Altered vitamin K biodistribution and metabolism in experimental and human chronic kidney disease

Kidney Int. 2022 Feb;101(2):338-348. doi: 10.1016/j.kint.2021.10.029. Epub 2021 Nov 11.


Chronic kidney disease (CKD) is accompanied with extensive cardiovascular calcification, in part correlating with functional vitamin K deficiency. Here, we sought to determine causes for vitamin K deficiency beyond reduced dietary intake. Initially, vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (menaquinone 4 and menaquinone 7, respectively) was determined in patients on dialysis therapy and healthy individuals. The patients incorporated very little menaquinone 7 but more menaquinone 4 into high density lipoprotein (HDL) and low-density lipoprotein particles than did healthy individuals. In contrast to healthy persons, HDL particles from the patients could not be spiked with menaquinone 7 in vitro and HDL uptake was diminished in osteoblasts. A reduced carboxylation activity (low vitamin K activity) of uremic HDL particles spiked with menaquinone 7 vs. that of controls was confirmed in a bioassay using human primary vascular smooth muscle cells. Kidney menaquinone 4 tissue levels were reduced in 5/6-nephrectomized versus sham-operated C57BL/6 mice after four weeks of a vitamin K rich diet. From the analyzed enzymes involved in vitamin K metabolism, kidney HMG-CoA reductase protein was reduced in both rats and patients with CKD. In a trial on the efficacy and safety of atorvastatin in 1051 patients with type 2 diabetes receiving dialysis therapy, no pronounced vitamin K deficiency was noted. However, the highest levels of PIVKA-II (biomarker of subclinical vitamin K deficiency) were noted when a statin was combined with a proton pump inhibitor. Thus, profound disturbances in lipoprotein mediated vitamin K transport and metabolism in uremia suggest that menaquinone 7 supplementation to patients on dialysis therapy has reduced efficacy.

Keywords: 5/6 nephrectomy; dialysis; high-density lipoprotien particles; matrix Gla protein; statins; vitamin K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Renal Insufficiency, Chronic* / metabolism
  • Tissue Distribution
  • Vitamin K / metabolism*
  • Vitamin K / therapeutic use
  • Vitamin K 1 / metabolism
  • Vitamin K 1 / therapeutic use
  • Vitamin K 2 / metabolism
  • Vitamin K 2 / therapeutic use
  • Vitamin K Deficiency* / complications
  • Vitamin K Deficiency* / metabolism


  • Vitamin K 2
  • Vitamin K
  • Vitamin K 1