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Article

Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study

by
Marcel Palamar
1,2,
Iulia Grosu
2,3,*,
Adalbert Schiller
2,3,
Ligia Petrica
2,3,
Madalina Bodea
2,3,
Alexandru Sircuta
2,3,
Cornel Rusan
4,
Daniela Maria Tanasescu
5,6 and
Flaviu Bob
2,3
1
Deva Emergency County Hospital, 330004 Deva, Romania
2
Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babeș University of Medicine and Pharmacy, 300041 Timișoara, Romania
3
Division of Nephrology, Department of Internal Medicine II, County Emergency Hospital Timisoara, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
4
Dialysis, Fresenius Nephrocare Deva, 330004 Deva, Romania
5
Nephrology Department, Bucharest Emergency University Hospital, 050098 Bucharest, Romania
6
Department 1 of Medical Semiology, Discipline of Medical Semiology and Nephrology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
*
Author to whom correspondence should be addressed.
Appl. Sci. 2023, 13(19), 10938; https://doi.org/10.3390/app131910938
Submission received: 6 August 2023 / Revised: 27 September 2023 / Accepted: 29 September 2023 / Published: 3 October 2023
Browse Figures
Versions Notes

Abstract

:
(1) Background: Vitamin K deficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and an increased risk of vascular calcifications. A method to indirectly assess the vitamin K status is measuring the blood level of vitamin K-dependent proteins (VKDP): osteocalcin (OC) and matrix GLA protein (MGP). The aim of this study is to correlate the level of total OC and inactive MGP (dp-uc MGP) with markers of CKD mineral bone disorder (CKD-MBD). (2) Methods: We conducted a single-center cross-sectional study that included 45 CKD G5D patients and measured their blood biochemistry, complete blood count and total osteocalcin and dp-uc MGP contents. (3) Results: We found a strong, statistically significant correlation of the total OC with the markers of CKD-MBD, such as: iPTH, serum calcium and serum phosphorus, and a strong, indirect statistically significant correlation with abdominal circumference. There was also a statistically significant correlation of dp-uc MGP with the markers of inflammation (CRP). Higher levels of dp-uc MGP were found in the patients treated with vitamin K antagonists, non-calcium-based phosphate binders and the vitamin D receptor activator, paricalcitol. (4) Conclusions: In our study, we found that when it is measured indirectly using VKDP levels, vitamin K deficiency is associated with CKD-MBD. Certain widely used medications such as phosphate binders reduce vitamin K absorption, supplementary vitamin D increases vitamin K requirements, and also vitamin K antagonists influence the blood level of VKDPs.

