Vintamina K

www.kidney-international.
org review
Vitamin K and cardiovascular complications

Q1
in chronic kidney disease patients
1 54
2 Q29Q3
Q4
Nadine Kaesler1, Leon J. Schurgers2,3 and Jurgen Floege1 55
3 1 56
Division of Nephrology and Rheumatology, University Hospital, Rheinisch Westfälische Technische Hochschule, Aachen, Germany;
4 Q5 2 57
Department of Biochemistry and CARIM, School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands; and
5 Q6Q7 3Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
58
6 59
7 60
V
8 61
9 Vitamin K, well known for its role in coagulation, itamin K is well known for its role in coagulation and 62
10 encompasses 2 major subgroups: vitamin K1 is exclusively the therapeutic interference with it in patients 63
11 synthesized by plants, whereas vitamin K2 mostly requiring systemic anticoagulation. Less well known 64
12 originates from bacterial synthesis. Vitamin K serves as a are the roles of vitamin K in cardiovascular disease, in 65
13 cofactor for the enzyme g-glutamyl carboxylase, which particular calcification. In the present review, we discuss the 66
14 carboxylates and thereby activates various vitamin K– physiology of the vitamin K system and its disturbances in 67
15 dependent proteins. Several vitamin K–dependent proteins patients with chronic kidney disease (CKD) as well as 68
16 are synthesized in bone, but the role of vitamin K for bone emerging intervention studies targeting the cardiovascular 69
17 health in chronic kidney disease patients, in particular the system in CKD. 70
18 prevention of osteoporosis, is still not firmly established. 71
19 Herein, we focus on another prominent action of vitamin K, Vitamin K sources and subforms 72
20 in particular vitamin K2 (namely, the activation of matrix g- Vitamin K comprises different entities of naphthoquinone 73
21 carboxyglutamic acid protein, the most potent inhibitor of derivatives with a variably long phytylic side chain. It was first 74
22 cardiovascular calcifications). Multiple observational described in 1935 by the Danish noble laureate, Henrik Dam, 75
23 studies link relative vitamin K deficiency or low intake to as an essential vitamin for blood coagulation (“Koagulation”). 76
24 cardiovascular calcification progress, morbidity, and The 2 major physiologic forms are vitamin K1 (phylloqui- 77
25 mortality. Patients with advanced chronic kidney disease none) and vitamin K2 species (menaquinones [MKs] 4–13) 78
26 are particularly vitamin K deficient, in part because of (Figure 11). 79
27 dietary restrictions but possibly also due to impaired Vitamin K1 is exclusively synthesized by plants, where it 80
28 endogenous recycling of vitamin K. At the same time, this serves as an electron carrier inside the chloroplastic mem- 81
29 population is characterized by markedly accelerated brane in photosystem I. Photosystem I is a complex of pro- 82
30 cardiovascular calcifications and mortality. High-dose teins and pigments (carotenes and chlorophyll) and can be 83
31 dietary supplementation with vitamin K2, in particular the described as a light-driven electron pump,2 where the initial 84
32 most potent form, menaquinone 7, can potently reduce light reaction of photosynthesis takes place. Thus, green, leafy 85
33 circulating levels of dephosphorylated uncarboxylated (i.e., vegetables are the mainstay of nutritional K1 supply.3 Foods 86
34 inactive matrix g-carboxyglutamic acid protein) in patients with the highest phylloquinone contents are kale, parsley, 87
35 with end-stage kidney disease. However, despite this spinach, leek, and purslane4 (Table 15–8). Vitamin K1 levels 88
36 compelling data basis, several randomized controlled trials are higher in fresh frozen compared with canned food, but 89
37 with high-dose menaquinone 7 supplements in patients the highest contents per gram are detected in dried products.4 90
38 with advanced chronic kidney disease have failed to Overall, all natural vitamin K forms are stable to heat, and 91
39 confirm cardiovascular benefits. Herein, we discuss cooking losses are negligible. Steaming or microwaving K- 92
40 potential reasons and solutions for this. rich food items can even increase the cellular vitamin K 93
41 Kidney International (2021) -, -–-; https://doi.org/10.1016/ release.9 In contrast, vitamin K is highly sensitive to daylight. 94
j.kint.2021.06.037 For example, exposure of rapeseed or safflower oil to daylight
42 95
43 KEYWORDS: calcification; cardiovascular disease; lipoproteins; matrix Gla decreased its vitamin K1 content by z95% within 2 days of 96
protein; vitamin K
44 light exposure.10 97
Copyright ª 2021, International Society of Nephrology. Published by
45 Elsevier Inc. All rights reserved.
Vitamin K2 mostly originates from bacterial synthesis. 98
46 One synthesis pathway occurs in lactic acid bacteria, where 99
47 menaquinones are used for electron transport.5,11 Lacto- 100
48 coccus lactis strains can synthesize MK5 to MK912 and are 101
49 used in food manufacturing to ferment and preserve dairies, 102
50 such as yogurt or cheese, as well as vegetables (e.g., sauer- 103
51 Correspondence: Jürgen Floege, Division of Nephrology, RWTH University of kraut). In humans, the most relevant forms are MK4 and 104
52 Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail: jfloege@ukaachen.de MK7. Beyond bacterial synthesis, MK4 can also be synthe- 105
53 Received 26 March 2021; revised 8 June 2021; accepted 11 June 2021 sized endogenously from K1 or menadione by the enzyme 106
Kidney International (2021) -, -–- 1

REV 5.6.0 DTD KINT2706_proof 21 September 2021 7:29 pm ce
review N Kaesler et al.: Vitamin K and cardiovascular complications in CKD patients Q2
107 O CH3 C H3 163

