Inhibitor Of Vascular Calcification Research Articles

Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension

In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)],-5.3 [5.2] versus-6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI):-2.5, 3.0]; p=0.88) and Pain VAS (mean [SD],-19.5 [26.9] versus-32.2 [38.5]; least squares mean difference, 11.5 [96% CI:-4.8, 27.8]; p=0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group. Funded by Sanifit, a CSL Vifor company.

The impact of vitamin k2 supplementation on inhibition of vascular calcification in chronic kidney disease patients

The impact of vitamin k2 supplementation on inhibition of vascular calcification in chronic kidney disease patients

Vitamin K for Vascular Calcification in Kidney Patients: Still Alive and Kicking, but Still a Lot to Learn.

Patients with chronic kidney disease (CKD) suffer disproportionately from a high burden of cardiovascular disease, which, despite recent scientific advances, remains partly understood. Vascular calcification (VC) is the result of an ongoing process of misplaced calcium in the inner and medial layers of the arteries, which has emerged as a critical contributor to cardiovascular events in CKD. Beyond its established role in blood clotting and bone health, vitamin K appears crucial in regulating VC via vitamin K-dependent proteins (VKDPs). Among these, the matrix Gla protein (MGP) serves as both a potent inhibitor of VC and a valuable biomarker (in its inactive form) for reflecting circulating vitamin K levels. CKD patients, especially in advanced stages, often present with vitamin K deficiency due to dietary restrictions, medications, and impaired intestinal absorption in the uremic environment. Epidemiological studies confirm a strong association between vitamin K levels, inactive MGP, and increased CVD risk across CKD stages. Based on the promising results of pre-clinical data, an increasing number of clinical trials have investigated the potential benefits of vitamin K supplementation to prevent, delay, or even reverse VC, but the results have remained inconsistent.

#170 Vasoconstriction Inhibiting Factor: An endogenous inhibitor of vascular calcification as calcimimetic of calcium-sensing receptor

Abstract Background and Aims Patients with chronic kidney disease (CKD), have an increased risk of cardiovascular disease due to the massively accelerated calcification they develop. Vascular calcification is a highly regulated process mediated by different inducers and inhibitors. Recently, the peptide ‘vasoconstriction inhibiting factor’ (VIF) was isolated from bovine adrenal glands and has been described as an inhibitor of the angiotensin II-induced vasoconstriction. Angiotensin II inhibits calcium deposition, but VIF effect on vascular calcification is still unknown. In the present study, VIF has been characterised on vascular calcification assays. Method The effect of VIF was analysed in vitro in human aortic smooth muscle cells (hAoSMC) and ex vivo in rat aortic rings, both cultivated under high phosphate concentrations. VIF was also studied in vivo in rats treated with vitamin D and nicotine (calcification model). Results VIF inhibits calcium deposition in all the models studied. Furthermore, in hAoSMC VIF reduces the production of ROS and the initiation of diverse cascades in the cells, like activation of inflammatory cytokines and MAPK kinases, which in turn trigger the expression of various genes involved in the development of vascular calcification. Furthermore, in presence of VIF the population of apoptotic cells, directly linked to vascular calcification, is decreased. Calcium-sensing receptor (CaSR) has been found as VIF binding partner, pointing to VIF as a new calcimimetic of this receptor, that inhibits vascular calcification by increasing the production of carboxylated Matrix Gla Proteins (cMGP). Conclusion In conclusion, VIF is a new potent endogenous inhibitor of vascular calcification acting as a calcimimetic of CaSR, that leads to an increase cMGP production. This finding represents a basis for a new target for the prevention and therapy of patients with increased vascular calcification and shows an encouraging perspective for the future.