1. Introduction

Chronic kidney disease (CKD) patients, and especially those with end-stage renal disease (ESRD), have a very high cardiovascular (CV) burden. Patients on renal replacement therapies (RRT) are reported to have particular cardiovascular presentations, such as arterial medial calcifications, heart valve calcifications and calcific arteriolopathy [1]. Moreover, once they have occurred, the calcification processes are considered largely irreversibile [2]. In light of these clinical observations, the mortality of ESRD patients is largely accounted by CV factors and is 30 times higher than it is in the same age-matched general population [3].
The mechanisms that lead to increased vascular calcifications in CKD patients are represented by determinant risk factors, which can be traditional (hypertension, diabetes, smoking and age) and non-traditional. The latter ones are represented by factors associated with CKD-associated mineral bone disorder (CKD-MBD), such as high levels of calcium x phosphorus product and fibroblast growth factor 23 (FGF23), and low vitamin D levels or high parathormone levels (PTH) [4], and also inflammation, oxidative stress or uremic toxins. Currently, it is widely accepted that high phosphate levels will trigger the overproduction of FGF23, which acts as a phosphaturic hormone and negatively regulates PTH levels [5].
Despite similar exposure to the risk factors, not all CKD patients develop vascular calcifications. This fact could be explained by the presence of protecting factors in some of the patients, including Fetuin A, Bone morphogenetic protein 7 (BMP 7) and Adenosine, as well as vitamin K [5]. Vitamin K is a fat-soluble vitamine which constitutes the substrate for several vitamin K-dependent proteins (VKDPs), and some of them are involved in the coagulation cascade, cellular adhesion and migration, and bone and vascular homeostasis. The VKDPs implicated in calcification processes are matrix Gla protein (MGP), osteocalcin (OC), bone Gla protein, growth arrest-specific protein 6 and Gla-rich protein [6].
Vitamin K deficiency is a frequent concern among CKD patients, particularly patients undergoing hemodialysis (HD) treatment [7]. The underlying mechanism of vitamin K deficiency is a combination between its increased consumption in order to produce vitamin K-dependent calcification inhibiting proteins and reduced vitamin K intake due to low potassium and phosphate diets.
Some therapeutic interventions performed for CKD patients have been mentioned to have an impact on vitamin K homeosthasis. First of all, we address warfarin-based anticoagulation. A warfarin prescription for ESRD patients is implied in order to reduce the stroke risk in patients with atrial fibrillation or prosthetic valves, but sometimes also in order to preserve vascular access patency. Warfarin acts through the inhibition of a vitamin K epoxide reductase enzyme and contributes to ectopic calcification processes by reducing the activity level of endogenous mineralization inhibitors [8]. On the other hand, there are several therapeutic interventions available in order to control CKD-MBD, and thus, reduce vascular calcifications. However, the interaction between vitamin K and phosphate binders could potentially limit vitamin K bioavailability because the formed calcium phosphate salt can bind vitamin K as well [9]. Moreover, current vitamin K statuses are not routinely assessed in ESRD patients; therefore, reports regarding the possible interactions between concurrent medications and vitamin K deficiency are scarce. A method used to assess vitamin K status is to measure the fragments of VKDPs; increased levels reflect a vitamin K deficiency.
MGP is transformed in an active form through phosphorylation and vitamin K-dependent carboxylations. The MGP inactive form (dephosphorylated-uncarboxylated MGP- dp-ucMGP) reflects the subject’s vitamin K status, and higher levels have been associated with more ectopic calcifications [10]. The completely unfunctional form of MGP (dp-ucMGP) has a low affinity for calcium and matrix vesicles, and only after being carboxilated, it forms a mass with calcium phosphate, thus preventing vascular calcifications. This is the explanation for why high levels of dp-ucMGP reflect an impaired vitamin K status [11].
Osteocalcin (OC) is produced by osteoblasts and has a role in increasing mineral bone density. OC transformation from its uncarboxylated form to its fully functional carboxylated form is vitamin K-mediated. Increased uncarboxylated OC is a marker of vitamin K deficiency [12]. However, the immunoassays commonly used in the literature to measure the different fragments of OC do not provide complete information on how many of the fragments are actually carboxylated, which leads to the idea of using the total OC concentration instead of truncated fragments [13]. The total osteocalcin value (that recognizes both intact and N-MID fragments of osteocalcin), which we determined in our study, is even more stable compared to the use of assays measuring intact osteocalcin only.
The present study aims to assess the total OC and dp-ucMGP levels in a cohort of hemodialysis patients and their relationship with CKD-MBD markers, nutritional status as well as concomitant medications.

2. Materials and Methods

We conducted a cross-sectional study including 45 CKD G5D patients; all the patients were undergoing maintenance hemodialysis for 6 months to 10 years in a single outpatient hemodialysis unit. The patients scheduled in the next 3 months for a renal transplantation, for a change in the renal replacement method or a change in dialysis center were excluded from the study.
All the procedures were conducted in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki. The current study has the approval of the Ethical Committee of the University of Medicine and Pharmacy “Victor Babes” Timisoara Nr 34/30.06.2021. Prior to any study procedure, the eligible patients were asked to provide written informed consent.