108 H
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109 n
K2: 165
110 C H3 menaquinone 4-10 166
O
111 167
112 K1: phylloquinone 168
113 K2: menaquinone 4-14 169
114 (n = 3-9) 170
115 O CH 3 CH 3 C H3 CH3 171
116 172
117 CH3 173
K1: phylloquinone
118 CH 3
K2: menaquinone 5-14
174
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O
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120 176
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124 Figure 1 | Exogenous and endogenous sources of vitamin K1 and vitamin K2. Vitamin K1 is present in green leafy vegetables, whereas 180
125 vitamin K2 can be found in various fermented foods. Vitamin K2 subform menaquinone (MK) 4 can be endogenously synthesized from vitamin 181
126 K1 by the enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1). However, next to vitamin K1, also vitamin K2 derivatives, 182
such as MK4 and MK7, can be converted into menadione to be used by UBIAD1 for conversion to MK4.1 Indeed, an increase in menadione after
127 vitamin K intake can be detected in urine. In addition, MK5 to MK13 can be synthesized by the microbiome (e.g., by Lactococcus species). 183
128 Whether the latter contributes to the pool, due to low amount of bile acids inside the colon, remains uncertain. Images are from https:// 184
129 pixabay.com/, with special thanks to Lipefontes, AStoKo, Shutterbug75, and Hui Wang. Q27
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130 186
131 187
132 UbiA prenyltransferase domain-containing protein 1 group at the g position of the glutamate residue, thereby 188
133 (UBIAD1; Figure 2).13 However, next to K1, also vitamin K2 adding an extra negative charge to the protein. Vitamin K– 189
134 derivatives, such as MK4 itself and MK7, can be used as oxidoreductase (VKOR) then converts vitamin K–epoxide to 190
135 source of MK4.1 The intermediate product in this conversion vitamin K and back to vitamin K–hydroquinone, generating a 191
136 is menadione, which might serve as a substrate for UBIAD1.1 recycling process.18 Vitamin K antagonists (VKAs) inhibit 192
137 This observation led to the conclusion that vitamin K is VKOR and thereby the recycling of vitamin K, resulting in a 193
138 converted in the intestine to menadione and that the pre- drug-induced vitamin K deficiency.19 Recent studies have also 194
139 nylation to MK4 takes place in tissues expressing UBIAD1. suggested a role for vitamin K as an antioxidant. This non- 195
140 So far, all major national nutritional databases lack sys- canonical function of vitamin K relates to the oxidation- 196
141 tematic information on vitamin K2 contents. The food with 197
142 by far the highest content of vitamin K2 is natto, made by 198
143 fermenting soy beans (vitamin K2 content, >1000 mg/100 g, Table 1 | Selected vitamin K1 and vitamin K2 sources in
199
human diets
144 mostly MK7).6 Natto is commonly consumed in Japan, 200
whereas in Western diets, dairy products are the predominant Vitamin K1 Amount, mg/100 g Vitamin K2 Amount, mg/100 g
145 201
146 source of vitamin K2.5 Specific sources are French cheese, Vegetables a
Vegetablesa
202
147 hard cheese, or minced meat (Table 1).6,7 The contribution of Kale 713–856 Natto 1096–10,985 203
148 K2 to the total vitamin K intake is estimated to be z25%.14 Parsley 548 Sauerkraut 5–55
204
Spinach 380–471 Dairya —
149 A third form, vitamin K3 (menadione), lacks the phytylic Chive 380 Gouda 473–644 205
150 side chain and is employed in animal nutrition. It remains Purslane 381–394 Camembert 681 206
151 mainly synthetic but was also shown to be an intermediate in Broccoli 156–180 Emmentaler 433 207
the endogenous conversion from K1 to MK4 by the enzyme Cabbage 80–154 Cheddar 235
152 Celery 40–41 Brie 125 208
153 UBIAD1.15 Reportedly, vitamin K3 exerts anti-cancer prop- Leek 47–49 Yogurt 1.0–1.2 209
154 erties via cytostatic effects.16,17 Natto 35 Meata — 210
Sauerkraut 25 Liver (beef) 112
155 211
Dairya Beef 18.9
156 Vitamin K recycling Emmentaler 3 Minced meat 9-76 212
157 Vitamin K serves as a cofactor for the enzyme g-glutamyl Yogurt 0–0.4 Chicken 9–101 213
158 carboxylase (GGCX), which catalyzes conversion of the Glu Oilsa Fisha — 214
159 Q8 residue of VKDPs into g-carboxyglutamic acid (Gla; Olive oil 54–55 Eel
Rainbow trout
3–631
3
215
160 Figure 2). This process is driven by the oxidation of vitamin Egg 20 216
161 K–hydroquinone to vitamin K–epoxide in the vitamin K cy- Data are from several sources.5–8 217
162 cle, generating the possibility to introduce an extra carboxyl a
Xxx. Q24 218
2 Kidney International (2021) -, -–-

N Kaesler et al.: Vitamin K and cardiovascular complications in CKD patients review
219 Ca2+ from the circulation within hours.23 Vitamin K1 is prefer- 275
220 Ca2+ entially retained in the liver to support carboxylation of 276
COO-
COO COO-
-
221 clotting factors. In contrast, vitamin K2, in particular long- 277
222 CH2 CH2 chain menaquinones, such as MK7, is redistributed to the 278
223 circulation and is equally available for extrahepatic tissues, 279
CH2 CH2
224 including bone and vasculature.24 280
225 Ile Arg Glu Arg Ile Arg Gla Arg Both vitamin K1 and K2 are taken up first by the liver via 281
226 GGCX the apolipoprotein E receptor. Long-chain menaquinones, 282
227 such as MK7, are taken up most efficiently.24,25 This was 283
MK4-H2 MK4>O
228 Cholesterol shown in healthy volunteers treated with vitamin K antagonist 284
229 acenocoumerol and supplemented with either K1 or 285
VKORC1
230 NQO1 MK7.25,26 MK7 was shown to interact with anticoagulation 286
231 VKORC1 several fold stronger than K1, indicating that the efficient 287
GGPP Mevalonate
232 MK4 uptake of MK7 corresponds with the greater bioactivity. 288
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233 Vitamin K1 and MK4 were readily cleared from the circula- 289
234 UBIAD1 HMGCR tion within 2 hours after ingestion, followed by MK7 within 4 290
235 hours and MK9 within 7 hours. However, postprandial serum 291
236 K1 HMG-CoA concentrations of long-chain menaquinones were some 10- 292
237 fold higher than K1.24 Thus, compared with vitamin K1, 293
Figure 2 | Vitamin K metabolism and recycling. A vitamin K–
238 dependent protein, such as matrix g-carboxyglutamic acid protein long-chain menaquinones are much longer available for 294
239 (MGP), is being g-glutamyl carboxylated by the g-glutamyl- extrahepatic tissues, because of their presence in circulating 295
240 carboxylase (GGCX). By introducing a second carboxyl group (COO–) lipoprotein particles.25 296
at the g c atom, MGP becomes a potent calcium chelator. The
241 297
reduced form of vitamin K (K-H2, here shown by MK4-H2) serves as a
242 cofactor for the GGCX and gets epoxidized (MK4 > 0). In the vitamin Intestinal microbiome 298
243 K cycle, the epoxidized form gets stepwise recycled by 2 enzymes, The intestinal microflora of humans produces large amounts 299
244 vitamin K epoxide reductase (VKORC1) and reduced nicotinamide of long-chain menaquinones, which theoretically could serve 300
adenine dinucleotide phosphate dehydrogenase–quinone 1 (NQO1).
245 MK4 can be derived from exogenous K1 by the enzyme UbiaA
as a source of vitamin K, in particular K2. However, by far the 301
246 prenyltransferase domain-containing protein 1 (UBIAD1). For the largest reservoir of intestinal bacteria is confined to the large 302
247 synthesis, UBIAD1 utilizes geranylgeranyl pyrophosphate (GGPP). intestine. Because the absorption of bile salts and fat-soluble 303
248 GGPP itself is derived from mevalonate, an intermediate of the compounds takes place in the duodenum and is completed in 304
cholesterol synthesis pathway, with hydroxyl-methyl-glutaryl-
249 coenzyme A reductase (HMGCR) as key enzyme. Thus, HMGCR and the ileum, the contribution of menaquinones produced in the 305
250 UBIAD1 are functionally connected, but they also do physically bind colon to human nutritional needs is still debated. Experi- 306
251 to each other. HMG-CoA, 3-hydroxy-3-methyl-glutaryl–coenzyme A. ments in vitamin K–deficient rats given vitamin K via either 307
252 the oral or the colorectal route showed that the bioavailability 308
253 of colonic vitamin K is z50-fold lower than that of oral 309
254 reduction potential of vitamin K and scavenging intracellular vitamin K.27 Moreover, feeding both conventionally housed 310
255 free radicals.20 Moreover, we showed that the CKD environ- rats or rats kept under germ-free conditions a vitamin K– 311
256 ment impacts on the activity of GGCX but not the activity of deficient diet, vitamin K deficiency became prevalent under 312
257
Q9 VKORC1.21 This led to increased vascular calcification in an both conditions within 3 days, demonstrating that mena- 313
258 animal model of CKD. quinones synthesized in the large intestine are not utilized 314
259 sufficiently to prevent vitamin K deficiency.28 Thus, it seems 315
260 Vitamin K metabolism that relevant nutritional usage of endogenously produced 316
261 Vitamin K needs to be absorbed from food to fulfill its un- vitamin K2 is confined to those species that exhibit cop- 317
262 equivocal, nonredundant role as cofactor in the carboxylation rophagia (i.e., rodents or monkeys). 318
263 of vitamin K–dependent proteins. Vitamin K1 is tightly In CKD, the colon plays an important role in the pro- 319
264 bound to the thylakoid membrane (i.e., parts of the chloro- duction of uremic toxins. CKD-related gut dysbiosis may also 320
265 plasts) of leafy green vegetables, thereby limiting its avail- lead to decreased microbial synthesis of vitamin K.29 Because 321
266 ability for absorption. Ingestion of vitamin K2 results in vitamin K is produced by microbiota to support energy 322
267 higher circulating vitamin levels, compared with K1.6 Because production via ATP generation, and support gut microbiota 323
268 all vitamin K isoforms are fat soluble, they are packaged into growth,30 the decreased colonic vitamin K synthesis in CKD 324
269 chylomicrons during absorption and taken up by enterocytes can further dysregulate gut microbiota. Drug and vitamin K 325
270 in the small intestine. Chylomicrons are transported via the metabolism interactions in CKD are discussed below. 326
271 lymph, after which they are taken up in the circulation. These 327
272 chylomicrons are then transformed to chylomicron remnants Vitamin K functions 328
273 in the capillaries by lipoprotein lipase before being taken up Coagulation. In the liver, vitamin K functions as a 329
274 by the liver.22 Radiolabeled phylloquinone is thus removed cofactor for vitamin K–dependent coagulation factors, 330

