Subclinical Vitamin K Deficiency in Hemodialysis Patients

doi:10.1053/j.ajkd.2006.11.041

American Journal of Kidney Diseases

Volume 49, Issue 3, March 2007, Pages 432-439

https://doi.org/10.1053/j.ajkd.2006.11.041 Get rights and content

Background

Subclinical vitamin K deficiency increasingly is associated with extraosseous calcification in healthy adults. Nondietary determinants of vitamin K status include apolipoprotein E (apoE) genotype, which may influence vitamin K transport to peripheral tissues.

Methods

Serum phylloquinone concentrations and percentage of uncarboxyated osteocalcin (%ucOC) were measured by means of high-performance liquid chromatography and radioimmunoassay in 142 hemodialysis patients, respectively. ApoE phenotype was determined by means of isoelectric focusing of delipidated serum samples and Western blot analysis. Clinical and laboratory data were obtained by using chart review.

Results

Mean age was 62.6 ± 14.8 (SD) years. Mean phylloquinone level was 0.99 ± 1.12 nmol/L; 29% of patients had levels less than 0.4 nmol/L. There was no association between phylloquinone level and %ucOC. There were positive correlations between phylloquinone and total cholesterol (P = 0.017), triglyceride (P = 0.022), and ionized calcium levels (P = 0.019). There was a negative correlation between phylloquinone level and dialysis adequacy (P = 0.002). Mean %ucOC was 51.1% ± 25.8%, and 93% of subjects had values greater than 20%. There were positive correlations between %ucOC and dialysis vintage (P < 0.001), phosphate level (P < 0.001), parathyroid hormone level (P < 0.001), albumin level (P = 0.035), and ionized calcium level (P = 0.046). Seventeen percent of patients were apoE4. Mean %ucOC was significantly greater in apoE4 carriers compared with all other apoE phenotypes (60.1% ± 28.4% versus 47.8% ± 24.4%; P = 0.035). In multiple regression analysis with phylloquinone level forced in, independent predictors of %ucOC were phosphate level, dialysis vintage, parathyroid hormone level, and apoE4.

Conclusion

These data indicate suboptimal vitamin K status in hemodialysis patients, shown by low phylloquinone concentrations and high %ucOC in 29% and 93% of subjects, respectively. The apoE4 allele influences osteocalcin γ-carboxylation in hemodialysis patients.

Section snippets

Study Population

This cross-sectional study included 142 HD patients older than 18 years receiving dialysis for irreversible CKD at Kingston General Hospital, Ontario, Canada. Consecutive patients were approached during an outpatient HD treatment session. All enrolled patients provided informed consent according to the Declaration of Helsinki. All procedures were in accordance with the ethical standards of Queen’s University and approved by the Tufts-New England Medical Center Institutional Review Board

Results

Baseline demographic data for the study population are listed in Table 1. There were 142 HD patients with a mean age of 62.6 years (range, 21 to 92 years) enrolled in the study.

Discussion

The present study confirms in a larger sample than previously studied that suboptimal vitamin K status is prevalent in HD patients. Based on ranges determined in healthy adults, 39 HD patients (29%) had very low phylloquinone concentrations and 131 patients (93%) had increased %ucOC. Results also indicate that the apoE4 phenotype is associated with decreased γ-carboxylation of the vitamin K–dependent protein OC in HD patients.

In a study of men and women participating in the Framingham Offspring

References (30)

K.L. Berkner et al.
The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis
J Thromb Haemost
(2004)
S.L. Booth et al.
Dietary phylloquinone depletion and repletion in older women
J Nutr
(2003)
J.A. Sadowski et al.
Phylloquinone in plasma from elderly and young adults: Factors influencing its concentration
Am J Clin Nutr
(1989)
S.L. Booth et al.
Dietary intake and adequacy of vitamin K
J Nutr
(1998)
M. Kohlmeier et al.
Bone health of adult hemodialysis patients is related to vitamin K status
Kidney Int
(1997)
K.W. Davidson et al.
Determination of vitamin K compounds in plasma or serum by high-performance liquid chromatography using postcolumn chemical reduction and fluorimetric detection
Methods Enzymol
(1997)
T. Lehtimaki et al.
Apolipoprotein E phenotypes in Finnish youths: A cross-sectional and 6-year follow-up study
J Lipid Res
(1990)
S.L. Booth et al.
Effects of a hydrogenated form of vitamin K on bone formation and resorption
Am J Clin Nutr
(2001)
S.L. Booth et al.
Vitamin K intake and bone mineral density in women and men
Am J Clin Nutr
(2003)
E. Liberopoulos et al.
Apolipoprotein E and renal disease
Am J Kidney Dis
(2004)

S.L. Booth et al.

Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans

J Nutr

(1997)

P. Urena et al.

Circulating biochemical markers of bone remodeling in uremic patients

Kidney Int

(1999)

G. Guz et al.

Effect of apolipoprotein E polymorphism on serum lipid, lipoproteins, and atherosclerosis in hemodialysis patients

Am J Kidney Dis

(2000)

C.M. Shanahan

Mechanisms of vascular calcification in renal disease

Clin Nephrol

(2005)

T.B. Drueke et al.

Disturbances of bone and mineral metabolism in chronic kidney disease: An international initiative to improve diagnosis and treatment

Nephrol Dial Transplant

(2004)

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Vitamin K and cardiovascular complications in chronic kidney disease patients
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Citation Excerpt :
Uncarboxylated osteocalcin is not solely a marker of vitamin K deficiency, but also released during bone resorption.72 Taken together, these CKD-related disturbances render osteocalcin measurements in CKD patients difficult to interpret and thus osteocalcin carboxylation may not be a useful marker to assess vitamin K status in advanced CKD.73 The development of conformation-specific antibodies against MGP has resulted in the detection and localization of uncarboxylated MGP (ucMGP) versus carboxylated MGP in vascular tissue.74
Vitamin K, well known for its role in coagulation, encompasses 2 major subgroups: vitamin K1 is exclusively synthesized by plants, whereas vitamin K2 mostly originates from bacterial synthesis. Vitamin K serves as a cofactor for the enzyme γ-glutamyl carboxylase, which carboxylates and thereby activates various vitamin K–dependent proteins. Several vitamin K–dependent proteins are synthesized in bone, but the role of vitamin K for bone health in chronic kidney disease patients, in particular the prevention of osteoporosis, is still not firmly established. Herein, we focus on another prominent action of vitamin K, in particular vitamin K2 (namely, the activation of matrix γ-carboxyglutamic acid protein, the most potent inhibitor of cardiovascular calcifications). Multiple observational studies link relative vitamin K deficiency or low intake to cardiovascular calcification progress, morbidity, and mortality. Patients with advanced chronic kidney disease are particularly vitamin K deficient, in part because of dietary restrictions but possibly also due to impaired endogenous recycling of vitamin K. At the same time, this population is characterized by markedly accelerated cardiovascular calcifications and mortality. High-dose dietary supplementation with vitamin K2, in particular the most potent form, menaquinone 7, can potently reduce circulating levels of dephosphorylated uncarboxylated (i.e., inactive matrix γ-carboxyglutamic acid protein) in patients with end-stage kidney disease. However, despite this compelling data basis, several randomized controlled trials with high-dose menaquinone 7 supplements in patients with advanced chronic kidney disease have failed to confirm cardiovascular benefits. Herein, we discuss potential reasons and solutions for this.
Relationship Between Chronic Kidney Disease, Glucose Homeostasis, and Plasma Osteocalcin Carboxylation and Fragmentation
2021, Journal of Renal Nutrition
Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study.
We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m² not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization–based mass spectrometric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test).
The total plasma osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses.
In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.
Vitamin metabolism and requirements in chronic kidney disease and kidney failure
2021, Nutritional Management of Renal Disease, Fourth Edition
People with advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD) commonly have altered metabolism or actions of many vitamins and abnormal vitamin function. Vitamin intake is frequently reduced at all CKD stages. The following are among the disorders or key findings concerning vitamins commonly encountered found in people with advanced CKD or ESKD. Plasma vitamin A is usually elevated, and even relatively small vitamin A supplements may cause toxicity. The potential benefits of supplemental vitamin E have not been confirmed. Vitamin K may have an important role in preventing vascular calcification, and clinical trials examining this potential benefit are being conducted. There is an increased dietary need for vitamin B6, in the form of pyridoxine hydrochloride, of about 5 mg/d for advanced CKD and chronic peritoneal dialysis patients and 10 mg/d for maintenance hemodialysis patients. Vitamin C intake is often low, and without vitamin C supplements, deficiency is not uncommon because of a low intake with potassium-restricted diets and because it is readily removed during the dialysis procedure. Folate supplements are effective for decreasing plasma homocysteine levels, but several randomized controlled clinical trials did not demonstrate a reduction in adverse cardiovascular events or mortality with large doses of either folic acid or combinations of folic acid, pyridoxine HCl, and vitamin B12. Vitamin B1 status should be assessed in CKD or ESKD patients who present with atypical neurologic symptoms. Niacin, in large doses, appears to effectively inhibit intestinal phosphate absorption but often causes unpleasant symptoms. Except for vitamins A and E, there is an increased risk of deficiency of other vitamins, such as riboflavin, biotin, and pantothenic acid, in both CKD and chronic dialysis patients, especially in those suffering from protein–energy wasting. It is suggested, even in the absence of a strong evidence base, that multivitamin supplements should commonly be used in advanced CKD and ESKD patients to prevent vitamin deficiencies.