2.1. Clinical and Biochemical Evaluation

Blood of the patients was drawn from the arteriovenous fistula just before the mid-week HD session. The specimens were kept at 4 °C for 1 h and centrifuged at 1000× g for 10 min. The resultant sera were stored in aliquots at −80 °C until they were assayed. The frozen samples were thawed, and the measurements were performed immediately.
We obtained the following parameters: iPTH, serum calcium, serum phosphorus, serum albumin, serum C-reactive protein (CRP), serum potassium (K) and serum bicarbonate using the COBAS 6000 analysis series from Roche Diagnostics (Basel, Switzerland). Complete blood count analysis was performed using the XN-1000 analyzer from Sysmex.
The level of total OC was determined in the sera of patients by employing the automated electrochemiluminescence immunoassay “ECLIA” method using Elecsys N-MID Osteocalcin kits from Roche on a Cobas e411 analyzer from Roche (Basel, Switzerland). For the assessment of the matrix GLA protein (dp-ucMGP), a quantitative chemiluminescence method was used with the IDS-iSYS InaKtif MGP (dp-u-MGP) kit from Immunodiagnosticsystems (Bolden, UK) and using Xprep equipment from TE Instruments (Delft, The Netherlands).
In every patient, a physical exam was performed before and after the dialysis session (including the assessment of weight, height, BMI and abdominal circumference). For the BMI assessment, we used their dry weight (weight at the end of the dialysis session). From the medical files of every individual, we recorded the patients’ demographic data, (including gender and age), as well as their medical history, dialysis vintage, CKD etiology, history of comorbidities, such as diabetes mellitus, the presence of coronary heart disease, the presence of stroke, and history of fractures. The use of concomitant medication for CKD-associated mineral bone disease was also recorded (including paricalcitol, phosphate binders and vitamin D supplements), as well as treatment with vitamin K antagonists.

2.2. Statistical Analysis

We used MedCalc Software, version 12.5.0 (MedCalc, Mariakerke, Belgium) for statistical analysis. We used the Kolmogrov–Smirnov test to assess the distribution of numeric variables. For variables with a normal distribution, we calculated the means and standard deviations. For group comparisons of continuous variables with a normal distribution, we used Student’s t tests, and we used Mann–Whitney U tests for variables with a non-normal distribution. For comparing qualitative variables, Pearson’s chi-squared test and the Spearman rank correlation test were used.

3. Results

In this study, we enrolled 45 patients on hemodialysis. The characteristics of the studied lot are presented in Table 1. The median levels of the VKDP measured in our patients were as follows: the median total OC value was 135.4 ng/mL (IQR 118.14 ng/mL), while the median dp-uc MGP total was 2953 pmol/L (IQR 2660.7 pmol/L). The current total OC normal reference ranges are the following: adult males (>22 years old)—5.8–14 ng/mL; adult females (>22 years old)—3.1–14.4 ng/mL [14]. The dp-uc MGP normal levels according to the literature are <300–532 pmol/L for the same type of assay used in our study [15].

3.1. Relationship with Clinical Parameters

There was a strong statistically significant correlation between the total OC and the CKD-MBD markers such as: iPTH (r = 0.48, p = 0.0007), serum calcium (r = 0.49, p = 0.0005) and serum phosphorus (r = 0.29, p = 0.04). We found no statistically significant correlation between dp-uc MGP and iPTH, serum calcium and serum phosphorus. Only two out of forty-five patients presented with a history of bone fractures.
Concerning the relationship with the patients’ nutritional status, we found no statistically significant correlations between the assessed VKDP and BMI and the serum albumin values. However, we did find a strong indirect statistically significant correlation between the total OC and the subjects’ abdominal circumference (r = −0.43, p = 0.003). Furthermore, we came across a statistically significant correlation between the dp-uc MGP levels and the markers of inflammation (CRP) (r = 0.55, p = 0.004).
We found no statistically significant differences regarding the level of VKDP of the patients with and without a history of different comorbidities, such as diabetes mellitus (13/45), coronary heart disease (18/45) or stroke (5/45).

3.2. Relationship with Treatment Patterns

The subgroup of patients undergoing treatment with vitamin K antagonists (13/45) presented with significantly higher levels of dp-uc MGP (5693.0 ± 1728.64 vs. 2276.5 ± 1232.54 pmol/L, p < 0.001) (Figure 1). Those treated with non-calcium-based phosphate binders (20 patients) presented with significantly higher levels of dp-uc MGP when compared to those of the patients treated with calcium-based phosphate binders (15 patients) (4089.2 ± 2045.79 vs. 2134.86 ± 1944.63 pmol/L, p = 0.019) (Figure 2). We found that the patients treated with the vitamin D receptor activator paricalcitol (20 patients) had significantly increased levels of dp-uc MGP (4224.55 ± 2162.32 vs. 2503.75 ± 1709.31 pmol/L, p = 0.005) (Figure 3). In the current study, we found no statistically significant correlation between the medication patterns and the total OC level.

