Molecules with vitamin K activity are important for optimal bone health. The major compound of this group in bone is vitamin K1 (phylloquinone), which is derived exclusively from plant foods in the diet. Vitamin K1 is absorbed along with dietary fat from the small intestine and transported by chylomicrons in blood. In serum obtained after an overnight fast from healthy men more than half of the vitamin K1 was recovered from the density fraction that contains chylomicrons and chylomicron remnants (CR), and only a quarter was associated with the major lipoprotein in serum, low density lipoprotein. The concentration of vitamin K1 in serum is closely related to the triglyceride concentration. Another determinant of vitamin K1 concentration in serum is the presence of specific variants of apolipoprotein E (apoE). ApoE is a small protein through which the vitamin K-rich CR bind to lipoprotein receptors. The three most common variants of apoE promote CR clearance from circulation with very different efficiency, in the order E2>E3>E4. The variant that promotes CR clearance best is associated with low vitamin K1 concentration in serum and increased response to vitamin K antagonists. Vitamin K1 concentration in serum is linked to vitamin K status of bone. The bone protein osteocalcin tends to be less completely carboxylated in people with low vitamin K concentrations in serum. Many hemodialysis patients with a history of bone fractures have indications of poor vitamin K status. The same patients also appear to have a greatly increased prospective bone fracture risk.

This investigation of 219 hemodialysis patients relates the history and prospective risk of bone fractures to apolipoprotein E (apoE) genotype. A greater percentage of the 41 patients with the E3/4 and E4/4 genotypes than of the 38 patients with the E2/3 and E2/2 genotypes had a history of bone fractures at the time of recruitment (44% versus 16%, P < 0.005). During the 4 years following recruitment, more of the patients with apoE genotypes E3/4 and E4/4 than with apoE genotypes E2/3 and E2/2 suffered bone fractures, but this difference was not statistically significant (17.1 versus 5.3%, P < 0.1). ApoE genotype appears to be an important genetic risk factor for bone fracture, possibly due to its previously reported influence on vitamin K concentrations in blood.

Plasma concentrations of phylloquinone in 42 fasting hemodialysis patients showed a much wider range than in healthy adults. Phylloquinone concentrations were best predicted by the concentration ratio of beta-very-low-density-lipoprotein to low-density-lipoprotein cholesterol (r = 0.71), which is closely related to chylomicron-remnant clearance. Phylloquinone concentrations in plasma were related to apolipoprotein E genotype in the order E2 > E3 > E4. The percentage of carboxylated osteocalcin (HBC) was related to the plasma concentration of phylloquinone in patients with the apolipoprotein E genotype E3/3 (r = 0.52, P < 0.05), and in patients with the genotypes E2/3 and E2/2 (r = 0.23, P < 0.1). Overall, plasma triglyceride concentration was a better predictor for HBC than was the plasma concentration of phylloquinone. These results point to the overriding importance of chylomicrons for the transport of phylloquinone to liver and bone. Delivery to osteocalcin-producing osteoblasts seemed impaired in patients with the low receptor-affinity apolipoprotein variant E2, suggesting a major role of receptor-mediated chylomicron-remnant uptake in the transport of phylloquinone to bone.

This investigation of 68 hemodialysis patients (ages 33 to 91) analyzed the association of biochemical indicators of vitamin K nutriture and bone metabolism, and related both to past bone fracture history and prospective bone fracture risk. Phylloquinone concentrations were significantly lower in the 23 patients with previous fractures compared to those without (0.93 vs. 1.50 nmol/liter, P < 0.003) and a smaller percentage of their serum osteocalcin was carboxylated (48.8 vs. 53.6%, P < 0.03). The 41 patients who never had fractures had nearly three times higher phylloquinone concentrations than the nine patients with fractures during a four-year follow-up period (1.59 vs. 0.55 nmol/liter, P < 0.002) and more carboxylated serum osteocalcin (55.2 vs. 42.0%, P < 0.01). None of the patients with phylloquinone concentrations over 2.2 nmol/liter had elevated intact parathyroid hormone (iPTH) concentrations, and only patients with less than 1 nmol/liter phylloquinone had severe hyperparathyroidism (iPTH > 300 ng/liter). Our data thus indicate that suboptimal vitamin K nutriture in hemodialysis patients is associated both with increased bone fracture risk and with a high prevalence of hyperparathyroidism.

IntroductionAdults with end-stage kidney disease (ESKD) treated with haemodialysis experience mortality of between 15% and 20% each year. Effective interventions that improve health outcomes for long-term dialysis patients remain unproven. Novel and testable determinants of health in dialysis are needed. Nutrition and dietary patterns are potential factors influencing health in other health settings that warrant exploration in multinational studies in men and women treated with dialysis. We report the protocol of the “DIETary intake, death and hospitalisation in adults with end-stage kidney disease treated with HaemoDialysis (DIET-HD) study,” a multinational prospective cohort study. DIET-HD will describe associations of nutrition and dietary patterns with major health outcomes for adults treated with dialysis in several countries.Methods and analysisDIET-HD will recruit approximately 10 000 adults who have ESKD treated by clinics administered by a single dialysis provider in Argentina, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and Turkey. Recruitment will take place between March 2014 and June 2015. The study has currently recruited 8000 participants who have completed baseline data. Nutritional intake and dietary patterns will be measured using the Global Allergy and Asthma European Network (GA2LEN) food frequency questionnaire. The primary dietary exposures will be n-3 and n-6 polyunsaturated fatty acid consumption. The primary outcome will be cardiovascular mortality and secondary outcomes will be all-cause mortality, infection-related mortality and hospitalisation.Ethics and disseminationThe study is approved by the relevant Ethics Committees in participating countries. All participants will provide written informed consent and be free to withdraw their data at any time. The findings of the study will be disseminated through peer-reviewed journals, conference presentations and to participants via regular newsletters. We expect that the DIET-HD study will inform large pragmatic trials of nutrition or dietary interventions in the setting of advanced kidney disease.

Vitamin K deficiency of liver or bone may occur independently. Prothrombin time is an insensitive marker. Individuals with ApoE4 allels might be more susceptible to osteopenia. As high expenditures are necessary to detect patients at risk, routine vitamin K supplementation for all PICF patients appears appropriate.

SummaryIntra- and interindividual variation of phylloquinone (vitamin K1) concentrations was investigated by repeat analysis of serum from 28 hemodialysis patients with different apolipoprotein E genotypes. Phylloquinone concentrations ranged from 0.1 to 9.0 nM, with a mean of 1.08 nM (standard deviation 1.90 nM).Most of the variation in serum phylloquinone concentrations was due to differences between patients; the ratio of intra-to interindividual variation was 0.17. Serum triglyceride concentrations and apoE genotype together accounted for 64% of interindividual variation; in contrast, only 6% of intraindividual variation could be attributed to differences in triglyceride concentrations.The small residual variance implies that different phylloquinone consumption levels contributed relatively little to the variation of serum concentrations (<36% of interindividual variance). The results suggest that individual disposition is a more important determinant of serum phylloquinone concentrations than dietary phylloquinone intake.

Rationale & Objective: Clinical practice guidelines for dietary intake in hemodialysis focus on individual nutrients. Little is known about associations of dietary patterns with survival. We evaluated the associations of dietary patterns with cardiovascular and all-cause mortality among adults treated by hemodialysis.