scholarly journals Role of Vitamin K in CKD: Is Its Supplementation Advisable in CKD Patients?

2021 ◽  
pp. 1-8
Author(s):  
Patrycja Grzejszczak ◽  
Ilona Kurnatowska
Keyword(s):  
Vitamin K ◽  
Disease Risk ◽  
Active Form ◽  
Serum Markers ◽  
Vitamin K2 ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Increased Risk ◽  
Wall Calcification ◽  
Bone Complications

<b><i>Background:</i></b> Patients with CKD are at an increased risk of developing vascular calcification (VC) and bone complications which translate into a higher morbidity and mortality. The dephosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP) is considered to be an indicator of vitamin K2 status and correlates with markers of VC. It is activated by γ-glutamyl carboxylase that converts inactive MGP into an active form, and vitamin K2 is a cofactor of this reaction. The active form of MGP is a known inhibitor of arterial wall calcification and plays an important role in bone turnover. Recent studies show poor vitamin K2 status in CKD patients. We aimed to review the literature for the association between vitamin K2 status and calcification and bone disease risk and the efficacy of vitamin K2 supplementation in CKD population. <b><i>Summary:</i></b> Most CKD patients, including those on renal replacement therapy, have vitamin K2 deficiency. The dp-ucMGP level, a marker of vitamin K2 status, is decreased by vitamin K2 supplementation in CKD patients, but there is no unequivocal proof that it influences arterial calcification progression and bone complications. <b><i>Key Messages:</i></b> CKD population are at risk of vitamin K deficiency. Supplementation of vitamin K2 is safe and improves the serum markers of its deficiency. There is lack of strong evidence that vitamin K2 supplementation slows progression of calcification or reduces the frequency of bone complications. More prospective studies are needed.

scholarly journals Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis

2021 ◽  
Vol 80 (5) ◽  
pp. 598-604
Author(s):  
Cindy G Boer ◽  
Ingrid Szilagyi ◽  
N Long Nguyen ◽  
Tuhina Neogi ◽  
Ingrid Meulenbelt ◽  
...  
Keyword(s):  
Vitamin K ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Vitamin K Antagonist ◽  
Matrix Gla Protein ◽  
Study Cohort ◽  
Single Nucleotide Variants ◽  
Increased Risk ◽  
Coagulation Proteins ◽  
Clinical Prevention

ObjectivesVitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP.MethodsWe investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association.ResultsAcenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94–3.20), both for knee (OR=2.34, 95% CI=1.67–3.22) and hip OA (OR=2.74, 95% CI=1.82–4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69–6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78–1.33).ConclusionsThese findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

Matrix Gla-protein: The calcification inhibitor in need of vitamin K

2008 ◽  
Vol 100 (10) ◽  
pp. 593-603 ◽  
Author(s):  
Ellen C. M. Cranenburg ◽  
Cees Vermeer ◽  
Leon J. Schurgers
Keyword(s):  
Vitamin K ◽  
Potent Inhibitor ◽  
Dominant Role ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Healthy Population ◽  
Alternative Mechanism ◽  
Vascular Health ◽  
Calcification Detection ◽  
Apparently Healthy

SummaryAmong the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.

scholarly journals Cardiovascular Calcification and Bone: A Comparison of the Effects of Dietary and Serum Vitamin K and its Dependent Proteins

2015 ◽  
Vol 4 ◽  
pp. 6 ◽  
Author(s):  
Rachel Nicoll ◽  
John McLaren Howard ◽  
Michael Henein
Keyword(s):  
Vitamin K ◽  
Bone Health ◽  
Animal Studies ◽  
Oral Anticoagulants ◽  
Human Study ◽  
Serum Vitamin ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Font Size ◽  
Considerable Uncertainty

<p style="margin: 0cm 0cm 0pt;"> </p><p style="margin: 0cm 0cm 0pt;"><span style="font-family: Times New Roman;"><span style="font-size: medium;">This review compares the effect of vitamin K on cardiovascular (CV) calcification and bone health and shows that, in principal, the γ-carboxylation of the vitamin K-dependent proteins matrix Gla protein (MGP) and its bone equivalent osteocalcin (OC), generally ensures that hydroxyapatite is kept out of the CV system and is deposited in bone. This is an important finding, since there is currently no reliable treatment for CV calcification.</span><span style="font-size: medium;">Vitamin K2 (menaquinone) may be more effective in the arteries, while vitamin K1 (phylloquinone) is more active in bone. Nevertheless, there remains considerable uncertainty over the precise scope of the functions of MGP and OC, and their carboxylated and under-carboxylated forms, as well as the newly discovered vitamin K-dependent proteins. Although a diet high in vegetables could deliver adequate phylloquinone, supplementation of menaquinone may be necessary for those at risk of CV calcification. Several animal studies and one human study have demonstrated that arterial calcification could be reduced with vitamin K supplementation and there are further trials in progress. Patients on warfarin are particularly prone to CV calcification but there has been concern that supplementation would either counter warfarin treatment or destabilise INR. In fact, studies suggest that low dose phylloquinone did not increase coagulation and may improve the stability of anticoagulant therapy. Furthermore, use </span><span style="mso-bidi-font-size: 12.0pt; mso-bidi-font-family: 'Times New Roman';"><span style="font-size: medium;">of oral anticoagulants which do not affect vitamin K metabolism, such as ximelagatran, could be used when there is a need for vitamin K supplementation for artery or bone health. </span></span></span></p><p style="margin: 0cm 0cm 0pt;"> </p>