4. Discussion

In recent years, the central role of vitamin K in vascular calcifications, cardiovascular issues and bone disease has become evident. Several studies have been performed assessing the link between vitamin K metabolism and mineral bone disease in CKD patients. CKD patients, and especially patients treated with hemodialysis, are vitamin K-deficient. In a study performed by Wikstrom et al., it was shown that dialysis patients were 100% vitamin K-deficient, not due to HD wash-out or absorption capacity [16], but due to low vitamin K intake. Low vitamin K intake could be due to potassium-sparing diets which restrict the consumption of leafy greens rich in vitamin K. The assessment of vitamin K status can be performed using the levels of fragments of VKDP, or the ratio between the fragments and total VKDP. However, in patients treated with HD, the use of these ratios might negate their significance as a bone metabolic marker to indicate vitamin K deficiency [17]. In our study, we have used the total OC and dp-uc MGP, and we found higher levels compared to the normal ranges, which is a fact that might lead to the conclusion of vitamin K deficiency.
The consequences of vitamin K deficiency are mainly related to CKD-MBD. In the present study, we obtained a significant correlation between the total OC and the markers of CKD-MBD. OC is secreted in bones by osteoblasts and plays a role in the synthesis and regulation of the bone matrix [6]. The previous literature results focus on the relationship between fragments of OC (undercarboxylated OC) and PTH and calcium phosphorus products [18]. However, our study confirmed the direct relationship between these markers of CKD-MBD and the total OC as well.
Regarding dp-uc MGP, we found no statistically significant correlation with the markers of CKD-MBD. In contrast to our observations, Kurnatowska et al. [19] found significant associations between these MGP fragments and serum PTH, FGF23 levels and calcium phosphorus products.
The clinical link between poor vitamin K status and bone health has also been proven in clinical studies assessing the incidence of fractures in CKD patients [20], with vitamin K1 deficiency being the strongest predictor of vertebral fractures [21]. In our study, we could not find any statistical correlation between vitamin K status assessed by dp-uc MGP and total OC and bone fractures because of the low number of patients with a history of fractures (two patients).
Another key point assessed in our study was the relationship between VKDP and malnutrition as well as inflammation. It seems that vitamin K plays a key role in counteracting inflammation, oxidative stress and senescence. The link between malnutrition and arterial calcifications in patients treated with HD has been studied by Zhang et al. [22]. The study included 68 chronic patients undergoing HD, and they learned that MGP immunostaining in calcified radial arteries positively correlates with calcium x phosphorus product, albumin, and with the modified quantitative subjective global assessment. In our study, we did find a significant correlation between the inflammatory markers, CRP and VKDP (dp-uc MGP). Persistent, low-grade inflammation is a novel non-traditional risk factor for accelerated atherosclerosis, either on its own, or included in the Malnutrition Inflammation Atherosclerosis Syndrome. Even though the molecular pathway through which vitamin K is involved in oxidative stress, DNA repairing and inflammation is well known, the relationship between inflammatory markers and vitamin K in patients undergoing HD has not been extensively studied.
Since vitamin K is known to be a protective factor against vascular calcifications, another consequence of vitamin K deficiency is the fact that it contributes to the high burden of vascular calcifications in CKD patients. The association between the level of VKDP and the presence of vascular calcifications, and also with the endpoint of cardiovascular or all-cause mortality, has been shown across numerous cross-sectional or prospective studies performed on CKD patients [23,24,25]. In our study, we did not find any significant correlation between previous cardiovascular events (stroke or coronary heart disease) and the levels of dp-uc MGP and total OC. This a surprising finding given the fact that cardiovascular events in dialysis patients rely on accelerated atherosclerosis and vascular calcifications as an underlying pathophysiologic mechanism [19].