#1943 The association of uncarboxylated, non-phosphorylated Matrix Gla protein with arterial stiffness in hemodialysis and peritoneal dialysis patients

Abstract Background and Aims Vitamin K deficiency has been identified as a marker of vascular calcification AND STIFNESS and an independent cardiovascular risk factor in hemodialysis (HD) and peritoneal dialysis (PD) patients, as the most powerful inhibitor of vascular calcification, Matrix Gla Protein requires vitamin K to become activated. However, until to date, it has not yet been clarified whether hepatic or extrahepatic markers of vitamin K status reflect the arterial status of dialysis patients. In this study we aimed to investigate the association of vitamin K deficiency with arterial stiffness in End-Stage Kidney Disease (ESKD) patients. Method In 42 ESKD patients undergoing either HD or PD, we measured plasma levels of the inactive vitamin-K dependent Matrix Gla Protein (dp-ucMGP) and serum levels of prothrombin (PIVKA-II) as markers of extrahepatic and hepatic insufficiency of vitamin K (CARIM Institute, Maastricht, Netherlands). In these patients we determined arterial stiffness parameters (pulse wave velocity-PWV) by the Mobil-O-Graph device (IEM, Stolberg, Germany). Results Serum PIVKA-II was associated with T2D duration (r = −0.38, p = 0.013), phosphorus levels (r = −0.41, p = 0.009) serum albumin (r = −0.33, p = 0.036) Spearman's rho test, and the type of transporter in PD patients (p = 0.039), Kruskal-Wallis test. Plasma dp-ucMGP was associated with PWV (r = 0.51, p = 0.001), peripheral (r = −0.37, p = 0.016) and central diastolic blood pressure (BP) (r = −0.34, p = 0.026) and age (r = 0.41, p = 0.007), Spearman's rho. Patients with T2DM, history of acute myocardial infarction and those receiving warfarin had significantly increased levels of circulating dp-ucMGP (p = 0.036, p = 0.039 and p < 0.0001, respectively, Kruskal-Wallis). Warfarin was associated with a 2.5-fold and a 23-fold increase in dp-ucMGP and PIVKA-II levels, respectively. Stepwise multiple regression analysis showed that PWV (p = 0.001, B = 494, 95% CI: 242-746) was an independent predictor of dp-ucMGP, independent of age, T2T2, history of myocardial infraction and diastolic BP. Conclusion Elevated plasma dp-ucMGP levels (suggesting extrahepatic vitamin K deficiency) were associated with increased arterial stiffness in dialysis patients.

Abstract 2040: Rapamycin Extends Life Of Matrix Gla Protein Knockout Mice Independent Of Vascular Calcification Content.

Background: Peripheral artery disease (PAD) is characterized by the narrowing and blockage of the vessels in lower extremities. While atherosclerosis has been the assumed culprit of PAD recent data now shows that medial arterial calcification (MAC) is the cause of below-the knee ischemia. MAC promotes thrombosis via inward remodeling, reduced elasticity, and arterial stiffness. The mechanisms driving MAC pathogenesis are unclear. Matrix Gla Protein (MGP) is an inhibitor of vascular calcification and present in arterial vessel walls. MGP -/- mice exhibit extensive MAC throughout their vasculature and die within 5-7 weeks due to aortic rupture or heart failure. The drug rapamycin functions as an inhibitor of cell proliferation and an activator of autophagy. Hypothesis: That rapamycin reduces MAC in MGP -/- mice via inhibiting inward remodeling and activating autophagy. Methods: MGP +/+ and MGP -/- mice treated with vehicle or rapamycin (5mg/kg, 3x weekly) starting at 10 days old for 2 weeks. Calcification was quantified via micro-computed tomography (uCT). Collagen structure and elastin quality were assessed histological staining. Markers of proliferation (Ki-67), cell death (Caspase 3), autophagy (LC3), and calcification (Runx2) were quantified via immunofluorescence staining. Western blot was used to assess autophagy flux and proliferation in smooth muscle cells (SMCs) isolated from MGP +/+ and MGP -/- mice. Results: While rapamycin treatment doubled the life-expectancy of MGP -/- mice, the calcification content was unchanged compared to the vehicle. However, rapamycin caused a significant decline in mineral density. Higher collagen content and improved elastin structure were observed in MGP -/- treated with rapamycin compared to vehicle. Runx2 and Ki-67 were elevated in MGP -/- mice compared to MGP +/+ , but there was no difference in response to rapamycin treatment. No difference was observed in caspase 3 levels. Under rapamycin treatment, MGP -/- SMCs exhibited higher autophagy flux than MGP +/+ SMCs. Conclusion: While rapamycin did not reduce MAC, our data suggest that rapamycin potentially preserves the integrity of the aortic vessel wall by inducing autophagy, which requires further investigation.