scholarly journals The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial

2019 ◽  
Vol 110 (4) ◽  
pp. 883-890 ◽  
Author(s):  
S R Zwakenberg ◽  
P A de Jong ◽  
J W Bartstra ◽  
R van Asperen ◽  
J Westerink ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Controlled Trial ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Secondary Outcome ◽  
Double Blind

ABSTRACT Background Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown. Objectives The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD. Methods In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated–uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables. Results We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: −0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: −0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (−205.6 pmol/L; 95% CI: −255.8, −155.3 pmol/L). No adverse events were reported. Conclusion MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Abstract P186: Circulating Desphospho-uncarboxylated Matrix Gla Protein and the Risk of Coronary Heart Disease and Stroke

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Geertje W Dalmeijer ◽  
Yvonne T van der Schouw ◽  
Elke J Magdeleyns ◽  
Cees Vermeer ◽  
W. Monique M Verschuren ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Cohort Study ◽  
Heart Disease ◽  
General Population ◽  
Vitamin K ◽  
Stroke Risk ◽  
Matrix Gla Protein ◽  
Chd Risk ◽  
Increased Risk ◽  
Incident Cases

Background: Matrix Gla protein (MGP) is a vitamin K dependent protein and a potent inhibitor of vascular calcification. Desphospho-uncarboxylated MGP (dp-ucMGP) is a marker for vitamin K status with high dp-ucMGP concentration reflecting a low vitamin K status. High dp-ucMGP concentrations are thought to be associated with an increased risk of cardiovascular disease, but this has never been investigated in the general population. Objective: This study aimed to investigate the association of dp-ucMGP with incident coronary heart disease (CHD) or stroke in the general population. Design and Methods: A prospective case-cohort study with a representative baseline sample of 1406 participants and 1154 and 380 incident cases of CHD and stroke, respectively, was nested within the EPIC-NL study. Dp-ucMGP concentrations were measured by ELISA technique in baseline plasma samples. The incidence of fatal and non-fatal CHD and stroke was obtained by linkage to national registers. Cox proportional hazard models adapted for the case-cohort design were used to calculate hazard ratios (HRs) per standard deviation (SD) and per quartile of circulating dp-ucMGP levels, adjusted for cardiovascular risk factors. Results: This case-cohort study had an average follow-up of 11.5 years. Circulating dp-ucMGP levels were not associated with CHD risk with a HR per SD of 1.00 (95% CI: 0.93-1.07) and a HR Q4 vs Q1 of 0.94 (95% CI: 0.79-1.13) after multivariate adjustment. Circulating dp-ucMGP was not associated with stroke risk with a HR per SD of 0.98 (95% CI: 0.90-1.08) and a HR Q4 vs Q1 of 1.09 (95% CI: 0.78-1.51). Conclusion: This study does not support the hypothesis that high dp-ucMGP levels, reflecting a poor vitamin K status, are associated with increased CHD or stroke risk.

scholarly journals Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

2020 ◽  
Author(s):  
Anton S M Dofferhoff ◽  
Ianthe Piscaer ◽  
Leon J Schurgers ◽  
Margot P J Visser ◽  
Jody M W van den Ouweland ◽  
...  
Keyword(s):  
Vitamin K ◽  
Elastic Fiber ◽  
Protein S ◽  
Coagulation Factors ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Fiber Damage ◽  
Fiber Degradation ◽  
Factor Ii ◽  
Poor Outcomes

Abstract Background Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2–infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. Methods A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K–dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography. Results dp-ucMGP was elevated in COVID-19 patients compared with controls (P &lt; .001), with even higher dp-ucMGP in patients with poor outcomes (P &lt; .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P &lt; .001) and with coronary artery (P = .002) and thoracic aortic (P &lt; .001) calcification scores. Conclusions dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

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

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247623
Author(s):  
Lu Dai ◽  
Longkai Li ◽  
Helen Erlandsson ◽  
Armand M. G. Jaminon ◽  
Abdul Rashid Qureshi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Matrix Gla Protein ◽  
Vitamin K Deficiency ◽  
Increased Risk ◽  
Ckd Stage ◽  
All Cause Mortality ◽  
K Deficiency

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.