Another significant part of our study is linked to the relationship of the studied parameters (total OC and dp-uc MGP) with different concomitant medications. Regarding the CKD-MBD treatment, we observed significant associations between dp-uc MGP (and not the total OC) and non-calcium-based phosphate binders and paricalcitol. Neradova et al. [26] performed an in vitro study regarding the interaction between different phosphate binders and vitamin K2. They showed that succroferric-oxyhydroxide and sevelamer carbonate were the only medications that did not bind vitamin K2, while calcium-based phosphate binders and lanthanum carbonate ligate vitamin K2. Similar to our results, the VIKI study [21] also observed the link between concomitant treatments for CKD-MBD versus the OC and MGP levels. They observed that vitamin D analogs (such as paricalcitol) increase the levels of OC and MGP. The potential link between CKD MBD and vitamin K2 metabolism may be of particular clinical interest given the fact that the choice of medication should take into account the prevention of vascular calcifications as well. The studies regarding this topic are, however, scarce, and further RCTs would be useful to determine the benefit of choosing certain medication classes over others.
Another class of drugs frequently used by patients treated with HD is anticoagulants. In our study, patients treated with vitamin K antagonists (VKA) showed higher levels of dp-uc MGP (p < 0.001). This result is concordant with the available literature [27]. Considering this mechanism, patients on dialysis who are already vitamin K-deficient and take warfarin are much more prone to develop vascular calcifications [28]. Randhawa et al. conducted a meta-analysis of patients with ESRD and atrial fibrillation and found that 22% were on warfarin treatment [29]. In the context of extensive warfarin use and CKD MBD in ESRD patients, vitamin K supplementation was mitigated to have potential benefits. Neither the RenaKvit study [30] nor the Valkyrie study [31] have showed that vitamin K2 supplementation in clinical practice can reduce vascular stiffness or calcifications in dialysis patients, and neither did the VIKTORIES trial [32] on transplanted patients. Thus, there is no evidence yet to support the protective effects of vitamin K supplementation against vascular calcification in CKD patients as it has been also proven in a recently published metanalysis [33].
Regarding anticoagulation in patients on HD, considering the potential harmful effects of VKA, the question is if they could be replaced with direct oral anticoagulants (DOAC). There is no evidence that DOAC therapy would be unsafe or less effective than VKA, but most studies are retrospective studies. There are however two RCTs showing the non-inferiority of DOAC (apixaban) vs. VKAs in hemodialysis patients regarding safety and efficacy [34,35] and one RCT (rivaroxaban vs. VKA) that shows a superior risk-benefit profile of DOACs versus VKAs, and this suggests that VKAs should be avoided by patients on HD [36].
The major limitations of our study are that it is a cross-sectional analysis, single-centered and used a small group of subjects. Another limitation of the study could be the fact that we determined the total OC and not the specific inactive fragments. This could explain why we could find statistically significant correlations only with dp-uc MGP regarding the relationship with concomitant medications. Another limitation of our study is the fact that no controls were used for the assessment of VKDP. Moreover, no quantitative or qualitative data were included regarding the presence of vascular calcifications in our study group. The associations obtained with features of malnutrition inflammation syndrome were scarce, but may be used as a hypothesis for future, more detailed analysis.