Inhibition of vascular calcification by Compound Danshen Dripping Pill through multiple mechanisms

BackgroundVascular calcification refers to the abnormal accumulation of calcium in the walls of blood vessels and is a risk factor often overlooked in cardiovascular disease. However, there is currently no specific drug for treating vascular calcification. Compound Danshen Dripping Pill (CDDP) is widely used to treat cardiovascular diseases, but its effect on vascular calcification has not been reported. PurposeWe investigated the effects of CDDP on vascular calcification in ApoE−/− mice and in vitro and elucidated its mechanism of action. Study designFirstly, we found that CDDP has the potential to improve calcification based on network pharmacology analysis. Then, we performed the following experiments: in vivo, ApoE−/− mice were fed a high-fat diet randomly supplemented with CDDP for 16 weeks. Atherosclerosis and vascular calcification were determined. In vitro, human aortic smooth muscle cells (HASMCs), human umbilical vein endothelial cells (HUVECs), and human aortic endothelial cells (HAECs) were used to determine the mechanisms for CDDP-inhibited vascular calcification. ResultsIn this study, we observed that CDDP reduced intimal calcification in atherosclerotic lesions of ApoE-deficient mice fed a high-fat diet, as well as the calcification in cultured SMCs and ECs. Mechanistically, CDDP inhibited the Wnt/β-catenin pathway by up-regulating the expression of DKK1 and LRP6, which are upstream inhibitors of Wnt, leading to a reduction in the expression of osteoblastic transition markers (ALP, OPN, BMP2, and RUNX2). Furthermore, CDDP enhanced the secretion of DKK1, which plays a role in mediating EC-SMC crosstalk in calcification. Additionally, VC contributes to vascular aging by inhibiting Sirt1 and increasing senescence parameters (SA-β-gal, p21, and p16). However, CDDP reversed these changes by activating Sirt1. CDDP also reduced the levels of pro-inflammatory cytokines and the senescence-associated secretory phenotype in vivo and in vitro. ConclusionsOur study suggests that CDDP reduces vascular calcification by regulating the DKK1/LRP6/β-catenin signaling pathway in ECs/SMCs and interactions with the crosstalk of ECs and SMCs. It also reduces the senescence of ECs/SMCs, contributing to the Sirt1 activation, indicating CDDP's novel role in ameliorating vascular calcification.

SNF472: a novel therapeutic agent for vascular calcification and calciphylaxis.

Vascular calcification is a common complication in patients with chronic kidney disease (CKD) and is strongly associated with an increased risk of cardiovascular events and all-cause mortality. Calciphylaxis is a specific and life-threatening manifestation of vascular calcifications that usually affects individuals with advanced kidney function impairment or those undergoing dialysis. Currently, the treatment of vascular calcification and calciphylaxis in CKD lacks approved treatments and focuses on controlling risk factors. SNF472, the intravenous formulation of myo-inositol hexaphosphate, is a novel vascular calcification inhibitor currently undergoing phase 3 clinical trials, demonstrating its ability to directly inhibit the formation of calcium and phosphorus crystals, thereby blocking the production and deposition of ectopic calcium. The efficacy and safety of SNF472 in inhibiting vascular calcification have been confirmed in recent clinical studies. This review summarizes the results of studies related to SNF472 to provide a comprehensive overview of itsmechanism of action, efficacy, safety, and ongoing clinical studies.

