Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: A cohort study

Patients with chronic kidney disease (CKD) suffer from vitamin K deficiency and are at high risk of vascular calcification (VC) and premature death. We investigated the association of functional vitamin K deficiency with all-cause mortality and whether this association is modified by the presence of VC in CKD stage 5 (CKD G5). Plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP), a circulating marker of functional vitamin K deficiency, and other laboratory and clinical data were determined in 493 CKD G5 patients. VC was assessed in subgroups by Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC). Backward stepwise regression did not identify dp-ucMGP as an independent determinant of VC. During a median follow-up of 42 months, 93 patients died. Each one standard deviation increment in dp-ucMGP was associated with increased risk of all-cause mortality (sub-hazard ratio (sHR) 1.17; 95% confidence interval, 1.01–1.37) adjusted for age, sex, cardiovascular disease, diabetes, body mass index, inflammation, and dialysis treatment. The association remained significant when further adjusted for CAC and AVC in sub-analyses (sHR 1.22, 1.01–1.48 and 1.27, 1.01–1.60, respectively). In conclusion, functional vitamin K deficiency associates with increased mortality risk that is independent of the presence of VC in patients with CKD G5.

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P1645VITAMIN K DEPENDENT PROTEINS AFTER KIDNEY TRANSPLANTATION: RESULTS FROM PROSPECTIVE STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1645 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Maria Fusaro ◽

Pascale Khairallah ◽

Andrea Aghi ◽

Mario Plebani ◽

Martina Zaninotto ◽

...

Keyword(s):

Kidney Transplantation ◽

Prospective Study ◽

Vascular Calcification ◽

Vitamin K ◽

Matrix Gla Protein ◽

Bone Gla Protein ◽

Vitamin K Deficiency ◽

Prospective Data ◽

K Deficiency ◽

The Impact

Abstract Background and Aims Two Vitamin K-dependent proteins (VDKPs) link bone and vasculature in CKD-MBD: Bone Gla Protein (BGP) and Matrix Gla Protein (MGP). In ESKD, Vitamin K deficiency is highly prevalent and leads to increased levels of inactive VKDPs (undercaboxylated (ucBGP and dephosphorylated (dp)-uMGP), which are linked to greater risk of fractures and severity of vascular calcification. We hypothesized that kidney transplantation (KT) would improve Vitamin K status and lower levels of inactive VKDPs. Method Between 2014-2017, we conducted a study in 34 patients to assess changes in VKDPs during the 1st year of KT. In a specialized lab we determined VKDPs pre- and 1-year post-KT: total BGP, uc BGP, total MGP, and dp-uc MGP. We determined the prevalence of Vitamin K deficiency based on levels of uc BGP and dp-uc MGP. Results Our cohort had a mean +/- SD age of 48+/-14 years, 32% were female and 97% were Caucasian. 1 year post-KT, there was a decrease in the levels of all VKDPs and the prevalence of Vitamin K deficiency (Table 1 and Figure 1). Patients with greatest severity of Vitamin K deficiency pre-KT had the largest decreases of inactive VDKPs post-KT. Conclusion KT was associated with improvement in Vitamin K status as manifested by decreased levels of inactive VKDPs. These are the first prospective data on VKDPs in CKD patients pre- and post-KT. Studies are needed to assess the impact of improvement in VKDP status after KT on CKD-MBD outcomes.

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Vitamin K deficiency: an emerging player in the pathogenesis of vascular calcification and an iatrogenic consequence of therapies in advanced renal disease

AJP Renal Physiology ◽

10.1152/ajprenal.00278.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F618-F623

Author(s):

David S. Levy ◽

Rickinder Grewal ◽

Thu H. Le

Keyword(s):

Bone Metabolism ◽

Vascular Calcification ◽

Vitamin K ◽

Hospital Admissions ◽

Fibroblast Growth Factor 23 ◽

Vitamin K Deficiency ◽

Increased Risk ◽

K Deficiency ◽

Human Aortic Valve

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3–5 has been shown to be as high as 79% ( 20 ). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease ( 6 , 20 , 50 , 55 ). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH)2 vitamin D decrease. These imbalances have been linked to the development of vascular calcification. More recently, additional factors have been found to play a role in vascular calcification. Matrix G1a protein (MGP) in its carboxylated form (cMGP) is a potent inhibitor of vascular calcification. Importantly, carboxylation of MGP is dependent on the cofactor vitamin K. In patients with CKD, vitamin K deficiency is prevalent and is exacerbated by warfarin, which is frequently used for anticoagulation. Insufficient bioavailability of vitamin K reduces the amount of cMGP available, and, therefore, it may lead to increased risk of vascular calcification. In vitro studies have shown that in the setting of a high-phosphate environment and vitamin K antagonism, human aortic valve interstitial cells become calcified. In this article, we discuss the pathophysiological consequence of vitamin K deficiency in the setting of altered mineral and bone metabolism, its prevalence, and clinical implications in patients with CKD.