review N Kaesler et al.: Vitamin K and cardiovascular complications in CKD patients
331 Harmful
inability to synthesize active, carboxylated molecules of fac- 387
Protective
332 tors II, VII, IX, and X, resulting in a hypocoagulable state, 388
333 Fetuin-A PTH, alkaline which promotes bleeding. 389
Klotho phosphatase, oxidative
334 Osteopontin and others stress, inflammation, Bone. Several vitamin K–dependent proteins are synthe- 390
335 diabetes, lipids, others sized in bone. Most extensively studied is osteocalcin, a small 391
336 Pyrophosphate protein of 49 amino acid residues with a central domain 392
337 Magnesium comprising 3 Gla residues. Osteocalcin is a highly abundant 393
Carbonic anhydrase
338 BMP-7 Ca2+/PO4- noncollagenous protein of bone extracellular matrix and 394
Inhibition
339 synthesized exclusively by osteoblasts and odontoblasts. It has 395
340 Vitamin K and a high-affinity binding to hydroxyapatite mineral in bone32 396
341 carboxylated MGP BMP-2/4/6 and appears to be involved in the regulation of bone 397
342 remodeling and mineralization.33 In Japan, vitamin K2 has 398
343 been licensed for the treatment of osteoporosis since 1995, 399
344 although so far there is insufficient evidence to recommend 400
345 the routine use of supplemental vitamin K to prevent osteo- 401
346 porosis and fractures in postmenopausal women.34,35 402
347 Vessels. Matrix Gla protein (MGP) is a vitamin K– 403
348 dependent protein, mainly synthesized by vascular smooth 404
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349 Healthy Calcified muscle cells, valvular interstitial cells, and chondrocytes.36,37 405
350 MGP is widely expressed, yet predominantly accumulates in 406
351 Elastin Extracellular Hydroxyapatite
calcified vascular tissue. The importance of carboxylated 407
352 VSMC vesicles MGP for cardiovascular health has been recognized for de- 408
353 Figure 3 | Processes involved in vascular calcification.
cades.38 Although originally found in bone, MGP-deficient 409
354 Calcification is an active process, resulting from an imbalance of anti- mice exhibit no prominent bone phenotype, but die within 2 410
355 calcific factors (fetuin, klotho, osteopontin, pyrophosphate, months after birth as a consequence of massively calcified 411
356 magnesium, carbonic anhydrase, bone morphogenic protein [BMP]- vessels, leading to hemorrhages due to, for example, aortic 412
7, vitamin K, and carboxylated matrix g-carboxyglutamic acid
357 protein [cMGP]) and procalcific factors (parathyroid hormone [PTH], rupture.39 Shortly thereafter, the role of vitamin K as a 413
358 alkaline phosphatase, oxidative stress, inflammation, diabetes, lipids, cofactor to activate MGP was shown by inhibition of MGP 414
359 calcium [Ca2þ], phosphate [PO4–], and BMP-2 and BMP-4). Fetuin (at function using warfarin, a vitamin K antagonist.40 The role of 415
360 tissue sites), carbonic anhydrase, pyrophosphate, osteopontin, and the Gla domain in inhibiting vascular calcification was 416
cMGP directly capture calcium phosphate crystals and prevent
361 release and precipitation of hydroxyapatite. Klotho, BMP-7, and revealed by mutagenesis of the protein-bound glutamate 417
362 magnesium target PO4– by stimulating its excretion or acting as residues, resulting in nonfunctional MGP.41 Although the 418
363 binding partners. Crystals, elastin breaks, and apoptotic bodies, as precise mode of action of MGP has not been unraveled, 419
364 wells as matrix vesicles, all activated by the crystals themselves, functions seem to include direct inhibition of calcium crystal 420
serve as a nidus for more crystals, contributing to vascular smooth
365 muscle cell (VSMC) death. growth and blocking of bone morphogenic protein-2 and 421
366 bone morphogenic protein-4 binding to the bone morpho- 422
367 including 4 vitamin K–dependent plasma procoagulants genic protein receptor42 (Figure 3). 423
368 (“1972”; i.e., factors II, VII, IX, and X) and 3 anticoagulants Genetics. The enzymes involved in vitamin K–dependent 424
369 (proteins C, S, and Z). After carboxylation in the liver, factors carboxylation, hence activation, are GGCX and VKORC1. 425
370 II, VII, IX, and X are essential in the formation of a fibrin clot. Mutations and/or polymorphisms affecting the activity of 426
371 Circulating as inactive (or zymogen) forms of serine pro- either enzyme can alter carboxylation, usually resulting in 427
372 teases, their biological activity depends on the ability to bind bleeding disorders, but they may also affect vascular calcifi- 428
373 to negatively charged phospholipid surfaces. Cleavage of these cation43 via reduced activation of MGP. Genetic screenings 429
374 zymogens bound to these surfaces yields the active protease identified many naturally occurring mutations in GGCX of 430
375 clotting factors. The carboxylation of these vitamin K– patients with vitamin K–related disorders.44 Nonbleeding 431
376 dependent coagulation factors is necessary as the resulting phenotypes of these GGCX mutations lead to cardiac, 432
377 Gla residues provide an efficient chelating site for calcium dermatologic, ophthalmologic, and osseous symptoms.44 In 433
378 ions that enables phospholipid surface binding.31 The intri- both genetic and CKD-associated reduced activity of GGCX, 434
379 cate control of coagulation is illustrated by the fact that dietary vitamin K supplementation can rescue the carboxyl- 435
380 protein C, once activated, acts as an anticoagulant by specif- ation of vitamin K–dependent proteins to some extent.21,45 436
381 ically degrading phospholipid-bound, activated factors V and Warfarin inhibits recycling of vitamin K by reducing the 437
382 VIII in the presence of calcium. This anticoagulant activity of activity of VKORC1. The presence of particular poly- 438
383 activated protein C, in turn, is dependent on protein S that morphisms in the VKORC1 gene is also associated with 439
384 acts as a synergistic cofactor by enhancing the binding of reduced enzyme expression and activity.46 Several clinical 440
385 activated protein C to negatively charged phospholipids. The studies have linked these polymorphisms to an increased risk 441
386 consequence of vitamin K deficiency for hemostasis is an of vascular calcification47 or cardiovascular disease.48 442