Extrahepatic Vitamin K-Dependent Gla-Proteins-Potential Cardiometabolic Biomarkers.

One mechanism to regulate pathological vascular calcification (VC) is its active inhibition. Loss or inactivation of endogenic inhibitors is a major inductor of VC. Such inhibitors are proteins rich in gamma-glutamyl residues (Gla-proteins), whose function strongly depends on vitamin K. The current narrative review is focused on discussing the role of extrahepatic vitamin K-dependent Gla-proteins (osteocalcin, OC; matrix Gla-protein, MGP; Gla-rich protein, GRP) in cardio-vascular pathology. Gla-proteins possess several functionally active forms whose role in the pathogenesis of VC is still unclear. It is assumed that low circulating non-phosphorylated MGP is an indicator of active calcification and could be a novel biomarker of prevalent VC. High circulating completely inactive MGP is proposed as a novel risk factor for cardio-vascular events, disease progression, mortality, and vitamin K deficiency. The ratio between uncarboxylated (ucOC) and carboxylated (cOC) OC is considered as an indicator of vitamin K status indirectly reflecting arterial calcium. Despite the evidence that OC is an important energy metabolic regulator, its role on global cardio-vascular risk remains unclear. GRP acts as a molecular mediator between inflammation and calcification and may emerge as a novel biomarker playing a key role in these processes. Gla-proteins benefit clinical practice as inhibitors of VC, modifiable by dietary factors.

Food to Prevent Vascular Calcification in Chronic Kidney Disease.

Vascular calcification (VC) is a consequence of chronic kidney disease (CKD) which is of paramount importance regarding the survival of CKD patients. VC is far from being controlled with actual medication; as a result, in recent years, diet modulation has become more compelling. The concept of medical nutritional therapy points out the idea that food may prevent or treat diseases. The aim of this review was to evaluate the influence of food habits and nutritional intervention in the occurrence and progression of VC in CKD. Evidence reports the harmfulness of ultra-processed food, food additives, and animal-based proteins due to the increased intake of high absorbable phosphorus, the scarcity of fibers, and the increased production of uremic toxins. Available data are more supportive of a plant-dominant diet, especially for the impact on gut microbiota composition, which varies significantly depending on VC presence. Magnesium has been shown to prevent VC but only in experimental and small clinical studies. Vitamin K has drawn considerable attention due to its activation of VC inhibitors. There are positive studies; unfortunately, recent trials failed to prove its efficacy in preventing VC. Future research is needed and should aim to transform food into a medical intervention to eliminate VC danger in CKD.

Dietary Vitamin K1 Intake and Incident Aortic Valve Stenosis.

Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K1 are associated with a lower incidence of aortic stenosis. In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K1 were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease-related mortality; secondary outcome). In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K1 intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63-0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56-0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors. In this study, a high intake of vitamin K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

Associations of Indoxyl Sulfate and p-cresyl Sulfate with Serum Uncarboxylated Matrix γ-carboxyglutamate Protein in Chronic Kidney Disease Patients.

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are two important protein-bound uremic retention solutes. Increased serum levels of IS and PCS are associated with cardiovascular calcification. Matrix γ-carboxyglutamate protein (MGP) is a potent inhibitor of vascular calcification and inactivated uncarboxylated MGP (ucMGP) is related to vascular calcification. Nevertheless, whether serum levels of IS and PCS are associated with the serum ucMGP level in chronic kidney disease (CKD) patients with different stages is unknown. This cross-sectional study enrolled 90 patients in different stages of chronic kidney disease. Serum levels of IS and PCS were determined. The serum concentration of ucMGP was measured with an enzyme-linked immunosorbent assay. Independent associations between serum total IS and PCS with ucMGP were evaluated. The mean serum level of ucMGP in participants of this study is 10.78±5.22 μg/mL. Serum levels of the two above-mentioned uremic toxins and ucMGP were elevated commensurately with deteriorating renal function. The serum level of ucMPG was associated with total IS (r = 0.456, p < 0.001) and total PCS (r =0.413, p < 0.001) levels. Multiple linear regression analysis showed that ucMGP was significantly related to levels of IS (β = 0.442, p <0.001), but not the level of PCS concentrations after adjusting for other confounding variables. Our study showed that a higher serum IS level was independently associated with ucMGP in deteriorating CKD. Therefore, it would be worthwhile to investigate the effect of IS on ucMGP in the pathogenesis of vascular calcification in future studies.