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P0895THE RELATIONSHIP OF ARTERIAL CALCIFICATIONS IN CHRONIC KIDNEY DISEASE PATIENTS WITH INDIRECT ANTICOAGULANT INTAKE AND HEART MORBIDITY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0895 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Asen Kamenov ◽

Stoyanka Georgieva ◽

Dobrina Mlachkova ◽

Daniela Valentinova Monova

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vertebral Body ◽

Vitamin K ◽

Abdominal Aorta ◽

Lumbar Vertebrae ◽

Calcium Score ◽

Arterial Calcification ◽

Vitamin K Deficiency ◽

K Deficiency

Abstract Background and Aims In patients with chronic kidney disease (CKD), arterial calcification (AC) is a potential mechanism for the progression of cardiovascular disease. AC is common in CKD patients and is a consequence of mineral-bone disorders. Indirect anticoagulants or vitamin K deficiency lead to matrix γ-carboxyglutamate decarboxylation, which may potentiate vascular calcification formation. The impaired renal function and indirect anticoagulants intake may lead to vitamin K deficiency and increased AC. The aim of this study is to determine if oral intake of Acenocoumarol has influence on abdominal aorta calcium score (AACS) and the AC relation with atrial fibrillation (AF) and / or ischemic heart disease (IHD) morbidity. Method We observe 129 patients with CKD (glomerular filtration rate below 44 ml/min/1,73 m2, MDRD formula calculated). X - ray of the lateral abdominal aorta is performed for the AACS assessment according to L. I. Kauppila et al. method. The assessment of calcium score is formed by the involvement grade of each segment on the anterior and posterior wall of the vessel along the first four lumbar vertebrae. Calcification affecting less than 1/3 of the anterior wall of the aorta along the lumbar vertebral body receives 1 score and calcification extending over ½ of the vertebral body length receives 3 scores (total score - 24). The patients are distributed into three groups: I group with calcium score from 0 to 7, II - from 8 to 15 and III group - from 16 to 24. The data from assessed AACS are compared with Acenocoumarol intake and the presence/absence of AF and/or IHD. The results are processed with χ2 statistical analysis. Results One hundred twenty nine patients with CKD (95 males and 34 females) are included in the study. The patients data (mean, percentages, degrees, etc.) are summarized in tabl.1 and tabl. 2. Clinically significant is the correlation between the grades of AACS and Acenocoumarol intake (p < 0,05). With the calcium score increasing, the patients percentage treated with Acenocoumarol also increases (fig. 1). There is a moderate correlation (Cramer’s coefficient is 0,39) between the AACS grades and heart morbidity from AF and / or IHD (p < 0,05). The data shows that the higher calcium score is related with increased patients percentage with AF and / or IHD morbidity (fig. 2). In our study, vascular calcifications are found in the abdominal aorta walls in all of the observed patients. We found that a higher AACS is associated with an Acenocoumarol intake in CKD patients and corresponds to an increased morbidity of AF and / or IHD. Acenocoumarol intake may lead to increased AACS. The higher calcium score is associated with a higher incidence of AF and / or IHD morbidity. Conclusion The study outcome supported the hypothesis that the increased AC formation and cardiovascular morbidity high risk could be a reason for the limited vitamin K antagonists (acenocoumarol) use in CKD patients. Furthermore, vitamin K2 supplementation is reasonable and may reduce the progression of AC.

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Vitamin K Metabolism in a Rat Model of Chronic Kidney Disease

American Journal of Nephrology ◽

10.1159/000451068 ◽

2016 ◽

Vol 45 (1) ◽

pp. 4-13 ◽

Cited By ~ 12

Author(s):

Kristin M. McCabe ◽

Sarah L. Booth ◽

Xueyan Fu ◽

Emilie Ward ◽

Michael A. Adams ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vitamin K ◽

Rat Model ◽

Relative Increase ◽

Kidney Cortex ◽

Vitamin K Deficiency ◽

Tissue Concentrations ◽

K Deficiency ◽

Very High

Background: Patients with chronic kidney disease (CKD) have very high levels of uncarboxylated, inactive, extra-hepatic vitamin K-dependent proteins measured in circulation, putting them at risk for complications of vitamin K deficiency. The major form of vitamin K found in the liver is phylloquinone (K1). Menaquinone-4 (MK-4) is the form of vitamin K that is preferentially found in extra-hepatic tissues. Methods: In the present study, we assessed tissue concentrations of K1 and MK-4 and the expression of vitamin K-related genes in a rat model of adenine-induced CKD. Results: It was found that rats with both mild and severe CKD had significantly lower amounts of K1 measured in liver, spleen and heart and higher levels of MK-4 measured in kidney cortex and medulla. All animals treated with high dietary K1 had an increase in tissue levels of both K1 and MK-4; however, the relative increase in K1 differed suggesting that the conversion of K1 to MK-4 may be a regulated/limiting process in some tissues. There was a decrease in the thoracic aorta expression of vitamin K recycling (Vkor) and utilization (Ggcx) enzymes, and a decrease in the kidney level of vitamin K1 to MK-4 bioconversion enzyme Ubiad1 in CKD. Conclusion: Taken together, these findings suggest that CKD impacts vitamin K metabolism, and this occurs early in the disease course. Our findings that vitamin K metabolism is altered in the presence of CKD provides further support that sub-clinical vitamin K deficiency may represent a modifiable risk factor for vascular and bone health in this population.