5. Conclusions

The main conclusion of our study is the fact that the vitamin K status of patients undergoing hemodialysis can be influenced by the use of certain medications that are frequently used in this type of patients, such as vitamin K antagonists, vitamin D receptor activators and non-calcium-based phosphate binders. This raises the potential perspective of the importance of assessing the relationship of vitamin K deficiency, especially by using dp-uc MGP, with these treatment regimens in patients treated for HD. However, more extensive studies are needed to validate these statements.

Author Contributions

Conceptualization, M.P. and F.B.; methodology, M.P., C.R., D.M.T. and F.B. software, I.G.; validation, F.B.; formal analysis, I.G. and M.B.; investigation, M.P. and A.S. (Alexandru Sircuta); resources; data curation; writing—original draft preparation, M.P. and I.G.; writing—review and editing, F.B.; visualization, I.G.; supervision, F.B. and A.S. (Adalbert Schiller); project administration, F.B.; funding acquisition, L.P. and F.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the University of Medicine and Pharmacy “Victor Babes” Timisoara, Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, Timișoara, Romania.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the University of Medicine and Pharmacy “Victor Babes” Timisoara. Approval nr 34/30.06.2021.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Cozzolino, M.; Mangano, M.; Stucchi, A. Cardiovascular disease in dialysis patients. Nephrol. Dial. Transplant. 2018, 33 (Suppl. 3), iii28–iii34. [Google Scholar] [CrossRef] [PubMed]
  2. Chen, N.C.; Hsu, C.Y.; Chen, C.L. The Strategy to Prevent and Regress the Vascular Calcification in Dialysis Patients. Biomed. Res. Int. 2017, 2017, 9035193. [Google Scholar] [CrossRef] [PubMed]
  3. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2020, 395, 709–733. [Google Scholar] [CrossRef]
  4. Waziri, B.; Duarte, R.; Naicker, S. Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Current Perspectives. Int. J. Nephrol. Renovasc. Dis. 2019, 12, 263–276. [Google Scholar] [CrossRef] [PubMed]
  5. Covic, A.; Kanbay, M.; Voroneanu, L. Vascular calcification in chronic kidney disease. Clin. Sci. 2010, 119, 111–121. [Google Scholar] [CrossRef]
  6. Fusaro, M.; Tondolo, F.; Gasperoni, L. The Role of Vitamin K in CKD-MBD. Curr. Osteoporos. Rep. 2022, 20, 65–77. [Google Scholar] [CrossRef]
  7. Cranenburg, E.C.M.; Schurgers, L.J.; Uiterwijk, H.H. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012, 82, 605–610. [Google Scholar] [CrossRef]
  8. Theuwissen, E.; Smit, E.; Vermeer, C. The role of vitamin K in soft-tissue calcification. Adv. Nutr. 2012, 3, 166–173. [Google Scholar] [CrossRef]
  9. Cozzolino, M.; Cianciolo, G.; Podestà, M.A. Current Therapy in CKD Patients Can Affect Vitamin K Status. Nutrients 2020, 12, 1609. [Google Scholar] [CrossRef]
  10. Roumeliotis, S.; Dounousi, E.; Eleftheriadis, T. Association of the Inactive Circulating Matrix Gla Protein with Vitamin K Intake, Calcification, Mortality, and Cardiovascular Disease: A Review. Int. J. Mol. Sci. 2019, 20, 628. [Google Scholar] [CrossRef]
  11. Barrett, H.; O’Keeffe, M.; Kavanagh, E. Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review. Nutrients 2018, 10, 415. [Google Scholar] [CrossRef]
  12. Caluwé, R.; Verbeke, F.; De Vriese, A.S. Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysispatients. Nephrol. Dial. Transplant. 2020, 35, 23–339. [Google Scholar] [CrossRef]
  13. Kratz, M.; Zelnick, L.R.; Trenchevska, O. Relationship Between Chronic Kidney Disease, Glucose Homeostasis, and Plasma Osteocalcin Carboxylation and Fragmentation. J. Ren. Nutr. 2021, 31, 248–256. [Google Scholar] [CrossRef] [PubMed]
  14. Pagana, K.D.; Pagana, T.J.; Pagana, T.N. Mosby’s Diagnostic & Laboratory Test Reference, 14th ed.; Elsevier: St. Louis, MO, USA, 2019; 168p. [Google Scholar]
  15. Griffin, T.P.; Islam, M.N.; Wall, D. Plasma dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP): Reference intervals in Caucasian adults and diabetic kidney disease biomarker potential. Sci. Rep. 2019, 9, 18452. [Google Scholar] [CrossRef]
  16. Wikstrøm, S.; Aagaard Lentz, K. Causes of Vitamin K Deficiency in Patients on Haemodialysis. Nutrients 2020, 12, 2513. [Google Scholar] [CrossRef] [PubMed]
