Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial.

BACKGROUND: Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin K-dependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K-dependent proteins in hemodialysis patients, assessed by circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]). STUDY DESIGN: Interventional randomized non-placebo-controlled trial with 3 parallel groups. SETTING & PARTICIPANTS: 53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls. INTERVENTIONS: Menaquinone-7 (vitamin K(2)) treatment at 45, 135, or 360 µg/d for 6 weeks. OUTCOMES: Plasma levels of dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II. MEASUREMENTS: Plasma levels were assessed using enzyme-linked immunosorbent assays. RESULTS: At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K(2) supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 µg and 360 µg of menaquinone-7, respectively. LIMITATIONS: Small sample size. CONCLUSIONS: This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K(2) supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation.

Renal dysfunction and atrial fibrillation recurrence following cardioversion.

BACKGROUND: No previous study has assessed the role of renal impairment in predicting the long-term risk of atrial fibrillation recurrence after cardioversion. METHODS: One hundred and fifty-nine consecutive patients with persistent atrial fibrillation undergoing successful cardioversion were enrolled. Renal function was assessed based on the estimated glomerular filtration rate (eGFR) at baseline and during follow-up. Patients were prospectively followed up for eGFR and recurrence of atrial fibrillation up to 1 year. RESULTS: Patients were divided into 4 groups based upon their eGFR (group 1 >90 mL/min: 33 patients, group 2: 60-90 mL/min: 55 patients, group 3: 30-59 mL/min: 53 patients, group 4: <30 mL/min: 18 patients). Overall, 101 out of 159 (64%) patients experienced atrial fibrillation recurrence within 1 year follow-up. Atrial fibrillation recurrence was independently associated with the level of reduction of eGFR at baseline (eGFR < 30 mL/min: hazard ratio [HR] 6.82, P < 0.001; eGFR 30-59 mL/min: HR 3.31, P = 0.01; eGFR 60-90 mL/min: HR 2.10, P = 0.13; eGFR > 90 mL/min reference group). In patients with maintained sinus rhythm after 12-month follow-up eGFR was increased (8.46 ± 9.49 mL/min [range -7 to 43]), whereas patients with atrial fibrillation recurrence showed a decrease in eGFR over time (-5.75 ± 9.4 [range -32 to 25], P < 0.001). CONCLUSION: Among a group of patients with persistent atrial fibrillation undergoing successful cardioversion, impaired renal function (based on estimated GFR) was associated with an increased risk of atrial fibrillation recurrence. Maintenance of sinus rhythm was associated with improvement in eGFR in patients with mild or moderate renal insufficiency.

Serological cardiovascular and mortality risk predictors in dialysis patients receiving sevelamer: a prospective study.

BACKGROUND: Cardiovascular morbidity and mortality are massively increased in patients with chronic kidney disease (CKD). Sevelamer hydrochloride has been shown to attenuate cardiovascular calcifications in CKD and end-stage renal disease (ESRD) patients. We assessed how sevelamer hydrochloride influences the evolution of serum fetuin-A and other serological factors predicting cardiovascular outcome and survival in haemodialysis patients. METHODS: Fifty-seven prevalent haemodialysis patients were included in a three-phase prospective interventional trial (A-B-A design; 8 weeks per phase). Sevelamer was only administered in the middle phase of the study. Within the other two phases, >or=90% of the patients received calcium acetate for phosphate binding. Detailed time courses of serum biochemistries were analysed in order to obtain detailed insight into the influence of sevelamer upon CKD-mineral and bone disorder (MBD) parameters as well as serum fetuin-A, fibroblast growth factor 23 (FGF23) and uraemic toxin levels [uric acid, indoxyl sulphate, hippuric acid, indole acetic acid, p-cresol and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF)]. RESULTS: Forty-one patients finished the three prospective study phases (intention-to-treat analysis). After treatment with sevelamer, serum fetuin-A significantly increased (+21%), showing a delayed increase outlasting the third (non-sevelamer) study period. Total and low-density lipoprotein (LDL) cholesterol levels, as well as serum calcium, decreased significantly. The opposite occurred with albumin, C-reactive protein and intact parathyroid hormone (iPTH). FGF23, uric acid, indoxyl sulphate, hippuric acid, indole acetic acid, CMPF and serum phosphate did not change significantly during sevelamer treatment. In contrast, in parallel to sevelamer treatment, there was a significant rise in serum P-cresol. CONCLUSIONS: In haemodialysis patients, treatment with sevelamer over 8 weeks was associated with a delayed yet long-lasting increase in serum fetuin-A levels. Increasing the serum level of fetuin-A, a negative acute-phase protein and systemic calcification inhibitor, might be one of the potential anti-calcification mechanisms of sevelamer. Since we failed to detect a decrease in systemic inflammation and uraemic toxins, the exact mechanisms by which sevelamer treatment affects serum fetuin-A remain to be determined.

Leaching of natural colloids from forest topsoils and their relevance for phosphorus mobility.

The leaching of P from the upper 20cm of forest topsoils influences nutrient (re-)cycling and the redistribution of available phosphate and organic P forms. However, the effective leaching of colloids and associated P forms from forest topsoils was so far sparsely investigated. We demonstrated through irrigation experiments with undisturbed mesocosm soil columns, that significant proportions of P leached from acidic forest topsoils were associated with natural colloids. These colloids had a maximum size of 400nm. By means of Field-flow fractionation the leached soil colloids could be separated into three size fractions. The size and composition was comparable to colloids present in acidic forest streams known from literature. The composition of leached colloids of the three size classes was dominated by organic carbon. Furthermore, these colloids contained large concentrations of P which amounted between 12 and 91% of the totally leached P depending on the type of the forest soil. The fraction of other elements leached with colloids ranged between 1% and 25% (Fe: 1-25%; Corg: 3-17%; Al: <4%; Si, Ca, Mn: all <2%). The proportion of colloid-associated P decreased with increasing total P leaching. Leaching of total and colloid-associated P from the forest surface soil did not increase with increasing bulk soil P concentrations and were also not related to tree species. The present study highlighted that colloid-facilitated P leaching can be of higher relevance for the P leaching from forest surface soils than dissolved P and should not be neglected in soil water flux studies.