The current study shows for the first time that both insufficient vitamin K intake and vascular vitamin K insufficiency (deduced from circulating dp-ucMGP levels) are very common in a population of stable kidney transplant recipients. Vitamin K deficiency in kidney transplant recipients has been reported previously by means of a coagulopathy responsive to vitamin K treatment in case series 
. Mazzaferro et al recently argued that total MGP levels in kidney transplant recipients were close to normal 
; however their study did not differentiate between carboxylated and uncarboxylated MGP which is important given the role for vitamin K in MGP carboxylation. When dp-ucMGP, an appropriate marker of vascular vitamin K status 
, was taken into account specifically in our study, we found clear indications of vascular vitamin K insufficiency in the majority of kidney transplant recipients.
Dietary recommendations for an adequate intake of vitamin K are based on the hepatic vitamin K1 requirement to for coagulation factor synthesis 
. It does not account for vitamin K2 requirement to inhibit vascular calcification. The actual necessary amount of vitamin K intake based on the role of extra-hepatic vitamin K-dependent proteins is still unknown but studies suggest that dietary recommendations for vitamin K are too low to ensure full carboxylation of MGP 
. Indeed, in our study even the subjects with adequate vitamin K intake according to U.S. guidelines 
still had median dp-ucMGP levels above the recommended level of 500 pmol/L, suggesting vascular vitamin K insufficiency. This suggests that either kidney transplant recipients should be recommended to increase their dietary vitamin K intake beyond amounts recommended to the general population, or these patients should be supplemented with extra vitamin K.
Whether for vascular vitamin K status the intake of vitamin K2 is superior to vitamin K1 is uncertain, but the intake of vitamin K2 appears to be more important than vitamin K1 to prevent coronary heart disease 
. Furthermore, in a recent pilot study in hemodialysis patients, a reduction of dp-ucMGP was dose-dependently achieved by treatment with vitamin K2 
. This can be mechanistically explained by the fact that the main transporters of vitamin K1 are triglyceride-rich lipoproteins that are retained by the liver and serve as a cofactor for proteins involved in coagulation. The vitamin accumulation and use in extrahepatic tissues such as the vascular wall, is low. Vitamin K2 on the other hand is transported not only by triglyceride-rich lipoproteins, but also by low density lipoproteins, the main carrier system to extrahepatic tissues 
. In our study, subjects with poor vitamin K intake had increased dp-ucMGP levels (lower vascular vitamin K status) compared to those with normal vitamin K intake. On the other hand, dietary vitamin K intake (neither vitamin K1 nor K2 or total vitamin K) was not an independent determinant of dp-ucMGP levels upon multivariate analysis. This suggests that either other factors such as renal function, together with coumarin use as an iatrogenic factor, are more important determinants of vascular vitamin K status in this population. Dietary intake of vitamin K2 intake may also be an inappropriate reflection of the actual amount of vitamin K2 generated by intestinal micro-organisms. The composition of the intestinal flora, and importantly the presence of Bacteroides species, the main producers of vitamin K2 
, is influenced by dietary factors including fibers 
. The subjects with poor vitamin K intake in our population ate significantly less fiber than those with normal vitamin K intake; this may have affected intestinal vitamin K2 production.
The observation that vascular vitamin K insufficiency was more common than may be expected by vitamin K intake alone could be explained for a considerable part by the contribution of renal function impairment. Our data confirm the previously known relationship between renal function 
and dp-ucMGP levels and the influence of vitamin K antagonists 
. Whether, as in hemodialysis patients 
, vitamin K2 supplementation may also reduce dp-ucMGP levels in kidney transplant recipients, especially those with compromised renal function, remains to be addressed in prospective trials. Our finding that vascular vitamin K status was associated with body mass index in multivariate analysis is in line with previous studies linking vitamin K status with parameters of glucose metabolism and atherosclerosis 
. The borderline significant association between dp-ucMGP levels and 24h-urine sodium excretion suggests that high dietary sodium intake may negative affect vitamin K metabolism. Although vitamin K deficiency 
and high sodium intake 
have both been associated with adverse cardiovascular outcomes, their possible interactions have not been addressed.
We found a trend towards an inverse relationship between vitamin K status and low-grade inflammation. Cell culture studies have shown anti-inflammatory effects of vitamin K in lipopolysaccharide-treated fibroblasts through inhibition of interleukin-6 
. In animals, a vitamin K-deficient diet enhanced the expression of inflammatory genes, which was reversed by vitamin K1-supplemented diets; furthermore the supplemented diet suppressed the inflammatory response induced by lipopolysaccharide 
. Recently, both plasma vitamin K status and intake were inversely related to inflammatory markers in a human general population cohort 
The reduced vascular vitamin K status in patients on calcineurin inhibitors is in line with the increased risk of cardiovascular complications in patients on these drugs, particularly ciclosporin 
. On the other hand, in our multivariate analysis of determinants of vitamin K status, none of the immunosuppressive drugs remained in the model after co-adjustment for creatinine clearance, suggesting that the differences in vitamin K status can be explained by differences in creatinine clearance. A recent report suggested that MGP levels were higher in patients on mTOR inhibitors 
; unfortunately our cohort contained only two patients using this class of drugs.
Our study has the limitation of being a relatively small single center study in Caucasian patients only, so the generalizability of our findings will require support by studies in other populations. The limited sample size may have influenced the results of multivariate regression analysis, e.g. regarding the role of immunosuppressive regimens as determinants of vitamin K status. Furthermore, although dp-ucMGP levels have been associated with cardiovascular morbidity and mortality in the chronic kidney disease population 
, these associations have not yet been established for the kidney transplant population.
In conclusion, we found that elevated dp-ucMGP levels, reflecting vascular vitamin K insufficiency, is common in kidney transplant recipients. Poor vitamin K intake is common in renal transplant recipients, and our data suggest that other factors including renal function may contribute to poor vascular vitamin K status as well. Correction of vitamin K status might be clinically relevant, given the known associations of vascular vitamin K deficiency with cardiovascular outcomes. Whether this can be achieved by relatively simple dietary measures in kidney transplant recipients should be addressed in future prospective studies.