443 Table 2 | Assessment of vitamin K status 499

444 Methods Normal range Remarks References 500
445 501
Food Frequency 70–200 mg intake per Includes K1 only 49
446 Questionaire day 51 502
447 52 503
53
448 K1 and K2 504
449 Biomarkers 505
Vitamin K1 in serum >0.15 ng/ml Highly dependent on short-term supply 54
450 International normalized 0.8–1.1 Target of vitamin K antagonists but also affected by, for example, hepatic 49 506
451 ratio dysfunction 55 507
452 PIVKA-II in serum #2 mg/L Interassay variability 54
508
453 Osteocalcin in serum 509
ucOCN/tOCN
454 ucOCN/cOCN <20% Experimental 52 510
455 dp-ucMGP in plasma <500 pmol/L 56
511
456 cOCN, carboxylated osteocalcin; dp-ucMGP, dephosphorylated-uncarboxylated matrix g-carboxyglutamic acid protein; PIVKA-II, proteins induced by vitamin K absence or 512
457 antagonism (factor II); tOCN, total osteocalcin; ucOCN, uncarboxylated osteocalcin. 513
458 514
459 515
460 Vitamin K status: biomarkers historical collective term for these uncarboxylated proteins is 516
461 Dietary assessments can provide an indirect tool to monitor PIVKA (proteins induced by vitamin K absence or antago- 517
462 nutrient supply (e.g., via validated food frequency question- nism). More recent terms specify the proteins and uncar- 518
463 naires), but this method is highly time-consuming and re- boxylated species of prothrombin (factor II), for example, 519
464 quires expertise. Vitamin K1 status can also be assessed using and are therefore named PIVKA-II. PIVKA-II is a biomarker 520
465 functional coagulation tests, such as the international for hepatic vitamin K status, as prothrombin is exclusively 521
466 normalized ratio.49,50 However, such functional tests are not produced in the liver. The half-life of prothrombin is some 522
467 particularly specific for vitamin K bioavailability. Therefore, 60 hours, and the half-life of PIVKA-II is several days and 523
468 direct measurement of circulating vitamin K levels or, better not impacted by recent dietary intake. Assays for PIVKA-II 524
469 even, of vitamin K–dependent proteins is preferred to assess are useful for monitoring subclinical vitamin K defi- 525
470 the vitamin K status, as described below (Table 249,51–56). ciency,63 especially in at-risk groups such as young infants64 526
471 Circulating vitamin K levels. Dietary intake or circulating and CKD patients.8,65 The most sensitive PIVKA-II assays 527
472 levels of vitamin K can be used as biomarkers of the vitamin are enzyme immunoassays with antibodies that recognize 528
473 K supply. Most of circulating vitamin K is in the form of uncarboxylated prothrombin but do not cross-react with the 529
474 phylloquinone.6 After a single phylloquinone ingestion, native, carboxylated prothrombin. A sensitive immunoassay 530
475 plasma levels peak 2 to 4 hours later and decrease rapidly for PIVKA-II exists that can detect uncarboxylated species of 531
476 thereafter.57 Thus, circulating vitamin K mainly reflects short- factor II when its circulating concentration is as low as 0.2% 532
477 term dietary supply rather than status, and interpretive errors of total factor II. This threshold is well below the reduction 533
478 arise from recent dietary intake.54 Therefore, measurements of z50% in circulating levels of active total factor II that is 534
479 of phylloquinone need to be performed in fasting individuals. needed to trigger a detectable change in the international 535
480 Fasting phylloquinone reference values in healthy adults normalized ratio.63 536
481 exhibit large interindividual variations and range from 0.15 to Osteocalcin. Osteocalcin is released during bone forma- 537
482 1.0 mg/L.58 tion and resorption and is thus regarded as a marker for bone 538
483 Vitamin K1 and K2 concentrations can be quantified in turnover. It can be produced as carboxylated, active osteo- 539
484 serum or plasma by high-performance liquid chromatog- calcin (in case of vitamin K sufficiency) and uncarboxylated 540
485 raphy coupled with different fluorescence detection units as osteocalcin (in case of vitamin K deficiency66). Carboxylated 541
486 well by liquid chromatography/mass spectrometry tech- osteocalcin has a high affinity for calcium ions and aids in 542
487 niques.59 The Vitamin K External Quality Assurance forming a hydroxyapatite lattice preceding mineralization of 543
488 Scheme20 monitors the accuracy of vitamin K analyses. For bone.67 An increase of total circulating osteocalcin has been 544
489 example, a reliable assay for MK7 in plasma requires 94% demonstrated in CKD due to parathyroid hormone–related 545
490 recovery.60 In addition, sensitivity is high, and the methods bone resorption and retention of intact and fragments of 546
491 mentioned above have lower detection limits, ranging from osteocalcin.68 Osteocalcin carboxylation was shown to be 547
492 0.1 mg/ml to 0.03 ng/ml.61,62 Of note, at present, there is no responsive to changes on dietary intake69 and associates with 548
493 international gold standard for determining circulating higher bone mineral content.70 Given the high prevalence of 549
494 vitamin K levels. bone loss in CKD, both uncarboxylated and carboxylated 550
495 Proteins induced by vitamin K absence or antagonism: factor II. In osteocalcin levels are increased, resulting in a normal ratio.71 551
496 states of vitamin K insufficiency or deficiency, uncarboxy- Uncarboxylated osteocalcin is not solely a marker of vitamin 552
497 lated vitamin K–dependent proteins are produced at their K deficiency, but also released during bone resorption.72 553
498 site of synthesis and released into the bloodstream. The Taken together, these CKD-related disturbances render 554

555 a and cardiovascular mortality in a Flemish general popula- 611

Vessel wall Circulation
556 tion78,79 as well in patients with coronary heart disease.80 612
Vitamin K sufficiency
557 Moreover, both dp-ucMGP and dephosphorylated carboxyl- 613
558 cMGP ated MGP may serve as predictors of mortality in dialysis 614
559 patients.8,76 Today, dp-ucMGP is most often used to measure 615
560 vascular vitamin K bioavailability in CKD68 (Figure 4). 616
561 b Besides CKD, dp-ucMGP concentrations in plasma are 617
Vessel wall
also increased in patients with diabetes,81 in patients with
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562 618
563 chronic obstructive pulmonary disease,82 and in hospitalized 619
564 Vitamin K deficiency dp-ucMGP coronavirus disease 2019 (COVID-19) patients.83 620
565 621
t-ucMGP t-ucMGP
566 Vitamin K status 622
567 Figure 4 | Matrix g-carboxyglutamic acid protein (MGP) is Status in healthy persons. Reports on vitamin K ingestion 623
568 produced by vascular smooth muscle cells to prevent unwanted mostly focus on vitamin K1 and range from 29 to 398 mg 624
569 mineralization of the vessel wall. For that function, MGP needs average daily intake.84 The average American aged $55 years 625
570 vitamin K as cofactor to become biologically active. (a) In case of
vitamin K sufficiency, MGP prevents vascular calcification by
consumes 80 to 210 mg of vitamin K1 per day, markedly 626
571 producing and releasing carboxylated MGP (cMGP). (b) In case of exceeding that of younger Americans (60–110 mg/d), which 627
572 vitamin K insufficiency or deficiency, MGP is produced in the seem to relate to a higher green leafy vegetable consumption 628
573 uncarboxylated form, unable to prevent or halt vascular in older persons.85,86 In a Norwegian prospective cohort 629
calcification. In the vessel wall, total uncarboxylated MGP (t-ucMGP)
574 is accumulating, likely because this fraction binds to hydroxyapatite study, the average intake of vitamin K1 varied widely, and the 630
575 via the negatively charged phosphorylation sites in MGP. The median daily intake was 48 mg for K1 and 7 mg for K2. Intake 631
576 dephosphorylated-uncarboxylated MGP (dp-ucMGP), lacking all of both subforms was higher in women, and higher K2 632
577 posttranslational modification and thus the most inactive form of consumption appeared to mitigate the risk for coronary heart 633
MGP, does not have affinity for hydroxyapatite in the vessel wall
578 and is thus easily released in the circulation. The dp-ucMGP is thus disease.87 A better vitamin K status was also detected in 634
579 the fraction that most likely resembles the vitamin K status of the Chinese women compared with men, as evidenced by lower 635
580 vessel wall. PIVKA-II levels.88 Above the age of 40 years, dp-ucMGP 636
581 plasma levels increased gradually and MK7 supplementation 637
582 was more effective in decreasing dp-ucMGP the more pro- 638
583 osteocalcin measurements in CKD patients difficult to inter- nounced the vitamin K insufficiency.89 639
584 pret and thus osteocalcin carboxylation may not be a useful Even in healthy individuals, vitamin K–dependent proteins 640
585 marker to assess vitamin K status in advanced CKD.73 are not fully carboxylated,90 and subclinical vitamin K defi- 641
586 Matrix Gla protein. The development of conformation- ciency can be present despite normal blood coagulation pa- 642
587 specific antibodies against MGP has resulted in the detec- rameters.91 A high prevalence of vitamin K deficiency occurs 643
588 tion and localization of uncarboxylated MGP (ucMGP) versus in newborns and during breast-fed early infancy. Vitamin K 644
589 carboxylated MGP in vascular tissue.74 Several studies have supplementation is part of standard care to support coagu- 645
590 demonstrated that ucMGP accumulates in and around lation in the newborn to prevent vitamin K deficiency 646
591 calcified vascular areas, whereas carboxylated MGP is less bleeding. Other studies show a high prevalence of low vitamin 647
592 abundant in calcified regions. Using these conformation- K status in hospitalized patients, particularly in intensive care 648
593 specific MGP antibodies as biomarkers for detecting patients.92 649
594 vascular calcification or extrahepatic vitamin K deficiency is Early observational studies revealed that patients with 650
595 an attractive possibility.65 Circulating MGP reflects what is previous femoral neck or spinal fractures had low circulating 651
596 spilled over from the vasculature into the blood stream, vitamin K levels.93,94 More recently, a prospective study in 652
597 which, in turn, depends on MGP synthesis, MGP activity, and Japanese women followed up for 3 to 4 years also confirmed 653
598 binding of MGP to calcified vascular areas. Using antibodies an association between low vitamin K concentrations and 654
599 against different epitopes of MGP, significantly lower serum increased incidence of vertebral fractures.95 Vice versa, in the 655
600 total ucMGP levels were detected in dialysis patients Japanese diet, where natto is popular, MK7 is the predomi- 656
601 compared with healthy controls.75 Moreover, total ucMGP nantly ingested subform; and high natto consumption 657
602 levels were inversely associated with aortic stiffness, suggest- correlated with a lower fracture risk.96 Finally, a meta-analysis 658
603 ing that low ucMGP levels reflect the extent of vascular of 21 articles, including 222,592 participants, found that 659
604 calcification.75 The development of an assay for higher dietary vitamin K consumption was associated with a 660
605 dephosphorylated-uncarboxylated MGP (dp-ucMGP), a moderately lower risk of coronary heart disease.97 Also, in 661
606 biomarker for vitamin K bioavailability of the vasculature, that analysis, vitamin K deficiency, as assessed via plasma dp- 662
607 was first described in patients with CKD.76 Plasma dp- ucMGP concentrations, associated with higher all-cause and 663
608 ucMGP increased progressively with progression of CKD cardiovascular mortality.97 664
609 and was associated with the severity of aortic calcification.77 Status in CKD patients. CKD patients commonly exhibit a 665
610 Higher dp-ucMGP was also associated with higher all-cause functional vitamin deficiency, as evidenced using 666

