Stefanos K. Roumeliotis. Department of Nephrology, Medical School Democritus University of Thrace, Alexandroupolis, Greece. Stefanos K.

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1 Department of Nephrology, Medical School Democritus University of Thrace, Alexandroupolis, Greece

2 Passive, degenerative accumulation process of Ca ++ /P +++ without treatment options

3 Active, complex, condition: vascular smooth muscle cell (VSMC) differentiation to osteoblast phenotype (the 1st step of VC)

4 In elderly: natural phenomenon In patients with high atherogenic status (T2DM, CKD) earlier + common greater degree correlates inversely with kidney function (egfr)

tunica media): HP, LV hypertrophy, arteriosclerosis

5 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

6 Common, early and both types Strongly linked with cardiovascular (CV) mortality and morbidity (50% of all deaths)

7 Temmar et al., J Hypertens 2010

8 Just X-RAY is enough for assessing VC Liabeuf S., Plos One 2015

9 Extent of VC depends on the balance between factors that favor calcification and those that inhibit it

10 20-40% of DN patients do not present severe VC natural inhibitors of VC that delay the calcification process

11 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

12 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

13 High affinity binding to Ca ++ in vessel wall MGP osteogenesis BMP-2= found only in severe calcification vascular smooth muscle cartilage

14 Transformation of VSMCs to osteoblasts MGP

15 A vitamin K-dependent protein, requiring Vitamin-K γ-carboxylation Phosphorylation to become active Vit K= active MGP = inhibits VC

16 Active MGP = stops VC De-phosphorylated Un-carboxylated (dpucmgp), mainly due to Vit. K deficiency promotes VC

17 Schurgers., Thromb Stefanos Haemost K. Roumeliotis 2008

18 Schurgers., Thromb Stefanos Haemost K. Roumeliotis 2008

19 VKA =vitamin K antagonist MK =menaquinone Cranenburg., Thromb Stefanos Haemost K. Roumeliotis 2010

20 Varik et al., Front Stefanos Genetics K. Roumeliotis 2012

21 mice with no MGP at all (phenotype MGP-/-) Luo et al., Nature 1997 Murshed M et al., Genes and Dev 2005

22 Severe VC Die of aortic rupture within 6-8 weeks after birth

24 Schurgers Stefanos et al., ATVB K. Roumeliotis 2005

25 Chatrou., Stefanos Plos K. One Roumeliotis 2015

Calcification inhibitors Diminished VDR activation Gender Age Vascular Disease Myocardial Disease Mortality Altered shear stress Vascular disease Vitamin

26 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

27 Could treatment with Vitamin K prevent mineralization in CKD or T2DM? =?

28 Hazard ratio Design: -cross-sectional: elderly Dutch followed for 10 years VC CV mortality Overall mortality < >32 Vitamin K2 intake (µg/day) Geleijnse et al. J Nutr 2004

29 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

31 suggesting deficiency of Vitamin K as a marker Stefanos of K. VC Roumeliotis in CKD

32 T2DM>10 years Micro/macroalbuminuria in 3 urine spots + Diabetic retinopathy

33 118 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/ n (total=158) Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017

34 Tumor Surgery/ active illness-inflammation Obstructive uropathy Any biochemical/clinical sign indicating NOT diabetic but other cause of nephropathy

35 Baseline cimt (B-mode ultrasonography) Polymorphism MGP T-138C (PCR-RFLP) Levels of dpucmgp (67) (ELISA)

36 cimt: median value of 12 indications in both arteries

37 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

38 Follow-up 7 years All-cause mortality Cardiovascular mortality Cardiovascular event Myocardial Infarction Peripheral Arterial Disease Stroke Angina

39 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, p

40 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, p

41 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

42 Plasma dpucmgp (pm) p< CKD 1 CKD 2 CKD 3/4 CKD 5 Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017

43 T allele predisposes to higher cimt

44 MGP Genotypes dpucmgp P TT 730 ( ) TC 708 ( ) 0,86 CC 775 ( ) 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.

45 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

46 All-cause mortality Cardiovascular mortality Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017

47 Roumeliotis Stefanos, et al. Journal of Diabetes and its Complications, 2017

48 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

49 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

51 350 HD with VC Standard care ++ Vitamin K1 x3/week 18 months VC Mortality CV

52 Thank you For your attention

Cardiovascular Mortality: General Population vs ESRD Dialysis Patients

Cardiovascular Mortality: General Population vs ESRD Dialysis Patients Annual CVD Mortality (%) 100 10 1 0.1 0.01 0.001 25-34 35-44 45-54 55-64 66-74 75-84 >85 Age (years) GP Male GP Female GP Black GP