Department of Nephrology, Medical School Democritus University of Thrace, Alexandroupolis, Greece
Passive, degenerative accumulation process of Ca ++ /P +++ without treatment options
Active, complex, condition: vascular smooth muscle cell (VSMC) differentiation to osteoblast phenotype (the 1st step of VC)
In elderly: natural phenomenon In patients with high atherogenic status (T2DM, CKD) earlier + common greater degree correlates inversely with kidney function (egfr)
Medial (Mönckeberg) Intimal Calcium deposits in the muscular middle layer of the walls of arteries (the tunica media): HP, LV hypertrophy, arteriosclerosis Cholesterol deposits in atheromatic plaqueplaque rapture, atheromatosis
Common, early and both types Strongly linked with cardiovascular (CV) mortality and morbidity (50% of all deaths)
Temmar et al., J Hypertens 2010
Just X-RAY is enough for assessing VC Liabeuf S., Plos One 2015
Extent of VC depends on the balance between factors that favor calcification and those that inhibit it
20-40% of DN patients do not present severe VC natural inhibitors of VC that delay the calcification process
Matrix Gla Protein (MGP) Osteoprotegerin These natural occurring inhibitors of VC in CKD present: Osteopontin BMP-7 Fetuin-a Reduced plasma concentration Less activity Limited function Pyrophosphate
84 amino-acids (MW=11kD) Gla residues (for activity) Serine phosphorylation (for activity) Expressed + secreted by chondrocytes and VSMCs Found in bone, cartilage, heart, kidney, vessels 1 st protein identified as in vivo VC inhibitor The strongest inhibitor
High affinity binding to Ca ++ in vessel wall MGP osteogenesis BMP-2= found only in severe calcification vascular smooth muscle cartilage
Transformation of VSMCs to osteoblasts MGP
A vitamin K-dependent protein, requiring Vitamin-K γ-carboxylation Phosphorylation to become active Vit K= active MGP = inhibits VC
Active MGP = stops VC De-phosphorylated Un-carboxylated (dpucmgp), mainly due to Vit. K deficiency promotes VC
Schurgers., Thromb Stefanos Haemost K. Roumeliotis 2008
Schurgers., Thromb Stefanos Haemost K. Roumeliotis 2008
VKA =vitamin K antagonist MK =menaquinone Cranenburg., Thromb Stefanos Haemost K. Roumeliotis 2010
Varik et al., Front Stefanos Genetics K. Roumeliotis 2012
mice with no MGP at all (phenotype MGP-/-) Luo et al., Nature 1997 Murshed M et al., Genes and Dev 2005
Severe VC Die of aortic rupture within 6-8 weeks after birth
Schurgers Stefanos et al., ATVB K. Roumeliotis 2005
Chatrou., Stefanos Plos K. One Roumeliotis 2015
Uniklinik RWTH Aachen Titel des Vortrags, Datum Altered tensile stress Anemia; iron-def. Left ventricular hypertrophy Vitamin K deficiency Diabetes Chronic renal failure FGF23 excess / klotho deficiency Uremic toxins Inflammation Calcification inhibitors Diminished VDR activation Gender Age Vascular Disease Myocardial Disease Mortality Altered shear stress Vascular disease Vitamin D (high / low) Genetic factors Local growth factors/inhibitors Endothelial dysfunction Bone disease Smoking Dyslipidemia Oxidative stress Ca, P, PTH Valvular disease mirna NO, ADMA, Lipoprotein modifications: oxidation; homocysteine
Could treatment with Vitamin K prevent mineralization in CKD or T2DM? =?
