Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation

Abstract

In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

Vitamin K Metabolism in a Rat Model of Chronic Kidney Disease

“…To the best of our knowledge, no previous study has directly measured vitamin K epoxides in tissues from a CKD model. Using microsomal protein derived from tissue from an adenine CKD model, Kaesler et al [9] measured VKOR activity and found no difference between CKD and control animals. They did, however, report that the activity of the vitamin K cycle enzyme GGCX was reduced in both the kidney and aorta, and that this could be overcome by increasing the amount of vitamin K in the diet [9] .…”

“…Vitamin K treatment has been shown to attenuate CKD-induced vascular calcification in 2 separate pre-clinical studies. Work from our laboratory and Kaesler et al reported that high dietary vitamin K decreased susceptibility to calcification in an adenine-induced model of CKD [8,9] . The impact on humans with CKD is currently being tested in 2 large randomized controlled trials.…”

“…Fusaro et al [13] also found that dialysis patients had significantly lower intakes of K1. However, recent evidence from an experimental CKD model suggests that uremia may also directly alter vitamin K metabolism [9] .…”

MICS, an easily ignored contributor to arterial calcification in CKD patients

“…Vitamin K is essential to turn uncarboxylated MGP into carboxylated MGP, which enables the protein to gain inhibited function (90). In uremic rats induced by adenine, Kaesler et al (35) found vitamin K deficiency measured by its impaired ␥-carboxylase activity, accompanied with an increase of AC after 7 wk. Pharmacological vitamin K supplementation restored plasma carboxylated MGP concentrations and slowed development of AC (35).…”

“…In uremic rats induced by adenine, Kaesler et al (35) found vitamin K deficiency measured by its impaired ␥-carboxylase activity, accompanied with an increase of AC after 7 wk. Pharmacological vitamin K supplementation restored plasma carboxylated MGP concentrations and slowed development of AC (35). Moreover, in a randomized, controlled trial involving 53 hemodialysis patients, Westenfeld et al (104) demonstrated that daily vitamin K supplementation for 6 wk significantly improved MGP bioactivity and ameliorated AC.…”