667 Table 3 | Classification of selected food items according to their vitamin K (K1 and K2) potassium and phosphorous contents 723
668 Phosphorous 724
669 High (>500 mg/100 g) Potassium
725
670 726
Medium (100–500 mg/100 g) High Medium Low
671 727
672 Low (<100 mg/100 g) (>350 mg/100 g) (100–350 mg/100 g) (<100 mg/100 g) 728
673 Vitamin K High Parsley, spinach Hard cheese: 729
674 (<350 mg/100 g) Chive, purslane Gouda, emmentaler 730
Celery
675 731
676 732
677 Medium Pistacho Eggs, natto Processed soft cheese 733
678 (20–350 mg/100 g) Goose meat Chinese cabbage Brined goat milk cheese 734
Broccoli Roquefort
679 735
680 Olive oil, butter 736
681 737
682 Low Poppy seeds Mushroom 738
(<20 mg/100 g) Peas, crisps Bun, pork Chick peas
683 Hazelnut, peanut Salami, chicken
739
684 Salmon Milk, yogurt 740
685 Cocoa, chips Apple Olives 741
686 Banana Cucumber, onion Rice, pasta 742
Tomato paste
687 743
Data are from several sources.5–8
688 744
689 745
690 746
691 biomarkers.8,98,99 Although vitamin K1 concentration in menaquinones into the dietary reference intake values for 747
692 Q10 serum was low in only 6% of CKD stage 3 to 5 patients,99 vitamin K. Thus, the current recommended daily allowance 748
693 PIVKA-II was increased in 97% of CKD stage 3 to 5 patients for vitamin K is based on its role in blood coagulation. It only 749
694 and in 64% of dialysis patients.8 The dp-ucMGP plasma includes vitamin K1 and is set in Europe by the European 750
695 concentrations also increased with the CKD stage and were Food Safety Authority for all reference groups to 1 mg/kg body 751
696 increased 3.3-fold to 6.5-fold in dialysis patients.8,76 An in- weight.49 The dietary reference intake by the US Department 752
697 crease of uncarboxylated osteocalcin in serum was found in of Agriculture is set to 90 mg/d for females and to 120 mg/d for 753
698 60% of CKD stage 3 to 5 patients,99 and there was a highly males.106 754
699 significantly increase in dialysis patients.100 Dietary recommendations in CKD patients. There are 755
700 The high prevalence of functional vitamin K deficiency in currently no dietary recommendations for vitamin K intake 756
701 CKD patients in part relates to dietary recommendations in CKD patients. In patients with decreased kidney function, 757
702 aimed at reducing potassium and phosphate intake.101 The dietary management usually targets hyperkalemia, hyper- 758
703 reduced consumption of potassium-rich leafy green vegeta- phosphatemia, protein intake, and salt and water load. In 759
704 bles will result in low vitamin K1 intake, and restriction of advanced CKD, potassium intake should be restricted to <3 760
705 phosphate-rich dairy products will decrease vitamin K2 g/d107,108 and dietary phosphorous intake should be restricted 761
706 intake.71 However, in a study in 85 dialysis patients, dietary to 800 to 1000 mg/d.109 Overall, by adherence to the dietary 762
707 intake and serum level of MK4, but not K1, were lower recommendations, a vitamin K–rich diet in CKD remains 763
708 compared with healthy controls.102 Furthermore, at least in highly challenging as the amount of either potassium (e.g., in 764
709 rats with adenine-induced CKD, we found reduced activity of spinach) or phosphorous (e.g., in hard cheese) is too high 765
710 vitamin K recycling enzymes, in particular GGCX.21,103 Via (Table 35–8). Interestingly, a Lactococcus strain was developed 766
711 this mechanism, CKD mimics the actions of pharmacologic to increase the menaquinone synthesis in fermented foods,12 767
712 inhibitors of the vitamin K cycle (i.e., warfarin or phenpro- but introducing genetically modified organisms to food is 768
713 coumon, which inhibit the VKOR by chemical binding).104 highly restricted.110 Vitamin K supplementation in CKD pa- 769
714 Frequently prescribed medications in CKD might further tients is discussed below. 770
715 aggravate the low vitamin K status in CKD (see below). Vitamin K status and cardiovascular disease in the general 771
716 In hemodialysis patients, high serum levels of uncar- population and CKD patients. In the Danish general adult 772
717 boxylated osteocalcin associated with a higher incidence of population, relative vitamin K deficiency, identified by 773
718 Q11 bone fractures.105 In the Italian VIKI study, vitamin K1 elevated plasma dp-ucMGP, correlated with obesity and a 774
719 deficiency also independently predicted vertebral fractures in history of cardiovascular events.111 Surprisingly, in chronic 775
720 hemodialysis patients.98 hemodialysis patients, there was also an inverse relationship 776
721 Dietary recommendations in healthy persons. In 2017, the between body weight and circulating MK7 levels.112 The 777
722 European food safety authority decided to not yet include assessment of dietary K1 and K2 intakes in healthy elderly 778