Uncarboxylated matrix Gla-protein: A biomarker of vitamin K status and cardiovascular risk
2020, Clinical Biochemistry
Dephosphorylated uncarboxylated matrix Gla-protein (dp-ucMGP) is a biomarker of functional vitamin K status. High plasma dp-ucMGP concentrations reflect a low vitamin K status and have been related to vascular calcification. Our aims were to assess plasma levels of dp-ucMGP and their association with cardiovascular risk in a general population.
Plasma dp-ucMGP measurements were performed using the IDS-iSYS InaKtif MGP assay in 491 consecutive participants in a Danish general population study (229 males and 262 females, aged 19–71 years). Multivariable linear and logistic regressions were used to assess the association between dp-ucMGP levels and cardiovascular risk factors.
Mean ± standard deviation (SD) for dp-ucMGP was 465 ± 181 pmol/L, and upper 95th percentile was 690 pmol/L. In logistic regression analyses, an increase in dp-ucMGP category (<300, 300–399, 400–499, ≥500 pmol/L) was positively associated with obesity, odds ratio (OR) 2.27 (95% confidence interval (CI) 1.54–3.33), history of cardiovascular disease, OR 1.77 (CI 1.02–3.05), and above-median estimated pulse wave velocity (ePWV), OR 1.54 (CI 1.21–1.96), when adjusted for age, sex, and lifestyle factors. 1 SD increase in diastolic and systolic blood pressure (BP) corresponded to a 5.5% (CI 2.9–8.0%) and 4.7% (CI 2.1–7.4%) increase in dp-ucMGP, respectively, when adjusted for age and sex.
Plasma dp-ucMGP levels were positively associated with obesity, BP, ePWV, and history of cardiovascular disease. These findings support that dp-ucMGP is a biomarker of cardiovascular risk, and that vitamin K status could play a role in vascular calcification. The strong association with obesity deserves further attention.
Vitamin K role in mineral and bone disorder of chronic kidney disease
2020, Clinica Chimica Acta
Vitamin K is a key cofactor for the activation of proteins involved in blood coagulation, apoptosis, bone mineralization regulation, and vessel health. Scientific evidence shows an important role of activated osteocalcin and matrix-Gla protein in bone and vessels, markedly affected along the course of chronic kidney disease (CKD). In fact, CKD corresponds to an unique condition of vitamin K deficiency caused by dietary restriction, intestinal dysfunction, and impaired vitamin K recycling. Clinical data suggest that vitamin K status can be modulated and this prompts us to speculate whether patients with CKD might benefit from vitamin K supplementation. However, as important as whether the improvement in vitamin K status would be able to result in better bone quality, less vascular calcification, and lower mortality rates, several issues need to be clarified. These include better standardized methods for measuring vitamin K levels, and definition of the optimal concentration range for supplementation in different subgroups. Here, we review the literature data concerning the impact of vitamin K deficiency and supplementation on CKD-associated mineral and bone disorders (CKD-MBD). We present and discuss the available evidence from basic science and clinical studies, and highlight perspectives for further research.
Biomarkers of vascular calcification in serum
2020, Advances in Clinical Chemistry
Over the last decades, the association between vascular calcification (VC) and all-cause/cardiovascular mortality, especially in patients with high atherogenic status, such as those with diabetes and/or chronic kidney disease, has been repeatedly highlighted. For over a century, VC has been noted as a passive, degenerative, aging process without any treatment options. However, during the past decades, studies confirmed that mineralization of the arteries is an active, complex process, similar to bone genesis and formation. The main purpose of this review is to provide an update of the existing biomarkers of VC in serum and develop the various pathogenetic mechanisms underlying the calcification process, including the pivotal roles of matrix Gla protein, osteoprotegerin, bone morphogenetic proteins, fetuin-a, fibroblast growth-factor-23, osteocalcin, osteopontin, osteonectin, sclerostin, pyrophosphate, Smads, fibrillin-1 and carbonic anhydrase II.

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Originally published online as doi:10.1053/j.ajkd.2006.11.041 on January 31, 2007.

Support: This material is based on work supported by the Bedel Foundation of Kingston General Hospital, Unrestricted Educational Grant from Shire Pharmaceuticals, and federal funds from the US Department of Agriculture, Agricultural Research Service under Cooperative Agreement No. 58-1950-001 and No. 58-1950-4-401. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture. Potential conflicts of interest: None.

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Original InvestigationDialysisSubclinical Vitamin K Deficiency in Hemodialysis Patients

Background

Methods

Results

Conclusion

Section snippets

Study Population

Results

Discussion

J Thromb Haemost

J Nutr

Am J Clin Nutr

J Nutr

Kidney Int

Methods Enzymol

J Lipid Res

Am J Clin Nutr

Am J Clin Nutr

Am J Kidney Dis

J Nutr

Kidney Int

Am J Kidney Dis

Mechanisms of vascular calcification in renal disease

Clin Nephrol

Disturbances of bone and mineral metabolism in chronic kidney disease: An international initiative to improve diagnosis and treatment

Nephrol Dial Transplant

Original Investigation
Dialysis
Subclinical Vitamin K Deficiency in Hemodialysis Patients