  17. Nagata, Y.; Inaba, M.; Imanishi, Y. Increased undercarboxylated osteocalcin/intact osteocalcin ratio in patients undergoing hemodialysis. Osteoporos. Int. 2015, 26, 1053–1061. [Google Scholar] [CrossRef]
  18. Elliott, M.J.; Booth, S.L.; Hopman, W.M. Assessment of potential biomarkers of subclinical vitamin K deficiency in patients with end-stage kidney disease. Can. J. Kidney Health Dis. 2014, 1, 13. [Google Scholar] [CrossRef]
  19. Kurnatowska, I.; Grzelak, P.; Masajtis-Zagajewska, A. Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease. Kidney Blood Press. Res. 2016, 41, 231–239. [Google Scholar] [CrossRef] [PubMed]
  20. Kohlmeier, M.; Salomon, A.; Saupe, J.; Shearer, M.J. Transport of vitamin K to bone in humans. J. Nutr. 1996, 126 (Suppl. 4), 1192S–1196S. [Google Scholar] [CrossRef]
  21. Fusaro, M.; Noale, M.; Viola, V. Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study. J. Bone Miner. Res. 2012, 27, 2271–2278. [Google Scholar] [CrossRef]
  22. Zhang, K.; Cheng, G.; Cai, X. Malnutrition, a new inducer for arterial calcification in hemodialysis patients? J. Transl. Med. 2013, 11, 66. [Google Scholar] [CrossRef]
  23. Schurgers, L.J.; Barreto, D.V.; Barreto, F.C. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: A preliminary report. Clin. J. Am. Soc. Nephrol. 2010, 5, 568–575. [Google Scholar] [CrossRef]
  24. Schlieper, G.; Westenfeld, R.; Krüger, T. Circulating nonphosphorylatedcarboxylated matrix gla protein predicts survival in ESRD. J. Am. Soc. Nephrol. 2011, 22, 387–395. [Google Scholar] [CrossRef]
  25. Zhang, S.; Guo, L.; Bu, C. Vitamin K status and cardiovascular events or mortality: A meta-analysis. Eur. J. Prev. Cardiol. 2019, 26, 549–553. [Google Scholar] [CrossRef] [PubMed]
  26. Neradova, A.; Schumacher, S.P.; Hubeek, I. Phosphate binders affect vitamin K concentration by undesired binding, an in vitro study. BMC Nephrol. 2017, 18, 149. [Google Scholar] [CrossRef]
  27. Donaldson, C.J.; Harrington, D.J. Therapeutic warfarin use and the extrahepatic functions of vitamin K-dependent proteins. Br. J. Biomed. Sci. 2017, 74, 163–169. [Google Scholar] [CrossRef]
  28. Danziger, J. Vitamin K-dependent proteins, warfarin, and vascular calcification. Clin. J. Am. Soc. Nephrol. 2008, 3, 1504–1510. [Google Scholar] [CrossRef]
  29. Randhawa, M.S.; Vishwanath, R.; Rai, M.P. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients with End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw. Open 2020, 3, e202175. [Google Scholar] [CrossRef]
  30. Levy-Schousboe, K.; Frimodt-Møller, M.; Hansen, D. Vitamin K supplementation and arterial calcification in dialysis: Results of the double-blind, randomized, placebo-controlled RenaKvit trial. Clin. Kidney J. 2021, 14, 2114–2123. [Google Scholar] [CrossRef] [PubMed]
  31. De Vriese, A.S.; Caluwé, R.; Pyfferoen, L. Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: The Valkyrie Study. J. Am. Soc. Nephrol. 2020, 31, 186–196. [Google Scholar] [CrossRef]
  32. Lees, J.S.; Rankin, A.J.; Gillis, K.A. The ViKTORIES trial: A randomized, double-blind, placebo-controlled trial of vitamin K supplementation to improve vascular health in kidney transplant recipients. Am. J. Transplant. 2021, 21, 3356–3368. [Google Scholar] [CrossRef] [PubMed]
  33. Geng, C.; Huang, L.; Pu, L. Effects of vitamin K supplementation on vascular calcification in chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials. Front. Nutr. 2023, 9, 1001826. [Google Scholar] [CrossRef]
  34. Reinecke, H.; Engelbertz, C.; Bauersachs, R. A Randomized Controlled Trial Comparing Apixaban with the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study. Circulation 2023, 147, 296–309. [Google Scholar] [CrossRef] [PubMed]
  35. Pokorney, S.D.; Chertow, G.M.; Al-Khalidi, H.R.; RENAL-AF Investigators. Apixaban for Patients with Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial. Circulation 2022, 146, 1735–1745. [Google Scholar] [CrossRef] [PubMed]
  36. De Vriese, A.S.; Heine, G. Anticoagulation management in haemodialysis patients with atrial fibrillation: Evidence and opinion. Nephrol. Dial. Transplant. 2022, 37, 2072–2079. [Google Scholar] [CrossRef]