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Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification

Nutrients ◽

10.3390/nu11010152 ◽

2019 ◽

Vol 11 (1) ◽

pp. 152 ◽

Cited By ~ 12

Author(s):

Yi-Chou Hou ◽

Chien-Lin Lu ◽

Cai-Mei Zheng ◽

Ruei-Ming Chen ◽

Yuh-Feng Lin ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Vitamin D ◽

Kidney Disease ◽

Vascular Calcification ◽

Vitamin K ◽

Matrix Vesicles ◽

Vital Role ◽

Matrix Gla Protein ◽

Protein Receptor ◽

Calciprotein Particles

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).

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Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug–Bug Interaction?

Toxins ◽

10.3390/toxins12060351 ◽

2020 ◽

Vol 12 (6) ◽

pp. 351

Author(s):

Lu Dai ◽

Björn K. Meijers ◽

Bert Bammens ◽

Henriette de Loor ◽

Leon J. Schurgers ◽

...

Keyword(s):

Kidney Disease ◽

Vitamin K ◽

Phosphate Binder ◽

Microbial Metabolism ◽

Uremic Toxins ◽

Matrix Gla Protein ◽

Vitamin K Deficiency ◽

End Stage Kidney Disease ◽

K Deficiency ◽

End Stage

Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.

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Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease

Scientific Reports ◽

10.1038/s41598-020-63013-8 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Armand M. G. Jaminon ◽

Lu Dai ◽

Abdul Rashid Qureshi ◽

Pieter Evenepoel ◽

Jonaz Ripsweden ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vascular Calcification ◽

Vascular Tissue ◽

Independent Predictor ◽

Matrix Gla Protein ◽

Snp Analysis ◽

Cross Sectional ◽

Ckd Stage ◽

Vascular Expression

AbstractMatrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.

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The Vitamin K Metabolome in Chronic Kidney Disease

Nutrients ◽

10.3390/nu10081076 ◽

2018 ◽

Vol 10 (8) ◽

pp. 1076 ◽

Cited By ~ 6

Author(s):

Mandy Turner ◽

Michael Adams ◽

Rachel Holden

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vitamin K ◽

Cardiovascular Events ◽

Vitamin K Deficiency ◽

Ectopic Mineralization ◽

K Deficiency ◽

Activity Of Enzymes ◽

The Impact ◽

Tissue Vitamin

The purpose of this review is to summarize the research to date on the impact of chronic kidney disease (CKD) on the vitamin K metabolome. Vitamin K-dependent proteins contribute to cardiovascular disease (CVD) prevention via the prevention of ectopic mineralization. Sub-clinical vitamin K deficiency is common in CKD patients, and evidence suggests that it may contribute to the CVD burden in this population. Research from animal models suggests that CKD alters tissue measures of the two predominant forms of vitamin K: KI and MK-4. The expression and/or activity of enzymes that regulate the recycling of vitamin K and the carboxylation of vitamin K-dependent proteins also appear to be altered in CKD. Evidence suggests that statins, a common pharmaceutical prescribed to CKD patients to prevent cardiovascular events, may impact the metabolism of vitamin K and therefore contribute to its relative inefficiency at preventing CVD in this population as kidney disease progresses. Human research on the tissue vitamin K metabolome in CKD patients is lacking.

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Vitamin K in Chronic Kidney Disease

Nutrients ◽

10.3390/nu11010168 ◽

2019 ◽

Vol 11 (1) ◽

pp. 168 ◽

Cited By ~ 17

Author(s):

Mario Cozzolino ◽

Michela Mangano ◽

Andrea Galassi ◽

Paola Ciceri ◽

Piergiorgio Messa ◽

...

Keyword(s):

Chronic Kidney Disease ◽

At Risk ◽

Kidney Disease ◽

Vitamin K ◽

Bone Health ◽

Vitamin K Deficiency ◽

Population At Risk ◽

K Deficiency ◽

Subclinical Vitamin ◽

Fat Soluble Vitamins

Vitamin K is a composite term referring to a group of fat-soluble vitamins that function as a cofactor for the enzyme γ-glutamyl carboxylase (GGCX), which activates a number of vitamin K-dependent proteins (VKDPs) involved in haemostasis and vascular and bone health. Accumulating evidence demonstrates that chronic kidney disease (CKD) patients suffer from subclinical vitamin K deficiency, suggesting that this represents a population at risk for the biological consequences of poor vitamin K status. This deficiency might be caused by exhaustion of vitamin K due to its high requirements by vitamin K-dependent proteins to inhibit calcification.

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