Cardiovascular Disease & Mortality in Kidney Transplant Recipients: Is Vitamin K Status the Missing Link?

Matrix Gla is a protein secreted in the arterial media that acts as a calcification inhibitor.  The active form of matrix Gla protein is both carboxylated and phosphorylated.  Carboxylation of matrix Gla protein is dependent on the availability of vitamin K.  Studies have shown higher dp-ucMGP levels in patients with low vitamin K intake and in patients treated with vitamin K antagonists.  Further support for a relationship between vitamin K status and dp-ucMGP comes from a study where vitamin K supplementation was shown to decrease dp-ucMGP.  Theoretically, vitamin K insufficiency, seen as a high concentration of the inactive form of GLA, could lead to increased vascular calcification and cardiovascular mortality.  In fact, several studies have already shown that high levels of dp-ucMGP correlate with vascular calcifications in patients with CKD.

In a recent article published in AJKD, Keyzer and colleagues expand upon the association between vitamin K status and mortality in a cohort of kidney transplant patients.  The authors assessed vitamin K status by measuring blood levels of dp-ucMGP.  Blood samples for dp-ucMGP were obtained from patients > 1 year post kidney transplantation.  Dp-ucMGP levels were correlated with the primary endpoint of all-cause mortality and death-censored transplant failure.  Of 518 patients studied, 91.3% had high dp-ucMGP levels (>500 pmol/L).  Participants were divided into 4 quartiles of plasma dp-ucMGP, where quartile 4 had the highest level (> 1,535).  Participants with the highest quartile of dp-ucMGP were older, less likely to be active smokers, more removed from transplant, and had higher BMI, systolic blood pressure, triglycerides, hemoglobin A1c, and C reactive protein values.  This quartile also had worse kidney function with more proteinuria, lower hemoglobin, lower albumin, and higher phosphate levels.  The highest quartile participants were more likely to be on a vitamin K antagonist (warfarin).  During a median follow-up of 9.8 yrs, all-cause mortality increased with each quartile of dp-ucMGP.  This held after multivariable adjustment.  Though Kaplan-Meyer analysis revealed a gradual increase in risk of transplant failure with increasing quartiles of dp-ucMGP, this relationship lost significance after adjustment for kidney function.

Cardiovascular events are the leading cause of death in patients with CKD and kidney transplants.  Although much has been done to understand atherosclerotic heart disease in the general population, patients with CKD and kidney transplants have additional risk factors for vascular calcification and cardiovascular disease.  The authors suggest that vitamin K status may be one of the missing links in understanding vascular calcification and mortality in transplant recipients.  This is clearly an intriguing association that could potentially lead to novel treatments.  However, it is important to note the many confounding factors of the current study, and the limitations in using a surrogate marker such as dp-ucMGP.

First the association of vitamin K status and dp-ucMGP may not be as clear as it seems.  The degree of vitamin K deficiency needed to result in an elevation of dp-ucMGP is not well understood.  In addition, vitamin K deficiency appears be local to the vascular system rather than systemic.  In fact, dp-ucMGP levels have found to strongly correlate with factors which may be unrelated to vitamin K status, such as eGFR, age, hemoglobin level, BMI, albumin, CRP, and FGF-23.  This suggests that vitamin K may not be the only factor effecting MGP, and the association between high dp-ucMGP levels and vitamin K deficiency may be more complicated.  Furthermore, mortality from high dp-ucMGP is thought to occur from vascular calcifications resulting from a lower level of biologically active MGP.  Although it sounds plausible that high levels of dp-ucMGP would mean low levels of biologically active MGP, this has not been proven.

Finally, the current study is retrospective and has associated limitations.  Participants in the highest quartile of dp-ucMGP had significantly more risk factors for cardiovascular mortality.  Although multivariate analysis still revealed dp-ucMGP to correlate with mortality, the differences in baseline characteristics cannot be ignored.  Furthermore, actual vitamin K intake could not be assessed.

In conclusion, the study by Keyzer and colleagues builds upon the association of vitamin K status, vascular calcifications, and mortality.  However, until a prospective trial evaluating vitamin K supplementation on calcifications and mortality is completed, it cannot be assumed that a deficiency of vitamin K increases mortality or that supplementation will ameliorate it.

Dr. Vinay Nair
AJKD Blog Advisory Board

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