779 Chronic dialysis patient with nonvalvular atrial fibrillation same time counteract the ectopic cardiovascular calcifications 835
780 and, for example, allow a more liberal calcium administration 836
781 Comorbidity No clear indication in the context of phosphate binding or osteoporosis treat- 837
Comorbidity
(mechanical or contraindiction
782 valve, prior
(falls, ment.124 However, although appealing, firm evidence for this 838
bleeding
783 thrombo- episodes, etc.) hypothesis is lacking in CKD patients so far. 839
784 embolism, etc.) 840
785 ?Lower Higher Higher Higher Therapeutic vitamin K antagonism 841
786 risk risk risk risk The administration of VKA potently increases circulating 842
VKA VKA
thrombo- bleeding cardio- calci-
print & web 4C=FPO
787 embolism, (GI, brain, vascular phylaxis markers of vitamin K deficiency in nonrenal and renal pa- 843
788 stroke? etc.) calcification tients. For example, a Dutch study compared patients on 844
789 antithrombotic therapy, who were randomized to aspirin, 845
790 regular-intensity VKA, or low-intensity VKA.125 At 1 year, 846
791 VKA VKA induced uncarboxylation of various Gla-containing 847
792 Figure 5 | Decision algorithm pro or contra vitamin K proteins, with osteocalcin identified as the most sensitive 848
793 antagonist (VKA) therapy in a chronic dialysis patient with marker of a poor vitamin K status. Excessively high levels of 849
794 nonvalvular atrial fibrillation. Although there is currently little circulating ucMGP have been observed in chronic dialysis 850
alternative for patients with particular comorbidity, including
795 patients receiving VKA.8 851
mechanical heart valves, prior lung embolism, or other systemic
796 thromboembolism, the risks associated with VKA in end-stage It is now well established that VKAs promote the devel- 852
797 kidney disease seem to outweigh the unproven benefits in most opment of cardiovascular calcification in many regions, 853
798 other patients. Modified from Kruger T, Brandenburg V, Schlieper G, including coronary arteries, aorta, breast arteries, and cardiac 854
et al., Sailing between Scylla and Charybdis: oral long-term
799 anticoagulation in dialysis patients, Nephrology Dialysis
valves.126–128 An extreme form of vascular calcification is 855
800 Transplantation, 2013, volume 28, issue 3, pages 534–541, by CUA (calciphylaxis), a disease mostly manifesting in dialysis 856
801 permission of Oxford University Press.132 GI, gastrointestinal. patients and characterized by cutaneous necroses associated 857
802 with bacterial superinfection and high mortality. It is now 858
803 well established that VKA markedly increases the risk of CUA 859
804 men and women also revealed a reduced all-cause mortality (z10-fold).129 In the EVOLVE trial, which evaluated a cal- Q12 860
805 risk, but not cardiovascular mortality, in those persons with a cimimetic (cinacalcet) in dialysis patients with secondary 861
806 higher vitamin K consumption.113 Similarly, a recent meta- hyperparathyroidism, we observed that 11 of 24 (45%) of the 862
807 analysis of 3 nonrenal cohorts revealed an inverse associa- CUA patients had been on active vitamin K antagonist ther- 863
808 tion between circulating vitamin K levels and all-cause mor- apy at the time of CUA manifestation in contrast to 5% to 7% 864
809 tality.114 Vice versa, a higher dietary menaquinone intake at any one time point in patients in whom CUA was not re- 865
810 associated with reduced risk for coronary heart disease115 and ported.130 All these observations plus the lack of proven 866
811 less coronary artery calcification.116 benefit explain why various guidelines suggest VKAs should 867
812 The dramatically higher cardiovascular morbidity and not be used in chronic hemodialysis patients with, for 868
813 mortality in CKD patients at least in part relates to accelerated example, nonvalvular atrial fibrillation131 (Figure 5132). 869
814 cardiovascular calcification,117 which, in turn, is linked to Indeed, there is some evidence that VKA administration in- 870
815 their altered vitamin K metabolism and supply.99 In diabetic creases morbidity and mortality in chronic dialysis pa- 871
816 CKD patients as well as in stable kidney transplant patients, tients,133 but despite multivariate adjustments, there are 872
817 higher dp-ucMGP levels in the circulation associated with concerns about unmeasured confounders that may explain 873
818 increased all-cause mortality, cardiovascular mortality, and this observation. 874
819 progression of CKD.118,119 Similarly, low carboxylation of 875
820 MGP increased the risk for calcific uremic arteriolopathy Impact of medication on vitamin K bioavailability 876
821 (CUA; calciphylaxis; see below) in dialysis patients.120 As in Several studies have investigated the impact of phosphate 877
822 the general population, in CKD patients, total vitamin K binders on vitamin K bioavailability. At least in vitro, most 878
823 intake above the current recommendations corresponded to a phosphate binders were found to bind fat-soluble vitamins, 879
824 reduced cardiovascular and all-cause mortality.121 Finally, in including vitamin K.134,135 In the clinical situation, phosphate 880
825 end-stage kidney disease patients, poor vitamin K status binder use versus nonuse did not affect dp-ucMGP levels in 881
826 associated with more systemic inflammation and low bone dialysis patients,136 but sevelamer monotherapy, when 882
827 mineral density,122 both conditions known to promote car- analyzed separately, was associated with higher dp-ucMGP 883
828 diovascular damage. levels as well as with an altered gut microbial meta- 884
829 Vitamin K and the bone-vascular axis. Metabolic abnor- bolism.29,136 In the Italian cross-sectional VIKI study in he- 885
830 malities in CKD disturb the balance between mineral modialysis patients, those treated with sevelamer not only 886
831 resorption and ectopic calcifications by disturbed mineral, exhibited MK4 deficiency but also more aortic calcification 887
832 parathyroid hormone, and vitamin D metabolism.123 In this and vertebral fractures.137 This may at least in part explain 888
833 bone-vascular axis, factors like vitamin K, which improve why it has been difficult to firmly establish differential effects 889
834 bone quality and allow better mineralization, might at the of calcium-containing versus calcium-free phosphate binders 890