Hazard ratio Design: -cross-sectional: 4.800 elderly Dutch followed for 10 years 120 100 VC CV mortality Overall mortality 80 60 40 20 0 <21 21-32 >32 Vitamin K2 intake (µg/day) Geleijnse et al. J Nutr 2004
Design 53 HD- 50 controls 45, 135 or 360 µg Vitamin-K2 daily 6 weeks Time and dosedependent decrease Westenfeld R, Krüger T et al, AJKD 2012
suggesting deficiency of Vitamin K as a marker Stefanos of K. VC Roumeliotis in CKD
T2DM>10 years Micro/macroalbuminuria in 3 urine spots + Diabetic retinopathy
118 DN patients in all 5 stages 40 controls with T2DM>10 years, normal egfr, no albuminuria CKD Stages 0 Stage Stage Stage HD controls 1/2 3 4 5 n (total=158) 40 23 34 31 30 Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017
Tumor Surgery/ active illness-inflammation Obstructive uropathy Any biochemical/clinical sign indicating NOT diabetic but other cause of nephropathy
Baseline cimt (B-mode ultrasonography) Polymorphism MGP T-138C (PCR-RFLP) Levels of dpucmgp (67) (ELISA)
cimt: median value of 12 indications in both arteries
Micro-calcifications are seen in lesions with pathological intimal thickening and appear as microscopic foci, typically >0.5μm and <15μm at histopathology These lesions are too small to be resolved by conventional CT which has resolution of approximately 500μm 86% with negative CT have already established VC Strauss et al., Stefanos J Nuc Med K. Roumeliotis 2015
Follow-up 7 years All-cause mortality Cardiovascular mortality Cardiovascular event Myocardial Infarction Peripheral Arterial Disease Stroke Angina
Roumeliotis, Stefanos K., et al. CAROTID ATHEROSCLEROSIS IS ASSOCIATED WITH DETERIORATION OF KIDNEY DISEASE IN PATIENTS WITH DIABETES MELLITUS TYPE 2. In: NEPHROLOGY DIALYSIS TRANSPLANTATION, 2014. p. 431-432.
Multiple regression analysis of factors associated with cimt Roumeliotis, Stefanos K., et al. CAROTID ATHEROSCLEROSIS IS ASSOCIATED WITH DETERIORATION OF KIDNEY DISEASE IN PATIENTS WITH DIABETES MELLITUS TYPE 2. In: NEPHROLOGY DIALYSIS TRANSPLANTATION, 2014. p. 431-432.
Factors correlated p CKD stage 0,0000 Albuminuria 0,0000 PAD 0,002 Triglycerides 0,004 ΗΒΑ1C 0,010 CRP 0,032 BMI>30 0,045
Plasma dpucmgp (pm) p<0.001 1200 1000 800 600 400 200 0 1175 833 376 107 CKD 1 CKD 2 CKD 3/4 CKD 5 Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017
T allele predisposes to higher cimt
MGP Genotypes dpucmgp P TT 730 (88-1839) TC 708 (250-2043) 0,86 CC 775 (71-2743) Roumeliotis, Stefanos K., et al. FP460 THE INACTIVE FORM OF MATRIX GLA PROTEIN (MGP) IS NOT ASSOCIATED WITH MGP GENE PROMOTER T-138C POLYMORPHISM IN PATIENTS WITH DIABETIC NEPHROPATHY. Nephrology Dialysis Transplanation, 2015, 30.suppl_3: iii225-iii225.
Roumeliotis, Stefanos, et al. MP486 MATRIX GLA PROTEIN T 138C POLYMORPHISM AND ITS INACTIVE DEPHOSPHORYLATED UNCARBOXYLATED FORM PREDICT MORTALITY IN PATIENTS WITH DIABETIC NEPHROPATHY. Nephrology Dialysis Transplantation, 2017, 32.suppl_3: Stefanos iii607-iii608 K. Roumeliotis
All-cause mortality Cardiovascular mortality Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017
Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017
TT genotype is more frequent in HD than CKD stages 1-4 and even less frequent in controls Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017
MGP is the strongest inhibitor of VC in the arterial wall Needs Vitamin K to be activated (carboxylated/phosphorylated) MGP is not active in Vitamin K2 insufficiency or warfarin The inactive form (dpucmgp) Reflects poor Vitamin K status Promotes VC Progresses along with CKD CKD.. DN ESRD Predicts mortality, cardiovascular events
350 HD with VC Standard care ++ Vitamin K1 x3/week 18 months VC Mortality CV
Thank you For your attention