Warfarin-Associated Calciphylaxis in a Patient without Renal Failure or Hyperparathyroidism: Investigation of the Matrix GLA Protein.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3969-3969 ◽  
Author(s):  
Rebecca Redman ◽  
Caron P. Misita ◽  
Darrell W. Stafford ◽  
David Sane ◽  
Stephan Moll
Keyword(s):  
Bone Morphogenetic Protein ◽  
Vitamin K ◽  
Calcium Homeostasis ◽  
Plasma Levels ◽  
Vessel Wall ◽  
Warfarin Therapy ◽  
Matrix Gla Protein ◽  
Morphogenetic Protein ◽  
Wall Calcification ◽  
Work Up

Abstract Background: The etiology of calciphylaxis is unknown. Case reports have suggested an association with warfarin therapy in some patients. Matrix Gla protein (MGP) is a crucial inhibitor of vessel calcification, requiring vitamin K dependent γ-carboxylation for full function. Vitamin K antagonists inhibit MGP carboxylation. In a patient who developed calciphylaxis on warfarin we sought to determine whether an underlying defect in the MGP gene was present, such that treatment with warfarin precipitated even lower levels of MGP, leaving the patient more susceptible to calcification. Case report: A 61 year old woman with normal renal function, calcium, phosphorus, and hyperparathyroid hormone levels developed painful, subcutaneous nodules in thighs, buttocks, and abdominal wall 14 months into warfarin therapy. Lesions became confluent and overlying skin ulcerated. Deep surgical biopsy showed extensive vascular wall calcification and fat necrosis; no inflammation was present. Thrombosis of some of the highly narrowed residual lumina was seen. Clinical presentation and pathology findings were consistent with calciphylaxis. Extensive thrombophilia work-up was negative. Warfarin was discontinued, and low-molecular weight heparin, aspirin, bisphosphonates, oral vitamin K, and antibiotics given. Within 3 months, the lesions began to heal. Additional imaging studies showed extensive calcification of medium-sized arteries, i.e. interdigital, coronary and epigastric arteries, as well as heart valves. The patient is alive 4 years after the onset of calciphylaxis, now with almost completely healed skin wounds, but with necrosis of several fingertips. Methods and Results: Sequencing of the patient’s MGP cDNA revealed only a well-known and common polymorphism, leading to an alanine to threonine replacement in amino acid position 83, pathophysiologically likely not relevant for the calcification problem. The MGP γ-carboxylation sites were intact. Determination of plasma levels of MGP and sequencing of the non-coding region of the MGP gene are pending. A list of other candidate proteins involved in vessel wall homeostasis to be examined for genetic variants and plasma levels has been assembled and work-up for mutations and protein plasma level abnormalities started: fetuin, osteoprotegerin, bone morphogenetic protein (BMP)-2, BMP-4, osteocalcin, osteopontin, bone morphogenetic protein receptor II (BMPR2), and Runx2. Discussion: It is known that animals treated with very large doses of warfarin develop severe vessel wall calcification due to depletion of carboxylated MGP. Other defects involving proteins of vessel wall calcium homeostasis, such as fetuin, osteoprotegerin, bone morphogenetic protein, etc., have also been shown to lead to such calcification. We postulate that calciphylaxis in our patient on warfarin developed due to a two-hit mechanism: decrease of MGP γ-carboxylation due to warfarin in an individual with a preexisting defect in vessel wall calcium homeostasis. A pathophysiologically relevant gene defect in the MGP protein has been excluded. Other candidate gene and protein abnormalities are currently being investigated.

scholarly journals The Association of Vitamin D and Vitamin K Status with Subclinical Measures of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study

2020 ◽  
Vol 150 (12) ◽  
pp. 3171-3179
Author(s):  
Elisa Dal Canto ◽  
Joline W J Beulens ◽  
Petra Elders ◽  
Femke Rutters ◽  
Coen D A Stehouwer ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin K ◽  
Cardiovascular Health ◽  
Cox Regression ◽  
Left Ventricular ◽  
Matrix Gla Protein ◽  
Cvd Risk ◽  
Increased Risk ◽  
Normal Vitamin ◽  
All Cause Mortality

ABSTRACT Background A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited. Objectives Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians. Methods We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000–2001 and 2007–2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)—high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders. Results Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status. Conclusions A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk.

scholarly journals Vitamin K Dependent Proteins in Kidney Disease

2019 ◽  
Vol 20 (7) ◽  
pp. 1571 ◽  
Author(s):  
Ciprian Silaghi ◽  
Tamás Ilyés ◽  
Vladimir Filip ◽  
Marius Farcaș ◽  
Adriana van Ballegooijen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Vitamin K ◽  
Specific Protein ◽  
Poor Quality ◽  
Matrix Gla Protein ◽  
Future Research ◽  
Current State ◽  
Increased Risk ◽  
Calcification Inhibitors

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

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