891 on cardiovascular calcification progress (i.e., the procalcific levels and reduced ucMGP in older adults.149 High-dose 947
892 effect of calcium loading might have been offset by a relative vitamin K1 supplementation at 2 mg per day orally for 1 948
893 vitamin K depletion using calcium-free phosphate binders, in year also significantly attenuated the progress of aortic valve 949
894 particular sevelamer). However, a recent meta-analysis calcification, with some 57% reduction compared with pla- 950
895 nevertheless concluded that sevelamer retards calcification cebo in patients with mild to moderate aortic stenosis.150 951
896 progress compared with calcium-containing binders.138 Un- Vitamin K2 trials so far have mostly been performed with 952
897 expectedly, a pilot study in nondialyzed patients with MK7. A Dutch double-blind randomized controlled trial 953
898 advanced CKD concluded that phosphate binders promoted tested the effects of 360 mg/d MK7 or placebo given for 6 954
899 cardiovascular calcification, but on closer inspection of the months in 68 diabetics with concomitant cardiovascular dis- 955
900 data, only those receiving calcium-acetate but not those ease.151,152 MK7 supplementation reduced dp-ucMGP by 956
901 randomized to placebo, sevelamer, or lanthanum carbonate z200 pmol/L compared with placebo. Unexpectedly, active, 957
902 did exhibit progressive vascular calcification.139 Whether, as ongoing calcification in the femoral artery, as detected by 18F- 958
903 in preclinical studies, calcium-free phosphate binders, in positron emission tomography, tended to increase in the MK7 959
904 particular sevelamer, could be “fortified” to reduce vascular group (P ¼ 0.06 vs. placebo), whereas no difference was 960
905 calcification and mortality by combining them with vitamin K detected by conventional computed tomography scanning. 961
906 therapy, remains to be proven in patients.124,140 The ongoing Dutch VitaK-CAC trial investigates progression Q13 962
907 Beyond phosphate binder therapy, a relative vitamin K of coronary artery calcification in patients with coronary ar- 963
908 deficiency can occur with prolonged antibiotic therapy.141 tery disease treated with either placebo or 360 mg of MK7 964
909 Whether there are differential effects of the various antibi- daily for 2 years.153 965
910 otics, whether there are thresholds for the duration of treat- Data on circulating dp-ucMGP and vascular stiffness and 966
911 ment, and whether these effects are similar in nonrenal and cardiovascular mortality in the general population are less 967
912 CKD patients are largely unknown. Another common class of consistent. A meta-analysis of 13 controlled trials and 14 968
913 drugs potentially affecting vitamin K homeostasis are proton interventional, longitudinal studies confirmed a reduction of 969
914 pump inhibitors. Although no data are available for CKD vascular calcification but not vascular stiffness with vitamin K 970
915 patients, in healthy volunteers on a vitamin K restricted diet, supplementation (K1 or K2) for >4 weeks in adults.154 971
916 proton pump inhibitors unexpectedly increased vitamin K Studies in patients with markedly reduced glomerular filtration 972
917 levels in the circulation and reduced levels of uncarboxylated rate or end-stage kidney disease. Most published intervention 973
918 proteins (i.e., partially corrected the vitamin K deficiency).142 trials in CKD patients so far have focused on vitamin K2, 974
919 This was related to intestinal bacterial overgrowth with sub- usually employing MK7. In a randomized trial with 3 parallel 975
920 sequent production of menaquinones in the small intestine. groups, we assessed the effects of MK7 given orally and daily 976
921 Finally, statins, frequently prescribed to inhibit 3-hydroxy- at 45, 135, or 360 mg daily for 6 weeks to 53 chronic hemo- 977
922 3-methyl-glutaryl coenzyme reductase, limit endogenous dialysis patients versus 50 healthy age-matched individuals.155 978
923 cholesterol synthesis and, as shown in Figure 2, 3-hydroxy-3- Vitamin K deficiency was confirmed in the hemodialysis 979
924 methyl-glutaryl–coenzyme A reductase and the vitamin K patients, given 4.5-fold higher ucMGP and 8.4-fold higher 980
925 conversion enzyme UBIAD1 are connected with each other. uncarboxylated osteocalcin serum levels compared with 981
926 In vitro lipophilic statins are known to directly inhibit controls. In the dialysis patients, MK7 supplementation 982
927 UBIAD1,143 thus reducing endogenous MK4 levels.15 More- reduced uncarboxylated MGP levels by 77% and 93% in the 983
928 over, it has been shown that vitamin K is converted to K3 groups receiving 135 and 360 mg of MK7, respectively. 984
929 (menadione), which is prenylated in target tissues to MK4.1 Similarly, a Belgian group performed a pilot trial in 200 he- 985
930 This conversion in target tissues, such as the vascular wall modialysis patients randomized to receive 360, 720, or 1080 986
931 (vascular smooth muscle cells), is inhibited by statins,144 mg of MK7 thrice weekly for 8 weeks. MK7 supplementation 987
932 thereby compromising vascular vitamin K status. reduced plasma dp-ucMGP by 17%, 33%, and 46%, 988
933 respectively.156 989
934 Vitamin K supplementation Effects of vitamin K2 on surrogate cardiovascular out- 990
935 Vitamin K, even if given at excessively high doses of up to comes have been studied in 4 randomized controlled trials 991
936 20,000 mg per day to Japanese pregnant women,145 has no (Table 443,126,157–161). A small Polish study in 42 patients with 992
937 known human toxicity.146 This markedly facilitates the CKD stages 3 to 5 compared 90 mg MK7 together with 10 mg 993
938 assessment, whether even intense therapy affects cardiovas- of cholecalciferol with cholecalciferol alone.158 Nine months 994
939 cular disease manifestation or progression, in particular that later, the MK7 group exhibited a lower increase in carotid 995
940 of calcifications. Only menadione, sometimes referred to as intima-media thickness, whereas coronary artery calcification 996
941 vitamin K3, in large doses has been shown to cause allergic progress was not slowed down. A Greek study randomized 997
942 reactions, hemolytic anemia, and cytotoxicity in liver 102 patients on hemodialysis to 200 mg MK7 orally every day 998
943 cells.147,148 for 1 year or no treatment.159 MK7 reduced ucMGP serum 999
944 Studies in patients with normal or mildly reduced glomerular levels by 47%. After 1 year of follow-up, 52 patients were 1000
945 filtration rate. With respect to vitamin K1, its supplemen- available for the analysis. Aortic calcification progress did not 1001
946 tation (500 mg/d) for 3 years increased serum phylloquinone differ between the 2 groups. In the British K4Kidneys trial, 1002

1003 Table 4 | Intervention trials evaluating effects of vitamin K supplementation in patients with advanced CKD 1059
1004 Relative reduction in Effect on 1060
1005 Duration of ucMGP plasma calcification in Effect on other outcomes in 1061
1006 Patients/trial Intervention follow-up, mo levels at study end vitamin K group vitamin K group 1062
1007 Hemodialysis patients MK7, 2 mg, thrice 18 47% None None on pulse-wave velocity, 1063
1008 with atrial fibrillation weekly all-cause death, stroke, and 1064
1009 (VALKYRIE)126 cardiovascular event rates 1065
1010 CKD stage 3b–4 patients MK7, 0.4 mg, daily 12 Uncertaina None None on pulse-wave velocity, 1066
1011 (K4Kidneys)157 augmentation index, blood 1067
pressure, B-type natriuretic
1012 peptide, or physical function 1068
1013 1069
CKD stage 3–5ND MK7, 0.09 mg, 9 19% None Reduced progression of
1014 patients158 daily common carotid artery intima- 1070
1015 media thickness 1071
1016 Hemodialysis patients159 MK7, 0.2 mg, daily 12 47% None — 1072
1017 Hemodialysis patients160 MK7, 0.36 mg, 24 39% after 1 y, 8% None None on pulse-wave velocity 1073
1018 daily after 2 y and blood pressure 1074
1019 1075
Ongoing trials with vitamin K1
1020 1076
1021 Hemodialysis patients K1, 5 mg, thrice 18 >70% To be determined To be determined 1077
(VITAVASK)161 weekly
1022 1078
1023 Hemodialysis patients K1, 10 mg, thrice 12 To be determined To be determined To be determined 1079
1024 (iPACK-HD)43 weekly 1080
1025 CKD, chronic kidney disease; iPACK-HD, xxx; MK, menaquinone; ucMGP, uncarboxylated matrix g-carboxyglutamic acid protein; VALKYRIE, xxx; VITAVASK, xxx. Q25 1081
a
No numbers given; the text states “Mean log-transformed dp-ucMGP results fell between baseline and 12 months with vitamin K treatment (7.08 versus 6.89) but not in the
1026 placebo group (7.01 versus 7.06).”157 Q26
1082
1027 1083
1028 1084
1029 159 patients with an estimated glomerular filtration rate of 15 regulatory bodies have argued that in clinical trials, where the 1085
1030 to 45 ml/min per 1.73 m2 were randomized to receive 400 mg daily recommended dose of vitamin K is markedly exceeded, 1086
1031 oral MK7 or placebo once daily for 1 year.157 The primary only drug-grade formulations can be used, which has 1087
1032 outcome, carotid-femoral pulse wave velocity at 12 months, restricted our choice to vitamin K1. At present, 2 similar 1088
1033 did not differ between the groups, nor did augmentation studies (iPACK-HD, NCT 01528800 in Canada; and Vita- Q14 1089
1034 index, blood pressure, B-type natriuretic peptide, or physical VasK, EudraCT No. 2010-021264-14 in Europe), both testing Q15 1090
1035 function. Finally, a Belgian randomized trial investigated the high-dose vitamin K1 therapy at 15 to 30 mg per week, and 1091
1036 effect of VKA, rivaroxaban, 10 mg daily, or rivaroxaban, 10 both investigating progression of cardiovascular calcification, 1092
1037 mg daily, plus MK7, 2000 mg, thrice weekly during 18 months are close to publication.43,161 1093
1038 on vascular calcification progression in 132 hemodialysis A study in the United Kingdom (ViKTORIES) will inves- 1094
1039 patients with atrial fibrillation.126 The ucMGP levels tigate the effects of vitamin K3 (menadiol diphosphate) in 1095
1040 decreased by z50% in the rivaroxaban plus MK7 group. renal transplant recipients.163 The primary end point is aortic 1096
1041 Cardiovascular calcification progress, changes in pulse-wave distensibility, assessed by magnetic resonance imaging; and 1097
1042 velocity, and cardiovascular event rates did not differ at the secondary end points include cardiovascular calcifications. 1098
1043 end of follow-up. Bleeding outcomes were not significantly So far, little information is available on the effect of sup- 1099
1044 different, except for a lower number of life-threatening and plemental vitamin K on bone fractures or density in dialysis 1100
1045 major bleeding episodes in the rivaroxaban arms versus the patients. In the ongoing iPACK-HD and RenaKvit studies, the 1101
1046 VKA arm. Finally, the RenaKvit trial lowered dp-ucMGP impact of vitamin K1 (NCT01528800) and MK7 1102
1047 serum levels in dialysis patients by up to 39% via the (NCT02976246) supplementation on the incidence of verte- 1103
1048 administration of 360 mg MK7 daily, but failed to observe a bral fractures and bone mineral density is evaluated in he- 1104
1049 significant impact on pulse-wave velocity, coronary artery modialysis patients.43 1105
1050 calcification, or abdominal aortic calcification.160 A Singa- 1106
1051 porian ongoing trial also assesses the cardiovascular effects of Conclusion 1107
1052 MK7, 360 mg, given 3 times weekly for a total duration of 18 There is a solid biochemical and experimental basis to 1108
1053 months to hemodialysis patients.162 None of the above studies implicate vitamin K, in particular K2, in the pathogenesis of 1109
1054 reported any adverse events related to vitamin K cardiovascular disease, especially calcifications. A multitude of 1110
1055 supplementation. clinical observations also supports this association. A partic- 1111
1056 One issue that so far has affected all vitamin K2 trials is ular high-risk population in this respect are patients with 1112
1057 that MK7 has not been available in a drug-grade formulation, end-stage kidney disease, because they not only exhibit (in 1113
1058 even if provided in a synthetic form. At least in Germany, part iatrogenic) low vitamin K intake but also probably have a 1114