Vascular calcification inhibitors and cardiovascular events in peritoneal dialysis patients.

The prevalence of cardiovascular diseases is high among patients with chronic kidney disease (CKD) and peritoneal dialysis (PD) patients, which increases morbidity and mortality in this population and represents a significant financial burden for both the patients and the healthcare systems. Vascular calcification (VC) is associated with increased morbidity and mortality and VC risk is higher in patients with CKD than in healthy individuals. Calcification inhibitors, compounds that inhibit VC, were discovered as a result of efforts to explain why some patients are spared. It was found that certain proteins (e.g., fetuin-A, osteopontin, osteoprotegerin, bone morphogenetic protein-7) inhibit calcification in dialysis patients. In this narrative review, we provide an overview of known calcification inhibitors, describe the relevant regulatory mechanisms, and discuss their relation to VC development in PD patients.

A Bioactive Disintegrable Polymer Nanoparticle for Synergistic Vascular Anticalcification.

Although poly(aspartic acid) (PASP), a strong calcium chelating agent, may be potentially effective in inhibition of vascular calcification, its direct administration may lead to side effects. In this study, we employed polysuccinimide, a precursor of PASP, to prepare targeted polysuccinimide-based nanoparticles (PSI NPs) that not only acted as a prodrug but also functioned as a carrier of additional therapeutics to provide powerful synergistic vascular anticalcification effect. This paper shows that chemically modified PSI-NPs can serve as effective nanocarriers for loading of hydrophobic drugs, in addition to anticalcification and antireactive oxygen species (anti-ROS) activities. Curcumin (Cur), with high loading efficiency, was encapsulated into the NPs. The NPs were stable for 16 h in physiological conditions and then slowly dissolved/hydrolyzed to release the therapeutic PASP and the encapsulated drug. The drug release profile was found to be in good agreement with the NP dissolution profile such that complete release occurred after 48 h at physiological conditions. However, under acidic conditions, the NPs were stable, and Cur cumulative release reached only 30% after 1 week. Though highly effective in the prevention of calcium deposition, PSI NPs could not prevent the osteogenic trans-differentiation of vascular smooth muscle cells (VSMCs). The presence of Cur addressed this problem. It not only further reduced ROS level in macrophages but also prevented osteogenic differentiation of VSMCs in vitro. The NPs were examined in vivo in a rat model of vascular calcification induced by kidney failure through an adenine diet. The inclusion of Cur and PSI NPs combined the therapeutic effects of both. Cur-loaded NPs significantly reduced calcium deposition in the aorta without adversely affecting bone integrity or noticeable side effects/toxicity as examined by organ histological and serum biochemistry analyses.

Enzymatic release of endogenous vascular calcification inhibitor: Calcification blocking factor

Enzymatic release of endogenous vascular calcification inhibitor: Calcification blocking factor

Calciphylaxis in Hemodialysis

Calciphylaxis (CP) or uremic calcific arterial disease (CUA) is a rare, potentially fatal calcific vasculopathy characterized by calcific and thrombotic occlusion of the vessels of the subcutaneous and dermis leading to extremely painful necrotic lesions. It mainly affects patients with end-stage kidney disease (ESKD) and under long time dialysis. The only therapeutic option is represented by intravenous sodium thiosulfate. Currently, clear guidelines are lacking. We have had a good therapeutic response with doses of sodium thiosulfate in association with multidisciplinary management of the patient (vulnologist, dermatologist, nephrologist, dietitian, and cardiologist). There is limited literature on the use of DOAC therapy as a successful alternative to warfarin in patients on dialysis with calciphylaxis. The left atrial appendage closure could represent an important alternative to dicumarolics in patients with atrial fibrillation with calciphylaxis. A new perspective for the treatment of this disease is SNF472 a selective inhibitor of vascular calcification.

Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK)

Vitamin K deficiency among patients on hemodialysis (HD) affects the function of matrix GLA protein (MGP), a potent vitamin K-dependent inhibitor of vascular calcification (VC). We conducted a single-center randomized controlled trial (RCT) on maintenance HD patients to examine if vitamin K2 supplementation can reduce progression of coronary artery calcification (CAC) over an 18-month study period. Patients were randomized to vitamin K2 group receiving menaquinone-7360 μg 3 times/wk or control group. The primary outcome was CAC scores at the end of the study period. The secondary outcomes were aortic valve calcification (AVC), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), dephosphorylated undercarboxylated MGP (dp-ucMGP) levels, major adverse cardiac events (MACE), and vascular access events. Of the 178 patients randomized, follow-up was completed for 138 patients. The CAC scores between the 2 groups were not statistically different at the end of 18 months (relative mean difference [RMD] 0.85, 95% CI 0.55-1.31). The secondary outcomes did not differ significantly in AVC (RMD 0.82, 95% CI 0.34-1.98), cfPWV (absolute mean difference [AMD] 0.55, 95% CI-0.50 to 1.60), and AIx (AMD 0.13, 95% CI-3.55 to 3.80). Supplementation with vitamin K2 did reduce dp-ucMGP levels (AMD-86, 95% CI-854 to-117). The composite outcome of MACE and mortality was not statistically different between the 2 groups (Hazard ratio= 0.98, 95% CI 0.50-1.94). Our study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of VC in this population at the studied dose and duration.

#5200 IMPACT OF MINERAL BONE PARAMETERS IN COGNITIVE IMPAIRMENT IN DIALYSIS PATIENTS

Abstract Background and Aims Mineral bone disease and cognitive impairment are related diseases in the CKD population. Vascular calcification, a marker of MBD, may play a role in the early detection of cognitive decline. This study aims to identify a relationship between MBD biomarkers and cognitive function and to identify dialysis patients with a high risk of dementia. Method A total of 98 patients participated in this cross-sectional study, with 63 on hemodialysis and 35 on peritoneal dialysis. They underwent the Montreal Cognitive Assessment (MoCA) questionnaire, which categorized mild, moderate, severe, and severe based on scoring. PTH, P, Ca, ALP, and Mg serum concentrations and vascular calcification were measured as MBD biomarkers. The Adragaos score was applied to graphs of the hands and pelvis to evaluate vascular calcification. Results The mean MoCA score was 20,28±5.8. Based on the responses, it was concluded that 70% of HD patients had mild cognitive impairment, compared to 63% of PD patients. According to the descriptive data, patients whose underlying CKD was caused by nephroangisclerosis had the lowest MOCA test results compared to other groups (p&amp;lt;0.001). The degree of calcification was observed to have an adverse effect on cognitive performance in both groups (p&amp;lt;0.012); the high Adragaos score contributed to the decline in the MoCA test score. In multivariate logistic regression analysis, hypercalcemia and hypomagnesemia were independent variables for cognitive function impairment (p = 0.006 and p = 0.04, respectively). The serum concentration of PTH (p = 0.008) and ALP (p = 0.001) were found to be risk factors for HD patients during the evaluation of the MoCA test in each of the groups. Conclusion Vascular calcifications are considered a risk factor for cognitive impairment. In our study, vascular calcification risk is positively impacted by indicators such as hyperparathyroidism, hypercalcemia, high levels of ALP, and hypomagnesemia. Recently research has demonstrated the effectiveness of magnesium as a vascular calcification inhibitor. So, nephrologists should be more careful in monitoring levels of MBD biomarkers.

