing of initiation of treatment.

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