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Figure 1. The group of patients undergoing vitamin K antagonists’ treatment (13 out of 45) had significantly higher mean levels of dp-uc MGP (5693.0 ± 1728.64 vs. 2276.5 ± 1232.54 pmol/L, p < 0.001). The level of dp-uc MGP is expressed in pmol/L.
Figure 1. The group of patients undergoing vitamin K antagonists’ treatment (13 out of 45) had significantly higher mean levels of dp-uc MGP (5693.0 ± 1728.64 vs. 2276.5 ± 1232.54 pmol/L, p < 0.001). The level of dp-uc MGP is expressed in pmol/L.
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Figure 2. The group of patients undergoing non-calcium-based phosphate binder treatment (20 patients) had significantly higher mean levels of dp-uc MGP compared to the levels of those treated with calcium-based phosphate binders (15 patients) (4089.2 ± 2045.79 vs. 2134.86 ± 1944.63 pmol/L, p = 0.019) (0—no phosphate binder (PB); 1—non-calcium-based PB; 2—calcium-based PB). The level of dp-uc MGP is expressed in pmol/L.
Figure 2. The group of patients undergoing non-calcium-based phosphate binder treatment (20 patients) had significantly higher mean levels of dp-uc MGP compared to the levels of those treated with calcium-based phosphate binders (15 patients) (4089.2 ± 2045.79 vs. 2134.86 ± 1944.63 pmol/L, p = 0.019) (0—no phosphate binder (PB); 1—non-calcium-based PB; 2—calcium-based PB). The level of dp-uc MGP is expressed in pmol/L.
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Figure 3. The group of patients treated with vitamin D receptor activator paricalcitol (20 patients) was associated with significantly increased mean levels of dp-uc MGP (4224.55 ± 2162.32 vs. 2503.75 ± 1709.31 pmol/L, p = 0.005). The level of MGP is expressed in pmol/L.
Figure 3. The group of patients treated with vitamin D receptor activator paricalcitol (20 patients) was associated with significantly increased mean levels of dp-uc MGP (4224.55 ± 2162.32 vs. 2503.75 ± 1709.31 pmol/L, p = 0.005). The level of MGP is expressed in pmol/L.
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Table 1. Characteristics of the studied patients group (the results are expressed as mean values ± standard deviations).
Table 1. Characteristics of the studied patients group (the results are expressed as mean values ± standard deviations).
VariableMean Values ± Standard Deviations
Age (years)64.3 ± 10.8
Gender female 19:26 male
BMI (kg/m2)28.08 ± 4.4
Abdominal circumference (cm)115.89 ± 18.12
Serum albumin (mmol/L)0.55 ± 0.04
Dialysis vintage (years)3.78 ± 2.65
Hemoglobin (g/L)110.9 ± 11.83
Hematocrit (%)33.58 ± 3.8982
Serum calcium (mmol/L)2.29 ± 0.20
Serum phosphorus (mmol/L)1.81 ± 0.45
iPTH (pmol/L)21.0 ± 13.79
Bicarbonate (mmol/L)21.46 ± 2.578
Predialysis K (mmol/L)5.47 ± 1
CRP (mg/dL)14.71 ± 15.34
Treatment with vitamin K antagonists (number/proportion of patients)13 (28.88%)
Treatment with phosphate binders (number/proportion of patients)Non-calcium based: 20 (44.44%):
calcium based:15 (33.33%)
Treatment with paricalcitol (number/proportion of patients)20 (44.44%)
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MDPI and ACS Style

Palamar, M.; Grosu, I.; Schiller, A.; Petrica, L.; Bodea, M.; Sircuta, A.; Rusan, C.; Tanasescu, D.M.; Bob, F. Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study. Appl. Sci. 2023, 13, 10938. https://doi.org/10.3390/app131910938

AMA Style

Palamar M, Grosu I, Schiller A, Petrica L, Bodea M, Sircuta A, Rusan C, Tanasescu DM, Bob F. Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study. Applied Sciences. 2023; 13(19):10938. https://doi.org/10.3390/app131910938

Chicago/Turabian Style

Palamar, Marcel, Iulia Grosu, Adalbert Schiller, Ligia Petrica, Madalina Bodea, Alexandru Sircuta, Cornel Rusan, Daniela Maria Tanasescu, and Flaviu Bob. 2023. "Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study" Applied Sciences 13, no. 19: 10938. https://doi.org/10.3390/app131910938

APA Style

Palamar, M., Grosu, I., Schiller, A., Petrica, L., Bodea, M., Sircuta, A., Rusan, C., Tanasescu, D. M., & Bob, F. (2023). Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study. Applied Sciences, 13(19), 10938. https://doi.org/10.3390/app131910938

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