Abstract 11540: Dephospho-Uncarboxylated Matrix Gla-Protein and Adverse Outcomes in Heart Failure: A Mendelian Randomization Analysis

Introduction: Matrix Gla-protein (MGP) is a known inhibitor of vascular calcification and is activated by vitamin K-dependent carboxylation. Carboxylation is reduced in vitamin K-deficient states, resulting in increased circulating dephospho-uncarboxylated MGP (dpucMGP). Elevated dpucMGP levels have been associated with large artery stiffenning and worse outcomes in heart failure (HF). We assessed the causal relationship between dpucMGP and adverse outcomes in human HF using Mendelian Randomization (MR). Methods: We measured dpucMGP among 2379 Penn Heart Failure Study (PHFS) participants and analyzed a subset with genotypic data (n=1334). We constructed a genetic risk score (GRS) using independent single nucleotide polymorphisms (SNPs) associated with dpucMGP levels at genome-wide significance, and utilized MR analysis to assess the association between genetically determined dpucMGP levels and 1) all-cause death, and 2) death or heart failure-related hospital admission (DHFA). Results: Measured dpucMGP levels were associated with an increased risk of death ( Figure 1A ) and DHFA ( Figure 1B ). DpucMGP levels were significantly associated with 55 genome-wide SNPs. MR analysis demonstrated a significant relationship between genetically determined dpucMGP and the risk of death (hazard ratio [HR] 1.67, P =0.013) and DHFA (HR 1.51, P =0.004). Conclusions: Elevated dpucMGP levels are associated with increased risk for all-cause death and DHFA in patients with heart failure, and this relationship is likely causal. Further studies are required to determine the role of vitamin K supplementation in this patient population.

Abstract 15322: O-glcnac Modification on Runx2 Promotes Vascular Calcification

Vascular calcification is prevalent in patients with diabetes mellitus and well documented in animal models of diabetes. We have previously reported that vascular calcification in diabetes is associated with elevated vascular protein O -linked GlcNAc modification ( O -GlcNAcylation). The present studies sought to determine a causative link of O -GlcNAcylation with diabetic vascular calcification and the underlying molecular mechanisms. Using coronary arteries from diabetic subjects, we identified increased O -GlcNAcylation in the highly calcified lesions compared to those in the surrounding uncalcified areas. By generating a new mouse model with inducible SMC-specific deletion of the O -GlcNAc transferase (OGT), we demonstrated that smooth muscle cell (SMC)-specific OGT deletion significantly inhibited protein O -GlcNAcylation and calcification, and decreased aortic stiffness in the low-dose streptozotocin-induced diabetic mice. Consistent with the observations in human tissues, inhibition of vascular calcification by OGT ablation was associated with down-regulation of Runx2, the essential osteogenic regulator for vascular calcification. OGT deficiency in VSMC further attenuated Runx2-induced VSMC calcification. Immunoprecipitation analysis uncovered a direct O-GlcNAc modification on Runx2, which was abolished in the OGT-deficient VSMC. With a serial of Runx2 truncation mutants and point mutations on putative O -GlcNAcylation sites, we localized the essential Runx2 osteogenic functional domain between amino acids 391 and 432, and identified Runx2 T412 was responsible for Runx2 O -GlcNAcylation and Runx2-induced VSMC calcification. Inhibition of Runx2 O -GlcNAcylation by T412A mutation decreased Runx2 transcription activity and inhibited Runx2 binding with its key co-factors. Taken together, our studies have provided the first genetic proof demonstrating the causative effects of O -GlcNAcylation on vascular calcification in diabetes, and identified a novel mechanism underlying the essential role of O -GlcNAcylation of Runx2 in Runx2 osteogenic activity and Runx2-induced VSMC calcification. These results may shed lights on novel targets that are amenable to drug discovery for diabetic vascular calcification.