Effect of vitamin K supplementation on serum calcification propensity and arterial stiffness in vitamin K-deficient kidney transplant recipients: A double-blind, randomized, placebo-controlled clinical trial.

Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 µg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline -0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline -385 [-631 to -269] pmol/L) compared with placebo (+39 [-188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs. TRIAL REGISTRY: EU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

Effects of magnesium citrate, magnesium oxide and magnesium sulfate supplementation on arterial stiffness in healthy overweight individuals: a study protocol for a randomized controlled trial.

BACKGROUND: Arterial stiffness is closely related to the process of atherosclerosis, an independent cardiovascular risk factor, and predictive of future cardiovascular events and mortality. Recently, we showed that magnesium citrate supplementation results in a clinically relevant improvement of arterial stiffness. It remained unclear whether the observed effect was due to magnesium or citrate, and whether other magnesium compounds may have similar effects. Therefore, we aim to study the long-term effects of magnesium citrate, magnesium oxide and magnesium sulfate on arterial stiffness. In addition, we aim to investigate possible underlying mechanisms, including changes in blood pressure and changes in gut microbiota diversity. METHODS: In this randomized, double-blind, placebo-controlled trial, a total of 162 healthy overweight and slightly obese men and women will be recruited. During a 24-week intervention, individuals will be randomized to receive: magnesium citrate; magnesium oxide; magnesium sulfate (total daily dose of magnesium for each active treatment 450 mg); or placebo. The primary outcome of the study is arterial stiffness measured by the carotid-femoral pulse wave velocity (PWVc-f), which is the gold standard for quantifying arterial stiffness. Secondary outcomes are office blood pressure, measured by a continuous blood pressure monitoring device, and gut microbiota, measured in fecal samples. Measurements will be performed at baseline and at weeks 2, 12 and 24. DISCUSSION: The present study is expected to provide evidence for the effects of different available magnesium formulations (organic and inorganic) on well-established cardiovascular risk markers, including arterial stiffness and blood pressure, as well as on the human gut microbiota. As such, the study may contribute to the primary prevention of cardiovascular disease in slightly obese, but otherwise healthy, individuals. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03632590 . Retrospectively registered on 15 August 2018.

Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients.

CONTEXT: Vitamin D deficiency is common in renal transplant recipients (RTR). The long-term implications of vitamin D deficiency in RTR remain unclear. OBJECTIVE: We investigated whether 25(OH) or 1,25(OH)2 vitamin D levels are associated with mortality, renal function decline, and graft failure in stable RTR. DESIGN: Observational study with longitudinal design. Followup was 7.0, interquartile range (IQR) 6.2-7.5 years. SETTING: Single-center outpatient clinic. PARTICIPANTS: 435 stable RTR (51% men, mean age 52 ± 12 years) were included at a median [IQR] of 6 [3-12] years after kidney transplantation. MAIN OUTCOME MEASURES: All-cause mortality, annual change of estimated glomerular filtration rate (eGFR), and graft failure. RESULTS: Mean 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 21.6 ± 9.1 ng/ml and 45.2 ± 19.0 pg/ml, respectively. During followup, 99 patients (22.8%) died and 44 patients (10.1%) developed graft failure. In univariable analysis, both 25(OH)D and 1,25(OH)2D were significantly associated with mortality (hazard ratio [HR], 0.64; 95% confidence interval (CI), 0.51-0.81; P < .001 and HR 0.69 [95% CI, 0.55-0.87], P = .002 per SD increase, respectively). The inverse association of 25(OH)D with mortality remained significant after adjustment for potential confounders (HR 0.68 [95% CI, 0.52-0.89], P = .004 per SD increase). The associations of 1,25(OH)2D with mortality and graft failure lost significance after adjustment for renal function. Severe vitamin D deficiency (25[OH]D <12 ng/ml) was independently associated with stronger annual eGFR decline. CONCLUSIONS: Low 25(OH)D is independently associated with an increased risk of all-cause mortality and 25(OH)D <12 ng/ml with a rapid eGFR decline in stable RTR. The association of low 1,25(OH)2D with mortality or graft failure depends on renal function. These results should encourage randomised controlled trials evaluating the effect of vitamin D supplementation after kidney transplantation.

Vitamin K status and mortality after kidney transplantation: a cohort study.

BACKGROUND: Vitamin K modulates calcification by activating calcification inhibitors such as matrix Gla protein (MGP). In kidney transplant recipients, vitamin K insufficiency is common, but implications for long-term outcomes are unclear. STUDY DESIGN: Single-center observational study with a longitudinal design. SETTING & PARTICIPANTS: 518 stable kidney transplant recipients; 56% men; mean age, 51±12 (SD) years; and a median of 6 (IQR, 3-12) years after kidney transplantation. FACTOR: Plasma desphosphorylated-uncarboxylated MGP (dp-ucMGP) levels, reflecting vitamin K status. OUTCOMES: All-cause mortality and transplant failure. RESULTS: At inclusion, median dp-ucMGP level was 1,038 (IQR, 733-1,536) pmol/L, with 473 (91%) patients having vitamin K insufficiency (defined as dp-ucMGP>500pmol/L). During a median follow-up of 9.8 (IQR, 8.5-10.2) years, 152 (29%) patients died and 54 (10%) developed transplant failure. Patients in the highest quartile of dp-ucMGP were at considerably higher mortality risk compared with patients in the lowest quartile (HR, 3.10; 95% CI, 1.87-5.12; P for trend<0.001; P for quartile 1 [Q1] vs Q4<0.001). After adjustment for potential confounders, including kidney function and exclusion of patients treated with a vitamin K antagonist, this association remained significant. Patients in the highest quartile also were at higher risk of developing transplant failure (HR, 2.61; 95% CI, 1.22-5.57; P for trend=0.004; P for Q1 vs Q4=0.01), but this association was lost after adjustment for baseline kidney function (HR, 1.20; 95% CI, 0.52-2.75; P for trend=0.6; P for Q1 vs Q4=0.7). LIMITATIONS: Although MGP exists as various species, only dp-ucMGP was measured. No data were available for vascular calcification as an intermediate end point. CONCLUSIONS: Vitamin K insufficiency, that is, a high circulating level of dp-ucMGP, is highly prevalent in stable kidney transplant recipients and is associated independently with increased risk of mortality. Future studies should address whether vitamin K supplementation may lead to improved outcomes after kidney transplantation.