1115 defect in vitamin K recycling, which would mimic the action 11. Boe CA, Holo H. Engineering Lactococcus lactis for increased vitamin K2 1171
production. Front Bioeng Biotechnol. 2020;8:191.
1116 of VKAs. Dietary supplementation of such high-risk patients 12. Liu Y, van Bennekom EO, Zhang Y, et al. Long-chain vitamin K2
1172
1117 with physiological or highly supraphysiological doses pre- production in Lactococcus lactis is influenced by temperature, carbon 1173
1118 dictably corrects the vitamin K deficiency at the biochemical source, aeration and mode of energy metabolism. Microb Cell Fact. 1174
2019;18:129.
1119 level and exhibits no toxic effects. Against this background, it 13. Nakagawa K, Hirota Y, Sawada N, et al. Identification of UBIAD1 as a
1175
1120 is frustrating to see yet another easy and safe approach tackling novel human menaquinone-4 biosynthetic enzyme. Nature. 2010;468: 1176
1121 cardiovascular disease in CKD failing in clinical trials. It is 117–121. 1177
14. Beulens JW, Booth SL, van den Heuvel EG, et al. The role of menaquinones
1122 tempting to speculate that this is one more situation where, in (vitamin K(2)) in human health. Br J Nutr. 2013;110:1357–1368.
1178
1123 the highly complex and comorbid patients with advanced 15. Hirota Y, Tsugawa N, Nakagawa K, et al. Menadione (vitamin K3) is a 1179
1124 CKD, a monotherapeutic intervention simply is not effective catabolic product of oral phylloquinone (vitamin K1) in the intestine 1180
and a circulating precursor of tissue menaquinone-4 (vitamin K2) in
1125 enough to yield measurable effects. However, of note, complete rats. J Biol Chem. 2013;288:33071–33080.
1181
1126 correction of vitamin K deficiency by MK7 was never achieved 16. Wellington KW, Hlatshwayo V, Kolesnikova NI, et al. Anticancer activities 1182
1127 in the interventional trials so far. In addition, vitamin K sup- of vitamin K3 analogues. Invest New Drugs. 2020;38:378–391. 1183
1128 plementation may only improve cardiovascular calcifications, if 17. Kishore C, Sundaram S, Karunagaran D. Vitamin K3 (menadione) suppresses 1184
epithelial-mesenchymal-transition and Wnt signaling pathway in human
1129 at the same time calcium and phosphate are well controlled. colorectal cancer cells. Chem Biol Interact. 2019;309:108725. 1185
1130 However, before setting up such more complex trials, we 18. van Gorp RH, Schurgers LJ. New insights into the pros and cons of the 1186
1131 suggest waiting for the outcome of the 2 trials using vitamin K1 clinical use of vitamin K antagonists (VKAs) versus direct oral 1187
anticoagulants (DOACs). Nutrients. 2015;7:9538–9557.
1132 instead of K2. Why? Because once again, we have extrapolated 19. Willems BA, Vermeer C, Reutelingsperger CP, et al. The realm of vitamin 1188
1133 from findings in nonrenal patients to dialysis patients. K dependent proteins: shifting from coagulation toward calcification. 1189
1134 Considering the massive alterations of the uremic high-density Mol Nutr Food Res. 2014;58:1620–1635. 1190
20. Petsophonsakul P, Furmanik M, Forsythe R, et al. Role of vascular
1135 lipoprotein–lipoprotein particle,164 we have detected promi- smooth muscle cell phenotypic switching and calcification in aortic 1191
1136 Q16 nent disturbances of vitamin K transport (unpublished data) aneurysm formation. Arterioscler Thromb Vasc Biol. 2019;39:1351–1368. 1192
1137 that indicate that not all vitamin K is created equal in the 21. Kaesler N, Magdeleyns E, Herfs M, et al. Impaired vitamin K recycling in 1193
uremia is rescued by vitamin K supplementation. Kidney Int. 2014;86:
1138 uremic situation. So, the story is not over (yet). 286–293. 1194
1139 22. Shearer MJ, Fu X, Booth SL. Vitamin K nutrition, metabolism, and 1195
1140 requirements: current concepts and future research. Adv Nutr. 2012;3:182– 1196
DISCLOSURE 195.
1141 LJS received institutional grants from Bayer, Boehringer Ingelheim, 23. Shearer MJ, Mallinson CN, Webster GR, et al. Clearance from plasma and 1197
1142 NattoPharma, and IDS. All the other authors declared no competing excretion in urine, faeces and bile of an intravenous dose of tritiated 1198
1143 interests. vitamin K 1 in man. Br J Haematol. 1972;22:579–588. 1199
24. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of
1144 K-vitamins in healthy subjects. Biochim Biophys Acta. 2002;1570:27–32. 1200
1145 ACKNOWLEDGEMENTS 25. Schurgers LJ, Teunissen KJ, Hamulyak K, et al. Vitamin K-containing 1201
1146 We apologize to all authors whose important work we could not cite dietary supplements: comparison of synthetic vitamin K1 and natto- 1202
Q28 because of space restrictions. This work was funded by the Deutsche derived menaquinone-7. Blood. 2007;109:3279–3283.
1147 26. Theuwissen E, Teunissen KJ, Spronk HM, et al. Effect of low-dose
1203
Forschungsgemeinschaft (German Research Foundation), TRR 219,
1148 C1–Project-ID 322900939. supplements of menaquinone-7 (vitamin K2 ) on the stability of oral 1204
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Vitamin K and cardiovascular complications

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443 Table 2 | Assessment of vitamin K status 499

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555 a and cardiovascular mortality in a Flemish general popula- 611

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